Eugene A Mash

Interests

Teaching

Organic Chemistry

Research

Organic Synthesis

Courses

Scholarly Contributions

Chapters

• Mash, E. (2012). Synthetically Derived Chiral Auxiliaries: Uses of Derivatives of Non-Carbohydrate Aldehydes andKetones in Asymmetric Synthesis. In Comprehensive Chirality(pp 377-407). Amsterdam: Elsevier.
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  Editors: Carreira, EM | Yamamoto, H; Volume: 3

Journals/Publications

• Abrell, L., Kadoya, W. M., Mash, E. A., Sierra-alvarez, R., Wong, S., Field, J. A., & Jagadish, B. (2019). Coupling reactions between reduced intermediates of insensitive munitions compound analog 4-nitroanisole.. Chemosphere, 222, 789-796. doi:10.1016/j.chemosphere.2019.01.163
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  Explosives, pesticides, and pharmaceuticals contain toxic nitroaromatic compounds that may form even more toxic azo compounds if they encounter reducing conditions in the environment. We investigated the mechanism by which 4,4'-dimethoxyazobenzene forms in anaerobic sludge incubations of 4-nitroanisole, an analog for the insensitive munitions compound 2,4-dinitroanisole (DNAN). Because studies have reported the mechanism to involve the coupling of reduced nitroaromatic intermediates, specifically aromatic amines and nitrosoaromatics, by nucleophilic processes, we abiotically paired 10 mM 4-aminoanisole with 2 mM 4-nitrosoanisole in nitrogen-flushed microcosms. However, only 7 μM of 4,4'-dimethoxyazobenzene had formed after 24 h. We identified the major product to be 4-methoxy-4'-nitrosodiphenylamine. Repeating this experiment in phosphate buffer at pH 5.1, 7.1, and 8.6 demonstrated that the formation of this unexpected product is acid catalyzed. We found that 4-methoxy-4'-nitrosodiphenylamine is more toxic than 4,4'-dimethoxyazobenzene to the bioluminescent bacterium Aliivibrio fischeri, with IC50 values of 0.1 μM and 0.5 μM, respectively. Both products are several orders of magnitude more toxic than reduced 4-nitroanisole intermediates 4-aminoanisole and 4-nitrosoanisole, as well as DNAN and its aromatic amine metabolites. Six-fold more 4,4'-dimethoxyazobenzene formed when we incubated 4-nitrosoanisole with ascorbic acid, a reducing agent, than when we incubated 4-nitrosoanisole with 4-aminoanisole in the absence of ascorbic acid. We therefore suspect that 4-hydroxylaminoanisole, the first reduction product of 4-nitrosoanisole, is a better nucleophile than 4-aminoanisole and couples more readily with 4-nitrosoanisole. Slightly basic and reducing conditions can prevent the formation and persistence of toxic coupling products on sites contaminated with nitroaromatics, i.e. DNAN-contaminated firing ranges.
• Kadoya, W. M., Sierra-Alvarez, R., Jagadish, B., Wong, S., Abrell, L., Mash, E. A., & Field, J. A. (2019). Coupling reactions between reduced intermediates of insensitive munitions compound analog 4-nitroanisole. Chemosphere, 222, 789-796.
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  Explosives, pesticides, and pharmaceuticals contain toxic nitroaromatic compounds that may form even more toxic azo compounds if they encounter reducing conditions in the environment. We investigated the mechanism by which 4,4'-dimethoxyazobenzene forms in anaerobic sludge incubations of 4-nitroanisole, an analog for the insensitive munitions compound 2,4-dinitroanisole (DNAN). Because studies have reported the mechanism to involve the coupling of reduced nitroaromatic intermediates, specifically aromatic amines and nitrosoaromatics, by nucleophilic processes, we abiotically paired 10 mM 4-aminoanisole with 2 mM 4-nitrosoanisole in nitrogen-flushed microcosms. However, only 7 μM of 4,4'-dimethoxyazobenzene had formed after 24 h. We identified the major product to be 4-methoxy-4'-nitrosodiphenylamine. Repeating this experiment in phosphate buffer at pH 5.1, 7.1, and 8.6 demonstrated that the formation of this unexpected product is acid catalyzed. We found that 4-methoxy-4'-nitrosodiphenylamine is more toxic than 4,4'-dimethoxyazobenzene to the bioluminescent bacterium Aliivibrio fischeri, with IC values of 0.1 μM and 0.5 μM, respectively. Both products are several orders of magnitude more toxic than reduced 4-nitroanisole intermediates 4-aminoanisole and 4-nitrosoanisole, as well as DNAN and its aromatic amine metabolites. Six-fold more 4,4'-dimethoxyazobenzene formed when we incubated 4-nitrosoanisole with ascorbic acid, a reducing agent, than when we incubated 4-nitrosoanisole with 4-aminoanisole in the absence of ascorbic acid. We therefore suspect that 4-hydroxylaminoanisole, the first reduction product of 4-nitrosoanisole, is a better nucleophile than 4-aminoanisole and couples more readily with 4-nitrosoanisole. Slightly basic and reducing conditions can prevent the formation and persistence of toxic coupling products on sites contaminated with nitroaromatics, i.e. DNAN-contaminated firing ranges.
• Jagadish, B., Hurley, N. R., & Mash, E. A. (2017). Solvent-free nitration of electron-rich arenes. SYNTHETIC COMMUNICATIONS, 47(24), 2395-2398.
• Raghunand, N., Scicinski, J., Guntle, G. P., Jagadish, B., Mash, E. A., Bruckheimer, E., Oronsky, B., & Korn, R. L. (2017). Magnetic resonance imaging of RRx-001 pharmacodynamics in preclinical tumors. Oncotarget, 8(60), 102511-102520.
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  RRx-001 is an anticancer agent that subjects cancer cells to reactive oxygen/nitrogen species (ROS/RNS) and acts as an epigenetic modifier. We have used a thiol-bearing MRI contrast agent, Gd-LC7-SH, to investigate the pharmacodynamics of RRx-001 in CHP-100 Ewing's Sarcoma, HT-29 colorectal carcinoma, and PANC-1 pancreatic carcinoma xenografts in SCID mice. Binding of Gd-LC7-SH to the Cysresidue on plasma albumin prolongs retention in the tumor microenvironment and increases tumor enhancement on MRI. Mice were imaged by MRI andT1 maps acquired 50 min (T1) after injection of 0.05 mmol/kg Gd-LC7-SH (i.v.) at baseline and 1, 24, and 72 h post-treatment with 10 mg/kg RRx-001 (i.v.). Consistent with an indirect thiol-modifying activity of RRx-001, tumor T1at 1 h post-drug was significantly longer than pre-drug tumor T1in all three tumor models, with the T1remaining significantly longer than baseline through 72 h post-drug in the HT-29 and PANC-1 tumors. The T1of CHP-100 tumors recovered to baseline by 24 h post-drug, suggesting a robust anti-oxidant response to the RRx-001 challenge that was presaged by a marked increase in perfusion at 1 h post-drug measured by DCE-MRI. MRI enhanced with Gd-LC7-SH provides a mechanistically rational biomarker of RRx-001 pharmacodynamics.
• Landowski, T. H., Guntle, G. P., Zhao, D., Jagadish, B., Mash, E. A., Dorr, R. T., & Raghunand, N. (2016). Magnetic Resonance Imaging Identifies Differential Response to Pro-Oxidant Chemotherapy in a Xenograft Model. Translational oncology, 9(3), 228-35.
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  Induction of oxidative stress is a key component of cancer therapy. Pro-oxidant drugs have been demonstrated to enhance the efficacy of radiotherapy and chemotherapy. An emerging concept is that therapeutic outcomes are dictated by the differential redox buffering reserve in subpopulations of malignant cells, indicating the need for noninvasive biomarkers of tumor redox that can be used for dose identification and response assessment in a longitudinal setting. Magnetic resonance imaging (MRI) enhanced with the thiol-binding contrast agent Gd-LC6-SH, and hemodynamic response imaging (HRI) in combination with hypercapnia and hyperoxia were investigated as biomarkers of the pharmacodynamics of the small molecule pro-oxidant imexon (IMX). Human multiple myeloma cell lines 8226/S and an IMX-resistant variant, 8226/IM10, were established as contralateral tumors in SCID mice. T1slope, an MRI measure of the washout rate of Gd-LC6-SH, was significantly lower post-IMX therapy in 8226/S tumors compared with vehicle controls, indicating treatment-related oxidization of the tumor microenvironment, which was confirmed by analysis of tumor tissue for thiols. T1slope and ex vivo assays for thiols both indicated a more reduced microenvironment in 8226/IM10 tumors following IMX therapy. HRI with hypercapnia challenge revealed IMX inhibition of vascular dilation in 8226/S tumors but not 8226/IM10 tumors, consistent with decreased immunohistochemical staining for smooth muscle actin in treated 8226/S tumors. MRI enhanced with Gd-LC6-SH, and HRI coupled with a hypercapnic challenge provide noninvasive biomarkers of tumor response to the redox modulator imexon.
• Dehigaspitiya, D. C., Anglin, B. L., Smith, K. R., Weber, C. S., Lynch, R. M., & Mash, E. A. (2015). Linear scaffolds for multivalent targeting of melanocortin receptors. Organic & biomolecular chemistry, 13(47), 11507-17.
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  Molecules bearing one, two, three, or four copies of the tetrapeptide His-dPhe-Arg-Trp were attached to scaffolds based on ethylene glycol, glycerol, and d-mannitol by means of the copper-assisted azide-alkyne cyclization. The abilities of these compounds to block binding of a probe at the melanocortin 4 receptor were evaluated using a competitive binding assay. All of the multivalent molecules studied exhibited 30- to 40-fold higher apparent affinites when compared to a monovalent control. These results are consistent with divalent binding to receptor dimers. No evidence for tri- or tetravalent binding was obtained. Differences in the interligand spacing required for divalent binding, as opposed to tri- or tetravalent binding, may be responsible for these results.
• Dehigaspitiya, D. C., Navath, S., Weber, C. S., Lynch, R. M., & Mash, E. A. (2015). Synthesis and bioactivity of MSH4 oligomers prepared by an A(2) + B-2 strategy. TETRAHEDRON LETTERS, 56(23), 3060-3065.
• Elshan, N. G., Jayasundera, T., Anglin, B. L., Weber, C. S., Lynch, R. M., & Mash, E. A. (2015). Trigonal scaffolds for multivalent targeting of melanocortin receptors. Organic & Biomolecular Chemistry, 13(6), 1778-91.
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  Melanocortin receptors can be used as biomarkers to detect and possibly treat melanoma. To these ends, molecules bearing one, two, or three copies of the weakly binding ligand MSH(4) were attached to scaffolds based on phloroglucinol, tripropargylamine, and 1,4,7-triazacyclononane by means of the copper-assisted azide-alkyne cyclization. This synthetic design allows rapid assembly of multivalent molecules. The bioactivities of these compounds were evaluated using a competitive binding assay that employed human embryonic kidney cells engineered to overexpress the melanocortin 4 receptor. The divalent molecules exhibited 10- to 30-fold higher levels of inhibition when compared to the corresponding monovalent molecules, consistent with divalent binding. The trivalent molecules were only statistically (∼2-fold) better than the divalent molecules, still consistent with divalent binding but inconsistent with trivalent binding. Possible reasons for these behaviors and planned refinements of the multivalent constructs targeting melanocortin receptors based on these scaffolds are discussed.
• Elshan, N. G., Jayasundera, T., Weber, C. S., Lynch, R. M., & Mash, E. A. (2015). Development of a time-resolved fluorescence probe for evaluation of competitive binding to the cholecystokinin 2 receptor. Bioorganic & medicinal chemistry, 23(8), 1841-8.
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  The synthesis, characterization, and use of Eu-DTPA-PEGO-Trp-Nle-Asp-Phe-NH2 (Eu-DTPA-PEGO-CCK4), a luminescent probe targeted to cholecystokinin 2 receptor (CCK2R, aka CCKBR), are described. The probe was prepared by solid phase synthesis. A Kd value of 17±2nM was determined by means of saturation binding assays using HEK-293 cells that overexpress CCK2R. The probe was then used in competitive binding assays against Ac-CCK4 and three new trivalent CCK4 compounds. Repeatable and reproducible binding assay results were obtained. Given its ease of synthesis, purification, receptor binding properties, and utility in competitive binding assays, Eu-DTPA-PEGO-CCK4 could become a standard tool for high-throughput screening of compounds in development targeted to cholecystokinin receptors.
• Elshan, N. G., Patek, R., Vagner, J., & Mash, E. A. (2014). Spectrophotometric determination and removal of unchelated europium ions from solutions containing Eu-diethylenetriaminepentaacetic acid chelate-peptide conjugates. Analytical Biochemistry, 464, 24-9.
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  Europium chelates conjugated with peptide ligands are routinely used as probes for conducting in vitro binding experiments. The presence of unchelated Eu ions in these formulations gives high background luminescence and can lead to poor results in binding assays. In our experience, the reported methods for purification of these probes do not achieve adequate removal of unchelated metal ions in a reliable manner. In this work, a xylenol orange-based assay for the quantification of unchelated metal ions was streamlined and used to determine levels of metal ion contamination as well as the success of metal ion removal on attempted purification. We compared the use of Empore chelating disks and Chelex 100 resin for the selective removal of unchelated Eu ions from several Eu-diethylenetriaminepentaacetic acid chelate-peptide conjugates. Both purification methods gave complete and selective removal of the contaminant metal ions. However, Empore chelating disks were found to give much higher recoveries of the probes under the conditions used. Related to the issue of probe recovery, we also describe a significantly more efficient method for the synthesis of one such probe using Rink amide AM resin in place of Tentagel S resin.
• Jagadish, B., Field, J. A., Chorover, J., Sierra-Alvarez, R., Abrell, L., & Mash, E. A. (2014). Synthesis of 13C and 15N labeled 2,4-dinitroanisole. Journal of labelled compounds & radiopharmaceuticals, 57(6), 434-6.
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  Syntheses of [(13)C6]-2,4-dinitroanisole (ring-(13)C6) from [(13)C6]-anisole (ring-(13)C6) and [(15)N2]-2,4-dinitroanisole from anisole using in situ generated acetyl nitrate and [(15)N]-acetyl nitrate, respectively, are described. Treatment of [(13)C6]-anisole (ring-(13)C6) with acetyl nitrate generated in 100% HNO3 gave [(13)C6]-2,4-dinitroanisole (ring-(13)C6) in 83% yield. Treatment of anisole with [(15)N]-acetyl nitrate generated in 10 N [(15)N]-HNO3 gave [(15)N2 ]-2,4-dinitroanisole in 44% yield after two cycles of nitration. Byproducts in the latter reaction included [(15)N]-2-nitroanisole and [(15)N]-4-nitroanisole.
• Jagadish, B., Ozumerzifon, T. J., Roberts, S. A., Hall, G. B., Mash, E. A., & Raghunand, N. (2014). IMPROVED SYNTHESIS OF 10-(2-ALKYLAMINO-2-OXOETHYL)-1,4,7,10-TETRAAZACYCLODODECANE-1,4,7-TRIACETIC ACID DERIVATIVES BEARING ACID-SENSITIVE LINKERS. Synthetic communications, 44(3).
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  Alkylation of the hydrobromide salts of 1,4,7-tris(methoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane and 1,4,7-tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane with appropriate α-bromoacetamides, followed by hydrolysis, provides convenient access to 10-(2-alkylamino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid derivatives that contain acid-sensitive functional groups. The utility of the method is demonstrated by improved syntheses of two known DOTA monoamides bearing acid-sensitive ω-tritylthio alkyl chains in much higher yields based on cyclen as the starting material.
• Mash, E. A. (2014). Crystal Engineering with 1,4-Piperazine-2,5-diones. CrystEngComm, 15(5), 8620-8637.
• Radhakrishnan, V. M., Kojs, P., Young, G., Ramalingam, R., Jagadish, B., Mash, E. A., Martinez, J. D., Ghishan, F. K., & Kiela, P. R. (2014). pTyr421 cortactin is overexpressed in colon cancer and is dephosphorylated by curcumin: involvement of non-receptor type 1 protein tyrosine phosphatase (PTPN1). PloS One, 9(1), e85796.
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  Cortactin (CTTN), first identified as a major substrate of the Src tyrosine kinase, actively participates in branching F-actin assembly and in cell motility and invasion. CTTN gene is amplified and its protein is overexpressed in several types of cancer. The phosphorylated form of cortactin (pTyr(421)) is required for cancer cell motility and invasion. In this study, we demonstrate that a majority of the tested primary colorectal tumor specimens show greatly enhanced expression of pTyr(421)-CTTN, but no change at the mRNA level as compared to healthy subjects, thus suggesting post-translational activation rather than gene amplification in these tumors. Curcumin (diferulolylmethane), a natural compound with promising chemopreventive and chemosensitizing effects, reduced the indirect association of cortactin with the plasma membrane protein fraction in colon adenocarcinoma cells as measured by surface biotinylation, mass spectrometry, and Western blotting. Curcumin significantly decreased the pTyr(421)-CTTN in HCT116 cells and SW480 cells, but was ineffective in HT-29 cells. Curcumin physically interacted with PTPN1 tyrosine phosphatases to increase its activity and lead to dephosphorylation of pTyr(421)-CTTN. PTPN1 inhibition eliminated the effects of curcumin on pTyr(421)-CTTN. Transduction with adenovirally-encoded CTTN increased migration of HCT116, SW480, and HT-29. Curcumin decreased migration of HCT116 and SW480 cells which highly express PTPN1, but not of HT-29 cells with significantly reduced endogenous expression of PTPN1. Curcumin significantly reduced the physical interaction of CTTN and pTyr(421)-CTTN with p120 catenin (CTNND1). Collectively, these data suggest that curcumin is an activator of PTPN1 and can reduce cell motility in colon cancer via dephosphorylation of pTyr(421)-CTTN which could be exploited for novel therapeutic approaches in colon cancer therapy based on tumor pTyr(421)-CTTN expression.
• Belzer, M., Morales, M., Jagadish, B., Mash, E. A., & Wright, S. H. (2013). Substrate-dependent ligand inhibition of the human organic cation transporter OCT2. Journal of Pharmacology and Experimental Therapeutics, 346(2), 300-310.
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  PMID: 23709117;Abstract: Organic cation transporter 2 (OCT2) mediates the initial step in renal secretion of organic cations: uptake from the blood, across the basolateral membrane, and into the renal proximal tubule cells. Because of its potential as a target for unwanted drug-drug interactions (DDIs), considerable attention has been directed toward understanding the basis of OCT2 selectivity. These studies typically assess selectivity based on ligand inhibition profiles for OCT2-mediated transport of a probe substrate. However, little attention has been given to the potential influence of the substrate on the profile of ligand inhibition. Here we compared the IC50 values obtained for a set of structurally distinct inhibitors against OCT2-mediated transport of three structurally distinct substrates: 1-methyl-4-phenylpyridinium (MPP); metformin; and a novel fluorescent substrate, N,N,Ntrimethyl- 2-[methyl(7-nitrobenzo[c][l, 2,5]oxadiazol-4-yl)amino] ethanaminium iodide (NBD-MTMA). The median IC 50 value for inhibition of MPP transport was 9-fold higher than that for inhibition of metformin transport. Similarly, the median IC50 value for inhibition of MPP transport was 5-fold higher than that for NBD-MTMA transport. However, this was not a systematic difference in inhibitory efficacy; the ratio of IC50 values, MPP versus NBD-MTMA, ranged from 88-fold (ipratropium) to 0.3-fold (metformin). These data show that 1) the choice of OCT2 substrate significantly influences both quantitative and qualitative inhibitory interactions with cationic drugs; and 2) ligand interactions with OCT2 are not restricted to competition for a common ligand binding site, consistent with a binding surface characterized by multiple, possibly overlapping interaction sites. Development of predictive models of DDIs with OCT2 must take into account the substrate dependence of ligand interaction with this protein. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.
• Martinez, G. V., Navath, S., Sewda, K., Rao, V., Foroutan, P., Alleti, R., Moberg, V. E., Ahad, A. M., Coppola, D., Lloyd, M. C., Gillies, R. J., Morse, D. L., & Mash, E. A. (2013). Demonstration of a sucrose-derived contrast agent for magnetic resonance imaging of the GI tract. Bioorganic & Medicinal Chemistry Letters, 23(7), 2061-2064.
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  PMID: 23481651;PMCID: PMC3602218;Abstract: A scaffold bearing eight terminal alkyne groups was synthesized from sucrose, and copies of an azide-terminated Gd-DOTA complex were attached via copper(I)-catalyzed azide-alkyne cycloaddition. The resulting contrast agent (CA) was administered by gavage to C3H mice. Passage of the CA through the gastrointestinal (GI) tract was followed by T1-weighted magnetic resonance imaging (MRI) over a period of 47 h, by which time the CA had exited the GI tract. No evidence for leakage of the CA from the GI tract was observed. Thus, a new, orally administered CA for MRI of the GI tract has been developed and successfully demonstrated. © 2013 Elsevier Ltd. All rights reserved.
• Mash, E., Mash, E. A., Alleti, R., Vagner, J., Dehigaspitiya, D. C., Moberg, V. E., Elshan, N. G., Tafreshi, N. K., Brabez, N., Weber, C. S., Lynch, R. M., Hruby, V. J., Gillies, R. J., & Morse, D. L. (2013). Synthesis and characterization of time-resolved fluorescence probes for evaluation of competitive binding to melanocortin receptors. Bioorganic & Medicinal Chemistry, 21(17).
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  Probes for use in time-resolved fluorescence competitive binding assays at melanocortin receptors based on the parental ligands MSH(4), MSH(7), and NDP-α-MSH were prepared by solid phase synthesis methods, purified, and characterized. The saturation binding of these probes was studied using HEK-293 cells engineered to overexpress the human melanocortin 4 receptor (hMC4R) as well as the human cholecystokinin 2 receptor (hCCK2R). The ratios of non-specific binding to total binding approached unity at high concentrations for each probe. At low probe concentrations, receptor-mediated binding and uptake was discernable, and so probe concentrations were kept as low as possible in determining Kd values. The Eu-DTPA-PEGO-MSH(4) probe exhibited low specific binding relative to non-specific binding, even at low nanomolar concentrations, and was deemed unsuitable for use in competition binding assays. The Eu-DTPA-PEGO probes based on MSH(7) and NDP-α-MSH exhibited Kd values of 27±3.9nM and 4.2±0.48nM, respectively, for binding with hMC4R. These probes were employed in competitive binding assays to characterize the interactions of hMC4R with monovalent and divalent MSH(4), MSH(7), and NDP-α-MSH constructs derived from squalene. Results from assays with both probes reflected only statistical enhancements, suggesting improper ligand spacing on the squalene scaffold for the divalent constructs. The Ki values from competitive binding assays that employed the MSH(7)-based probe were generally lower than the Ki values obtained when the probe based on NDP-α-MSH was employed, which is consistent with the greater potency of the latter probe. The probe based on MSH(7) was also competed with monovalent, divalent, and trivalent MSH(4) constructs that previously demonstrated multivalent binding in competitive binding assays against a variant of the probe based on NDP-α-MSH. Results from these assays confirm multivalent binding, but suggest a more modest increase in avidity for these MSH(4) constructs than was previously reported.
• Guntle, G. P., Jagadish, B., Mash, E. A., Powis, G., Dorr, R. T., & Raghunand, N. (2012). Tumor xenograft response to redox-active therapies assessed by magnetic resonance imaging using a thiol-bearing DOTA complex of gadolinium. Translational Oncology, 5(3), 190-199.
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  Abstract: Gd-LC6-SH is a thiol-bearing DOTA complex of gadolinium designed to bind plasma albumin at the conserved Cys 34 site. The binding of Gd-LC6-SH shows sensitivity to the presence of competing thiols. We hypothesized that Gd-LC6-SH could provide magnetic resonance imaging (MRI) enhancement that is sensitive to tumor redox state and that the prolonged retention of albumin-bound Gd-LC6-SH in vivo can be exploited to identify a saturating dose above which the shortening of MRI longitudinal relaxation time (T 1) of tissue is insensitive to the injected gadolinium dose. In the Mia-PaCa-2 pancreatic tumor xenograft model in SCID mice, both the small-molecule Gd-DTPA-BMA and the macromolecule Galbumin MRI contrast agents produced dose-dependent decreases in tumor T 1. By contrast, the decreases in tumor T 1 provided by Gd-LC6-SH at 0.05 and 0.1 mmol/kg were not significantly different at longer times after injection. SCID mice bearing Mia-PaCa-2 or NCI-N87 tumor xenografts were treated with either the glutathione synthesis inhibitor buthionine sulfoximine or the thiol-oxidizing anticancer drug Imexon, respectively. In both models, there was a significantly greater increase in tumor R1 (=1/T 1) 60 minutes after injection of Gd-LC6-SH in drug-treated animals relative to saline-treated controls. In addition, Mercury Orange staining for nonprotein sulfhydryls was significantly decreased by drug treatment relative to controls in both tumor models. In summary, these studies show that thiol-bearing complexes of gadolinium such as Gd-LC6-SH can serve as redox-sensitive MRI contrast agents for detecting differences in tumor redox status and can be used to evaluate the effects of redox-active drugs. © 2012 Neoplasia Press, Inc.
• Jagadish, B., Guntle, G. P., Zhao, D., Gokhale, V., Ozumerzifon, T. J., Ahad, A. M., Mash, E. A., & Raghunand, N. (2012). Redox-active magnetic resonance imaging contrast agents: Studies with thiol-bearing 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid derivatives. Journal of Medicinal Chemistry, 55(23), 10378-10386.
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  PMID: 23148501;PMCID: PMC3607631;Abstract: The synthesis and structure-activity relationships of a homologous series of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid gadolinium(III) complexes bearing thiol-terminated alkyl side chains from three to nine carbons in length are reported. The observed binding with human serum albumin (HSA) of the compounds having C-3 through C-7 side chain lengths was inhibited by homocysteine in a manner consistent with single-site binding. The observed binding with HSA of the compounds having C-8 and C-9 side chain lengths was only partly inhibited by homocysteine, consistent with multisite binding. The binding affinity of the C-7 compound could be related to the HSA oxidation state. 2D 1H-1H NMR TOCSY provided evidence of covalent binding of the europium analog of the C-6 compound to HSA-Cys34. The longitudinal water-proton MRI relaxivities of the gadolinium complexes at 7 T increased upon binding to HSA. On the basis of these results, the C-6 and C-7 compounds were identified as promising redox-sensitive MRI contrast agents. © 2012 American Chemical Society.
• Jagadish, B., Guntle, G. P., Zhao, D., Gokhale, V., Ozumerzifon, T. J., Ahad, A. M., Mash, E. A., & Raghunand, N. (2012). Redox-active magnetic resonance imaging contrast agents: studies with thiol-bearing 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid derivatives. Journal of Medicinal Chemistry, 55(23), 10378-86.
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  The synthesis and structure-activity relationships of a homologous series of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid gadolinium(III) complexes bearing thiol-terminated alkyl side chains from three to nine carbons in length are reported. The observed binding with human serum albumin (HSA) of the compounds having C-3 through C-7 side chain lengths was inhibited by homocysteine in a manner consistent with single-site binding. The observed binding with HSA of the compounds having C-8 and C-9 side chain lengths was only partly inhibited by homocysteine, consistent with multisite binding. The binding affinity of the C-7 compound could be related to the HSA oxidation state. 2D 1H-1H NMR TOCSY provided evidence of covalent binding of the europium analog of the C-6 compound to HSA-Cys34. The longitudinal water-proton MRI relaxivities of the gadolinium complexes at 7 T increased upon binding to HSA. On the basis of these results, the C-6 and C-7 compounds were identified as promising redox-sensitive MRI contrast agents.
• Navath, S., Rao, V., Woodford, R. T., Midura-Kiela, M. T., Ahad, A. M., Alleti, R., Kiela, P. R., & Mash, E. A. (2012). Design, synthesis, and testing of a molecular truck for colonic delivery of 5-aminosalicylic acid. ACS Medicinal Chemistry Letters, 3(9), 710-714.
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  Abstract: A molecular scaffold bearing eight terminal alkyne groups was synthesized from sucrose. Eight copies of an azide-terminated, azo-linked precursor to 5-aminosalicylic acid were attached to the scaffold via copper(I)-catalyzed azide-alkyne cycloaddition. The resulting compound was evaluated in a DSS model of colitis in BALB/c mice against sulfasalazine as a control. Two independent studies verified that the novel pro-drug, administered in a dose calculated to result in an equimolar 5-ASA yield, outperformed sulfasalazine in terms of protection from mucosal inflammation and T cell activation. A separate study established that 5-ASA appeared in feces produced 24-48 h following administration of the pro-drug. Thus, a new, orally administered pro-drug form of 5-aminosalicylic acid has been developed and successfully demonstrated. © 2012 American Chemical Society.
• Wells, K. E., Weatherhead, R. A., Murigi, F. N., Nichol, G. S., Carducci, M. D., Selby, H. D., & Mash, E. A. (2012). Organic crystal engineering with 1,4-piperazine-2,5-diones. 8. Synthesis, crystal packing, and thermochemistry of piperazinediones derived from 2-amino-4,7-dialkoxyindan-2-carboxylic acids. Crystal Growth & Design, 12(10), 5056-5068.
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  Abstract: 1,4-Piperazine-2,5-diones possessing C 2hmolecular symmetry and bearing four methoxy, ethoxy, butoxy, hexyloxy, octyloxy, nonyloxy, dodecyloxy, or octadecyloxy groups weresynthesized from 2-amino-4,7-dialkoxyindan-2- carboxylic acids. Where possible, the piperazinediones were crystallized from appropriate solvents and the supramolecular organizations were determined by X-ray crystallography. In each case so studied, crystal assembly via three mutually orthogonal interactions, namely, R22(8) hydrogen bonding, arene perpendicular edge-to-center interactions, and alkyl chain interdigitation, was observed. The thermochemical properties of these compounds were studied by modulated differential scanning calorimetry. In most cases, one or more reversible thermal events were observed between room temperature and melting to an isotropic liquid. In the cooling cycle, freezing point temperatures were observed to decrease with increasing hydrocarbon chain length. This may be due to greater entropic penalties for hydrogen-bond association of molecules with longer hydrocarbon chains. © 2012 American Chemical Society.
• Xu, L., Josan, J. S., Vagner, J., Caplan, M. R., Hruby, V. J., Mash, E. A., Lynch, R. M., Morse, D. L., & Gillies, R. J. (2012). Heterobivalent ligands target cell-surface receptor combinations in vivo. Proceedings of the National Academy of Sciences of the United States of America, 109(52), 21295-300.
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  A challenge in tumor targeting is to deliver payloads to cancers while sparing normal tissues. A limited number of antibodies appear to meet this challenge as therapeutics themselves or as drug-antibody conjugates. However, antibodies suffer from their large size, which can lead to unfavorable pharmacokinetics for some therapeutic payloads, and that they are targeted against only a single epitope, which can reduce their selectivity and specificity. Here, we propose an alternative targeting approach based on patterns of cell surface proteins to rationally develop small, synthetic heteromultivalent ligands (htMVLs) that target multiple receptors simultaneously. To gain insight into the multivalent ligand strategy in vivo, we have generated synthetic htMVLs that contain melanocortin (MSH) and cholecystokinin (CCK) pharmacophores that are connected via a fluorescent labeled, rationally designed synthetic linker. These ligands were tested in an experimental animal model containing tumors that expressed only one (control) or both (target) MSH and CCK receptors. After systemic injection of the htMVL in tumor-bearing mice, label was highly retained in tumors that expressed both, compared with one, target receptors. Selectivity was quantified by using ex vivo measurement of Europium-labeled htMVL, which had up to 12-fold higher specificity for dual compared with single receptor expressing cells. This proof-of-principle study provides in vivo evidence that small, rationally designed bivalent htMVLs can be used to selectively target cells that express both, compared with single complimentary cell surface targets. These data open the possibility that specific combinations of targets on tumors can be identified and selectively targeted using htMVLs.
• Ahad, A. M., Zuohe, S., Du-Cuny, L., Moses, S. A., Zhou, L. L., Zhang, S., Powis, G., Meuillet, E. J., & Mash, E. A. (2011). Development of sulfonamide AKT PH domain inhibitors. Bioorganic and Medicinal Chemistry, 19(6), 2046-2054.
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  PMID: 21353784;PMCID: PMC3088502;Abstract: Disruption of the phosphatidylinositol 3-kinase/AKT signaling pathway can lead to apoptosis in cancer cells. Previously we identified a lead sulfonamide that selectively bound to the pleckstrin homology (PH) domain of AKT and induced apoptosis when present at low micromolar concentrations. To examine the effects of structural modification, a set of sulfonamides related to the lead compound was designed, synthesized, and tested for binding to the expressed PH domain of AKT using a surface plasmon resonance-based competitive binding assay. Cellular activity was determined by means of an assay for pAKT production and a cell killing assay using BxPC-3 cells. The most active compounds in the set are lipophilic and possess an aliphatic chain of the proper length. Results were interpreted with the aid of computational modeling. This paper represents the first structure-activity relationship (SAR) study of a large family of AKT PH domain inhibitors. Information obtained will be used in the design of the next generation of inhibitors of AKT PH domain function. © 2011 Elsevier B.V. All rights reserved.
• Hahn, T., Jagadish, B., Mash, E. A., Garrison, K., & Akporiaye, E. T. (2011). α-Tocopheryloxyacetic acid: A novel chemotherapeutic that stimulates the antitumor immune response. Breast Cancer Research, 13(1).
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  PMID: 21232138;PMCID: PMC3109570;Abstract: Introduction: α-Tocopheryloxyacetic acid (α-TEA) is a novel ether derivative of α-tocopherol that has generated interest as a chemotherapeutic agent because of its selective toxicity toward tumor cells and its ability to suppress tumor growth in various rodent and human xenograft models. We previously reported that oral α-TEA inhibited the growth of both a transplanted (4T1) and a spontaneous MMTV-PyMT mouse model of breast cancer.Methods: Because little is known about the possible immunological mechanisms underlying the in vivo α-TEA effects, we evaluated the impact of α-TEA therapy on the immune response by characterizing immune cell populations infiltrating the tumor site.Results: α-TEA treatment resulted in higher frequencies of activated T cells in the tumor microenvironment and twofold and sixfold higher ratios of CD4 + and CD8 + T cells to regulatory T cells, respectively. This finding was correlated with an increased ability of tumor-draining lymph node cells and splenocytes from α-TEA-treated mice to secrete interferon (IFN)-γ in response to CD3 or to mediate a cytolytic response in a tumor-specific fashion, respectively. That the α-TEA-mediated antitumor effect had a T cell-dependent component was demonstrated by the partial abrogation of tumor suppression when CD4 + and CD8 + T cells were depleted. We also determined the intratumoral cytokine and chemokine profile and found that α-TEA treatment increased intratumoral IFN-γ levels but decreased interleukin (IL)-4 levels, suggesting a shift toward a TH1 response. In addition, α-TEA induced higher levels of the inflammatory cytokine IL-6 and the chemokine CCL5.Conclusions: Taken together, these data suggest that α-TEA treatment, in addition to its direct cytotoxic effects, enhanced the anti-tumor immune response. This study provides a better understanding of the mechanisms of action of α-TEA and its effect on the immune system and may prove useful in designing immune-stimulating strategies to boost the antitumor effects of α-TEA in breast cancer patients. © 2011 Hahn et al.; licensee BioMed Central Ltd.
• Hahn, T., Jagadish, B., Mash, E. A., Garrison, K., & Akporiaye, E. T. (2011). α-Tocopheryloxyacetic acid: a novel chemotherapeutic that stimulates the antitumor immune response. Breast cancer research : BCR, 13(1), R4.
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  α-Tocopheryloxyacetic acid (α-TEA) is a novel ether derivative of α-tocopherol that has generated interest as a chemotherapeutic agent because of its selective toxicity toward tumor cells and its ability to suppress tumor growth in various rodent and human xenograft models. We previously reported that oral α-TEA inhibited the growth of both a transplanted (4T1) and a spontaneous MMTV-PyMT mouse model of breast cancer.
• Jagadish, B., Brickert-Albrecht, G. L., Nichol, G. S., Mash, E. A., & Raghunand, N. (2011). On the synthesis of 1,4,7-tris(tert-butoxycarbonylmethyl)-1,4,7,10- tetraazacyclododecane. Tetrahedron Letters, 52(17), 2058-2061.
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  Abstract: 1,4,7-Tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane is widely used as an intermediate in the preparation of medically important DO3A and DOTA metal chelators. Despite its commercial availability and importance, the literature describing the preparation and properties of the free base is limited and sometimes unclear. We present herein an efficient synthesis of the hydrobromide salt of 1,4,7-tris(tert-butoxycarbonylmethyl)-1,4,7,10- tetraazacyclododecane, characterize this compound spectroscopically and by X-ray crystallographic analysis, describe its simple conversion to the corresponding free base, characterize this compound spectroscopically and by X-ray crystallographic analysis, and make observations on the reactivity of this interesting and useful compound. © 2010 Elsevier Ltd. All rights reserved.
• Josan, J. S., Handl, H. L., Sankaranarayanan, R., Xu, L., Lynch, R. M., Vagner, J., Mash, E. A., Hruby, V. J., & Gillies, R. J. (2011). Cell-specific targeting by heterobivalent ligands. Bioconjugate chemistry, 22(7), 1270-8.
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  Current cancer therapies exploit either differential metabolism or targeting to specific individual gene products that are overexpressed in aberrant cells. The work described herein proposes an alternative approach--to specifically target combinations of cell-surface receptors using heteromultivalent ligands ("receptor combination approach"). As a proof-of-concept that functionally unrelated receptors can be noncovalently cross-linked with high avidity and specificity, a series of heterobivalent ligands (htBVLs) were constructed from analogues of the melanocortin peptide ligand ([Nle(4), dPhe(7)]-α-MSH) and the cholecystokinin peptide ligand (CCK-8). Binding of these ligands to cells expressing the human Melanocortin-4 receptor and the Cholecystokinin-2 receptor was analyzed. The MSH(7) and CCK(6) were tethered with linkers of varying rigidity and length, constructed from natural and/or synthetic building blocks. Modeling data suggest that a linker length of 20-50 Å is needed to simultaneously bind these two different G-protein coupled receptors (GPCRs). These ligands exhibited up to 24-fold enhancement in binding affinity to cells that expressed both (bivalent binding), compared to cells with only one (monovalent binding) of the cognate receptors. The htBVLs had up to 50-fold higher affinity than that of a monomeric CCK ligand, i.e., Ac-CCK(6)-NH(2). Cell-surface targeting of these two cell types with labeled heteromultivalent ligand demonstrated high avidity and specificity, thereby validating the receptor combination approach. This ability to noncovalently cross-link heterologous receptors and target individual cells using a receptor combination approach opens up new possibilities for specific cell targeting in vivo for therapy or imaging.
• Morrow, J. K., Du-Cuny, L., Chen, L., Meuillet, E. J., Mash, E. A., Powis, G., & Zhang, S. (2011). Recent development of anticancer therapeutics targeting AKT. Recent Patents on Anti-Cancer Drug Discovery, 6(1), 146-159.
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  PMID: 21110830;PMCID: PMC3784017;Abstract: The serine/threonine kinase Akt has proven to be a significant signaling target, involved in various biological functions. Because of its cardinal role in numerous cellular responses, Akt has been implicated in many human diseases, particularly cancer. It has been established that Akt is a viable and feasible target for anticancer therapeutics. Analysis of all Akt kinases reveals conserved homology for an N-terminal regulatory domain, which contains a pleckstrin-homology (PH) domain for cellular translocation, a kinase domain with serine/threonine specificity, and a C-terminal extension domain. These well defined regions have been targeted, and various approaches, including in silico methods, have been implemented to develop Akt inhibitors. In spite of unique techniques and a prolific body of knowledge surrounding Akt, no targeted Akt therapeutics have reached the market yet. Here we will highlight successes and challenges to date on the development of anticancer agents modulating the Akt pathway in recent patents as well as discuss the methods employed for this task. Special attention will be given to patents with focus on those discoveries using computer-aided drug design approaches. © 2011 Bentham Science Publishers Ltd.
• Rao, V., Alleti, R., Liping, X. u., Tafreshi, N. K., Morse, D. L., Gillies, R. J., & Mash, E. A. (2011). A sucrose-derived scaffold for multimerization of bioactive peptides. Bioorganic and Medicinal Chemistry, 19(21), 6474-6482.
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  PMID: 21940174;PMCID: PMC3197697;Abstract: A spherical molecular scaffold bearing eight terminal alkyne groups was synthesized in one step from sucrose. One or more copies of a tetrapeptide azide, either N 3(CH 2) 5(C=O)-His-DPhe-Arg-Trp- NH 2 (MSH4) or N 3(CH 2) 5(C=O)-Trp-Met- Asp-Phe-NH 2 (CCK4), were attached to the scaffold via the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Competitive binding assays using Eu-labeled probes based on the superpotent ligands Ser-Tyr-Ser-Nle-Glu-His-DPhe-Arg-Trp-Gly-Lys-Pro-Val-NH 2 (NDP-a-MSH) and Asp-Tyr-Met-Gly-Trp-Met-Asp-Phe-NH 2 (CCK8) were used to study the interactions of monovalent and multivalent MSH4 and CCK4 constructs with Hek293 cells engineered to overexpress MC4R and CCK2R. All of the monovalent and multivalent MSH4 constructs exhibited binding comparable to that of the parental ligand, suggesting that either the ligand spacing was inappropriate for multivalent binding, or MSH4 is too weak a binder for a second 'anchoring' binding event to occur before the monovalently-bound construct is released from the cell surface. In contrast with this behavior, monovalent CCK4 constructs were significantly less potent than the parental ligand, while multivalent CCK4 constructs were as or more potent than the parental ligand. These results are suggestive of multivalent binding, which may be due to increased residence times for monovalently bound CCK4 constructs on the cell surface relative to MSH4 constructs, the greater residence time being necessary for the establishment of multivalent binding. © 2011 Elsevier Ltd. All rights reserved.
• Alleti, R., Rao, V., Liping, X. u., Gillies, R. J., & Mash, E. A. (2010). A solanesol-derived scaffold for multimerization of bioactive peptides. Journal of Organic Chemistry, 75(17), 5895-5903.
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  PMID: 20701315;PMCID: PMC2929268;Abstract: A flexible molecular scaffold bearing varying numbers of terminal alkyne groups was synthesized in five steps from solanesol. R(CO)-MSH(4)-NH2 ligands, which have a relatively low affinity for binding at the human melanocortin 4 receptor (hMC4R), were prepared by solid phase synthesis and were N-terminally acylated with 6-azidohexanoic acid. Multiple copies of the azide N3(CH2)5(CO)-MSH(4)-NH2 were attached to the alkyne-bearing, solanesol-derived molecular scaffold via the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Control studies showed that the binding affinity of the triazole-containing ligand, CH 3(CH2)3(C2N3)(CH 2)5(CO)-MSH(4)-NH2, was not significantly diminished relative to the corresponding parental ligand, CH3(CO)- MSH(4)-NH2. In a competitive binding assay with a Eu-labeled probe based on the superpotent ligand NDP-α-MSH, the monovalent and multivalent constructs appear to bind to hMC4R as monovalent species. In a similar assay with a Eu-labeled probe based on MSH(4), modest increases in binding potency with increased MSH(4) content per scaffold were observed. © 2010 American Chemical Society.
• Meuillet, E. J., Zuohe, S., Lemos, R., Ihle, N., Kingston, J., Watkins, R., Moses, S. A., Zhang, S., Du-Cuny, L., Herbst, R., Jacoby, J. J., Zhou, L. L., Ahad, A. M., Mash, E. A., Kirkpatrick, D. L., & Powis, G. (2010). Molecular pharmacology and antitumor activity of PHT-427, a novel akt/phosphatidylinositide-dependent protein kinase 1 pleckstrin homology domain inhibitor. Molecular Cancer Therapeutics, 9(3), 706-717.
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  PMID: 20197390;PMCID: PMC2837366;Abstract: Phosphatidylinositol 3-kinase/phosphatidylinositide-dependent protein kinase 1 (PDPK1)/Akt signaling plays a critical role in activating proliferation and survival pathways within cancer cells. We report the molecular pharmacology and antitumor activity of PHT-427, a compound designed to bind to the pleckstrin homology (PH) binding domain of signaling molecules important in cancer. Although originally designed to bind the PH domain of Akt, we now report that PHT-427 also binds to the PH domain of PDPK1. A series of PHT-427 analogues with variable C-4 to C-16 alkyl chain length were synthesized and tested. PHT-427 itself (C-12 chain) bound with the highest affinity to the PH domains of both PDPK1 and Akt. PHT-427 inhibited Akt and PDPK1 signaling and their downstream targets in sensitive but not resistant cells and tumor xenografts. When given orally, PHT-427 inhibited the growth of human tumor xenografts in immunodeficient mice, with up to 80% inhibition in the most sensitive tumors, and showed greater activity than analogues with C4, C6, or C8 alkyl chains. Inhibition of PDPK1 was more closely correlated to antitumor activity than Akt inhibition. Tumors with PIK3CA mutation were the most sensitive, and K-Ras mutant tumors were the least sensitive. Combination studies showed that PHT-427 has greater than additive antitumor activity with paclitaxel in breast cancer and with erlotinib in non-small cell lung cancer. When given >5 days, PHT-427 caused no weight loss or change in blood chemistry. Thus, we report a novel PH domain binding inhibitor of PDPK1/Akt signaling with significant in vivo antitumor activity and minimal toxicity. ©2010 AACR.
• Murigi, F. N., Nichol, G. S., & Mash, E. A. (2010). Synthesis of the conformationally constrained tyrosine analogues, (R)- and (S)-5-hydroxy-2-aminoindan-2-carboxylic acids. Journal of Organic Chemistry, 75(4), 1293-1296.
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  PMID: 20095557;Abstract: (Chemical Equation Presented) The conformationally constrained tyrosine analogues, (R)- and (S)-5-hydroxy-2-aminoindan-2-carboxylic acids, were prepared by chromatographic separation of diastereomeric dipeptide derivatives formed from N-Boc-L-phenylalanine. Absolute configurations were assigned by X-ray crystallographic analysis. © 2010 American Chemical Society.
• Nichol, G. S., Murigi, F. N., & Mash, E. A. (2010). A synchrotron study of (2R,5′S)-5′-benzyl-5-bromo-6-methoxy- spiro-[indane-2,2′-piperazine]-3′,6′-dione dimethyl-formamide solvate. Acta Crystallographica Section C: Crystal Structure Communications, 66(6), o302-o304.
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  PMID: 20522950;Abstract: Synchrotron radiation was used to study the structure of the title compound, C20H19BrN2O3·C 3H7NO, which was obtained as fine fragile needle-shaped crystals by recrystallization from dimethyl-formamide (DMF), one mol-ecule of which is incorporated per asymmetric unit into the crystal. The compound adopts a compact closed conformation with the orientation of the benzyl group such that the aryl ring is positioned over the piperazinedione ring, resulting in a Cspiro⋯Ctrans-C-CPh pseudo-torsion angle of-3.3 (3)°. The five-membered ring is present in an expected envelope conformation and the six-membered piperazinedione ring adopts a less puckered boat-like conformation. Reciprocal amide-to-amide hydrogen bonding between adjacent piperazinedione rings and C-H⋯O inter-actions involving DMF mol-ecules propagate in the crystal as a thick ribbon in the a-axis direction. © 2010 International Union of Crystallography.
• Raghunand, N., Guntle, G. P., Gokhale, V., Nichol, G. S., Mash, E. A., & Jagadish, B. (2010). Design, synthesis, and evaluation of 1,4,7,10-tetraazacyclododecane-1,4,7- triacetic acid derived, redox-sensitive contrast agents for magnetic resonance imaging. Journal of Medicinal Chemistry, 53(18), 6747-6757.
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  PMID: 20722424;PMCID: PMC2941433;Abstract: The design and synthesis of three 1,4,7,10-tetraazacyclododecane-1,4,7- triacetic acid (DO3A) derivatives bearing linkers with terminal thiol groups and a preliminary evaluation of their potential for use in assembling redox-sensitive magnetic resonance imaging contrast agents are reported. The linkers were selected on the basis of computational docking with a crystal structure of human serum albumin (HSA). Gd(III)-DO3A and Eu(III)-DO3A complexes were synthesized, and the structure of one complex was established by X-ray crystallographic analysis. The binding to HSA of a Gd(III)-DO3A complex bearing a thiol-terminated 3,6-dioxanonyl chain was competitively inhibited by homocysteine and by the corresponding Eu chelate. Binding to HSA was abolished when the terminal thiol group of this complex was absent. The longitudinal water-proton relaxivities (r1) of the three Gd(III)-DO3A complexes and of two Gd(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) complexes were measured in saline at 7 T. The DO3A complexes exhibited smaller r1 values, in both bound and free states, than the DOTA complexes. © 2010 American Chemical Society.
• Xu, L., Vagner, J., Alleti, R., Rao, V., Jagadish, B., Morse, D. L., Hruby, V. J., Gillies, R. J., & Mash, E. A. (2010). Synthesis and characterization of a Eu-DTPA-PEGO-MSH(4) derivative for evaluation of binding of multivalent molecules to melanocortin receptors. Bioorganic & medicinal chemistry letters, 20(8), 2489-92.
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  A labeled variant of MSH(4), a tetrapeptide that binds to the human melanocortin 4 receptor (hMC4R) with low microM affinity, was prepared by solid-phase synthesis methods, purified, and characterized. The labeled ligand, Eu-DTPA-PEGO-His-dPhe-Arg-Trp-NH(2), exhibited a K(d) for hMC4R of 9.1+/-1.4 microM, approximately 10-fold lower affinity than the parental ligand. The labeled MSH(4) derivative was employed in a competitive binding assay to characterize the interactions of hMC4R with monovalent and divalent MSH(4) constructs derived from squalene. The results were compared with results from a similar assay that employed a more potent labeled ligand, Eu-DTPA-NDP-alpha-MSH. While results from the latter assay reflected only statistical effects, results from the former assay reflected a mixture of statistical, proximity, and/or cooperative binding effects.
• Du-Cuny, L., Song, Z., Moses, S., Powis, G., Mash, E. A., Meuillet, E. J., & Zhang, S. (2009). Computational modeling of novel inhibitors targeting the Akt pleckstrin homology domain. Bioorganic and Medicinal Chemistry, 17(19), 6983-6992.
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  PMID: 19734051;PMCID: PMC2808703;Abstract: Computational modeling continues to play an important role in novel therapeutics discovery and development. In this study, we have investigated the use of in silico approaches to develop inhibitors of the pleckstrin homology (PH) domain of AKT (protein kinase B). Various docking/scoring schemes have been evaluated, and the best combination was selected to study the system. Using this strategy, two hits were identified and their binding behaviors were investigated. Robust and predictive QSAR models were built using the k nearest neighbor (kNN) method to study their cellular permeability. Based on our in silico results, long flexible aliphatic tails were proposed to improve the Caco-2 penetration without affecting the binding mode. The modifications enhanced the AKT inhibitory activity of the compounds in cell-based assays, and increased their activity as in vivo antitumor testing.
• Jones, I. W., Lynn, M. A., & Mash, E. A. (2009). Conformational analysis of bridgehead-substituted bicyclo[m.m.m]alkanes and bicyclo[8.8.n]alkanes. Tetrahedron, 65(50), 10317-10322.
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  Abstract: Conformational analyses of bicyclo[m.m.m]alkanes where m=1-10 and of bicyclo[8.8.n]alkanes where n=1-7 bearing methyl groups on the bridgeheads were carried out using a Monte Carlo search strategy. In the bicyclo[m.m.m]alkane series, greater variability was observed for the inter-bridgehead distance for larger values of m. This suggests that properly substituted bicyclo[8.8.8]hexacosanes or larger ring systems might serve as molecular springs. © 2009 Elsevier Ltd. All rights reserved.
• Moses, S. A., Ali, M. A., Zuohe, S., Du-Cuny, L., Li, L. Z., Lemos, R., Ihle, N., Skillman, A. G., Zhang, S., Mash, E. A., Powis, G., & Meuillet, E. J. (2009). In vitro and in vivo activity of novel small-molecule inhibitors targeting the pleckstrin homology domain of protein kinase B/AKT. Cancer Research, 69(12), 5073-5081.
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  PMID: 19491272;PMCID: PMC2914301;Abstract: The phosphatidylinositol 3-kinase/AKT signaling pathway plays a critical role in activating survival and antiapoptotic pathways within cancer cells. Several studies have shown that this pathway is constitutively activated in many different cancer types. The goal of this study was to discover novel compounds that bind to the pleckstrin homology (PH) domain of AKT, thereby inhibiting AKT activation. Using proprietary docking software, 22 potential PH domain inhibitors were identified. Surface plasmon resonance spectroscopy was used to measure the binding of the compounds to the expressed PH domain of AKT followed by an in vitro activity screen in Panc-1 and MiaPaCa-2 pancreatic cancer cell lines. We identified a novel chemical scaffold in several of the compounds that binds selectively to the PH domain of AKT, inducing a decrease in AKT activation and causing apoptosis at low micromolar concentrations. Structural modifications of the scaffold led to compounds with enhanced inhibitory activity in cells. One compound, 4-dodecyl-N-(1,3,4-thiadiazol-2-yl) benzenesulfonamide, inhibited AKT and its downstream targets in cells as well as in pancreatic cancer cell xenografts in immunocompromised mice; it also exhibited good antitumor activity. In summary, a pharmacophore for PH domain inhibitors targeting AKT function was developed. Computer-aided modeling, synthesis, and testing produced novel AKT PH domain inhibitors that exhibit promising preclinical properties. ©2009 American Association for Cancer Research.
• Weatherhead, R. A., Carducci, M. D., & Mash, E. A. (2009). Synthesis of conformationally constrained diaminodicarboxylic acid derivatives. Journal of Organic Chemistry, 74(22), 8773-8778.
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  PMID: 19848385;Abstract: (Chemical Presented) Functionally protected forms of three conformationally constrained diaminodicarboxylic acids were synthesized and characterized. 2,2′-Diaminospiro[3.3]heptane-2,2′-dicarboxylic acid, an analogue of diaminopimelic acid, was prepared in racemic form and the structure established by X-ray crystallographic analysis of the methyl ester hydrochloride. trans-1,4-Diaminocyclohexane-1,4-dicarboxylic acid was prepared and its structure established by X-ray crystallographic analysis of the corresponding Cbz-protected ethyl ester. cis- and trans-2,6-diamino-1,2,3,5,6,7-hexahydro- sindacene-2,6-dicarboxylic acids were synthesized and the structures assigned by X-ray crystallographic analysis of the corresponding Boc-protected ethyl ester and Cbz-protected ethyl ester, respectively. © 2009 American Chemical Society.
• Hammaker, J. R., & Mash, E. A. (2008). NOTE: Synthesis and characterization of a poly(acrylamide) with pendant 1,4-piperazine-2,5-dione moieties via post-polymerization cyclization. Journal of Macromolecular Science, Part A: Pure and Applied Chemistry, 45(10), 865-871.
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  Abstract: A poly(acrylamide) was synthesized from N -Boc-N -acrolyl-l-lysylglycine methyl ester via radical polymerization. This polymer typically had Mn 100,000 g/mol, Mw 300,000 g/mol, and a Tg of 93C. Removal of Boc with TFA and cyclization with DABCO in DMSO at 65C afforded a soluble piperazinedione- containing polymer that had a Tg of 157C and thermal stability up to 300C. These results demonstrate a viable and efficient synthetic route to piperazinedione-containing polyacrylamides of high molecular weight. Related polymers that incorporate substituted indane moieties could be useful high Tg materials for fabrication of LC and NLO devices.
• Jagadish, B., Carducci, M. D., Dawson, A., Nichol, G. S., & Mash, E. A. (2008). (S,S)-4′′-Cyano-7,7′′-dimeth-oxy-3′, 6′-dioxodispiro-[indane-2,2′-piperazine-5′, 2′′-indane]-4-carboxamide methanol solvate: Inter-rupting the amide-to-amide hydrogen-bonded tape. Acta Crystallographica Section C: Crystal Structure Communications, 64(8), o431-o433.
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  PMID: 18682650;Abstract: The title methanol solvate, C24H22N4O5·CH3OH, forms an extended three-dimensional hydrogen-bonded structure, assisted by the presence of several good donor and acceptor sites. It shows none of the crystal packing features typically expected of piperazinediones, such as amide-to-amide R 2 2(8) hydrogen bonding. In this structure the methanol solvent appears to play only a space-filling role; it is not involved in any hydrogen bonding and instead is disordered over several sites. This study reports, to the best of our knowledge, the first crystal structure of an indane-containing piperazinedione compound which exhibits a three-dimensional hydrogen-bonded structure formed by classical (N - H⋯O and N - H⋯N) hydrogen-bonding inter-actions. © 2008.
• Mahadevan, D., Powis, G., Mash, E. A., George, B., Gokhale, V. M., Zhang, S., Shakalya, K., Du-Cuny, L., Berggren, M., Ali, M. A., Jana, U., Ihle, N., Moses, S., Franklin, C., Narayan, S., Shirahatti, N., & Meuillet, E. J. (2008). Discovery of a novel class of AKT pleckstrin homology domain inhibitors. Molecular Cancer Therapeutics, 7(9), 2621-2632.
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  PMID: 18790745;PMCID: PMC2727864;Abstract: AKT, a phospholipid-binding serine/threonine kinase, is a key component of the phosphoinositide 3-kinase cell survival signaling pathway that is aberrantly activated in many human cancers. Many attempts have been made to inhibit AKT; however, selectivity remains to be achieved. We have developed a novel strategy to inhibit AKT by targeting the pleckstrin homology (PH) domain. Using in silico library screening and interactive molecular docking, we have identified a novel class of non-lipid-based compounds that bind selectively to the PH domain of AKT, with "in silico" calculated KD values ranging from 0.8 to 3.0 μmol/L. In order to determine the selectivity of these compounds for AKT, we used surface plasmon resonance to measure the binding characteristics of the compounds to the PH domains of AKT1, insulin receptor substrate-1, and 3-phosphoinositide-dependent protein kinase 1. There was excellent correlation between predicted in silico and measured in vitro KDs for binding to the PH domain of AKT, which were in the range 0.4 to 3.6 μmol/L. Some of the compounds exhibited PH domain-binding selectivity for AKT compared with insulin receptor substrate-1 and 3-phosphoinositide-dependent protein kinase 1. The compounds also inhibited AKT in cells, induced apoptosis, and inhibited cancer cell proliferation. In vivo, the lead compound failed to achieve the blood concentrations required to inhibit AKT in cells, most likely due to rapid metabolism and elimination, and did not show antitumor activity. These results show that these compounds are the first small molecules selectively targeting the PH domain of AKT. Copyright © 2008 American Association for Cancer Research.
• Ntirampebura, D., Jagadish, B., Nichol, G. S., Carducci, M. D., Dawson, A., Rajapakshe, A., Oliver, A. G., Clegg, W., Harrington, R. W., Layne Jr., L., Margolis, J. I., & Mash, E. A. (2008). Organic crystal engineering with 1,4-piperazine-2,5-diones. 7. Crystal packing of piperazinediones derived from 2-amino-7-nitro-4-methoxyindan-2- carboxylic acid. Crystal Growth and Design, 8(9), 3257-3270.
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  Abstract: 1,4-Piperazine-2,5-diones derived from 2-amino-7-nitro-4-methoxyindan-2- carboxylic acid were prepared in meso, racemic, and enantiomerically pure forms, crystallized from DMSO or DMF, and the supramolecular organization in the crystals determined by X-ray crystallography. These molecules were designed to bear two strongly dipolar p-nitroanisole groups, aligned in the enantiomeric stereoisomers and opposed in the meso stereoisomer. Consistent with piperazinediones of similar size and shape bearing nonpolar or weakly dipolar arene groups, these compounds engage in R22(8) hydrogen bonding, most often forming one-dimensional tapes. However, the preference for arene perpendicular edge-to-center interactions seen in the former is replaced by a preference for parallel edge-to-center arene interactions. While the dipoles of parallel edge-to-center associated arenes are often opposed, this is not a requirement in the solid state. © 2008 American Chemical Society.
• Mash, E., Bowen, M. E., Monguchi, Y., Sankaranarayanan, R., Vagner, J., Begay, L. J., Xu, L., Jagadish, B., Hruby, V. J., Gillies, R. J., & Mash, E. A. (2007). Design, synthesis, and validation of a branched flexible linker for bioactive peptides. The Journal of organic chemistry, 72(5).
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  A branched flexible linker that incorporates a fluorescent dansyl moiety was synthesized and used to connect two high affinity NDP-alpha-MSH ligands or two low affinity MSH(4) ligands. The linker was incorporated into the conjugate by solid-phase synthesis. In vitro biological evaluations showed that potency of binding to the human melanocortin 4 receptor was not diminished for linker-ligand combinations relative to the corresponding ligand alone.
• Mash, E., Jagadish, B., Sankaranarayanan, R., Xu, L., Richards, R., Vagner, J., Hruby, V. J., Gillies, R. J., & Mash, E. A. (2007). Squalene-derived flexible linkers for bioactive peptides. Bioorganic & medicinal chemistry letters, 17(12).
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  A regiochemical and stereochemical mixture of flexible linkers bearing terminal azide functionality was synthesized in two steps from squalene and was used to connect two high affinity NDP-alpha-MSH ligands or two low affinity MSH(4) ligands. The ligands were N-terminally acylated using N-hydroxysuccinimidoyl 5-hexynoate and were subsequently attached to the linker via copper-catalyzed 'click' 3+2 cyclization of the azide and alkyne moieties. In vitro biological evaluations showed that the binding affinity to the human melanocortin 4 receptor was not diminished for most linker-ligand combinations relative to the corresponding parental ligand. Statistical and cooperative binding effects were observed for dimeric constructs containing the low affinity ligand MSH(4), but not for dimeric NDP-alpha-MSH constructs, presumably due to slow off rates for this high affinity ligand.
• Aavula, B. R., Ali, M. A., Mash, E. A., Bednarczyk, D., & Wright, S. H. (2006). Synthesis and fluorescence of N,N,N-trimethyl-2-[methyl (7-nitrobenzo[c][l,2,5]oxadiazol-4-yl) amino]ethanaminium iodide, a pH-insensitive reporter of organic cation transport. Synthetic Communications, 36(6), 701-705.
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  Abstract: A synthesis of the title compound, its characterization, and the pH dependence of its fluorescence properties are described. This compound serves as a pH-insensitive real-time reporter of organic cation transport in biological systems. Copyright © Taylor & Francis Group, LLC.
• Bredfeldt, T. G., Jagadish, B., Eblin, K. E., Mash, E. A., & Gandolfi, A. J. (2006). Monomethylarsonous acid induces transformation of human bladder cells. Toxicology and Applied Pharmacology, 216(1), 69-79.
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  PMID: 16806342;PMCID: PMC2851136;Abstract: Arsenic is a human bladder carcinogen. Arsenic is methylated to both monomethyl and dimethyl metabolites which have been detected in human urine. The trivalent methylated arsenicals are more toxic than inorganic arsenic. It is unknown if these trivalent methylated metabolites can directly cause malignant transformation in human cells. The goal of this study is determine if monomethylarsonous acid (MMAIII) can induce malignant transformation in a human bladder urothelial cell line. To address this goal, a non-tumorigenic human urothelial cell line (UROtsa) was continuously exposed to 0.05 μM MMAIII for 52 weeks. Hyperproliferation was the first phenotypic change observed in exposed UROtsa (URO-MSC). After 12 weeks of exposure, doubling time had decreased from 42 h in unexposed control cells to 27 h in URO-MSC. Hyperproliferation continued to be a quality possessed by the URO-MSC cells after both 24 and 52 weeks of exposure to MMAIII, which had a 40-50% reduction in doubling time. Throughout the 52-week exposure, URO-MSC cells retained an epithelial morphology with subtle morphological differences from control cells. 24 weeks of MMAIII exposure was required to induce anchorage-independent growth as detected by colony formation in soft agar, a characteristic not found in UROtsa cells. To further substantiate that malignant transformation had occurred, URO-MSC cells were tested after 24 and 52 weeks of exposure to MMAIII for the ability to form tumors in SCID mice. Enhanced tumorigenicity in SCID mouse xenografts was observed after 52 weeks of treatment with MMAIII. These observations are the first demonstration of MMAIII-induced malignant transformation in a human bladder urothelial cell line and provide important evidence that MMAIII may be carcinogenic in human tissues. © 2006 Elsevier Inc. All rights reserved.
• Eblin, K. E., Bowen, M. E., Cromey, D. W., Bredfeldt, T. G., Mash, E. A., Lau, S. S., & Gandolfi, A. J. (2006). Arsenite and monomethylarsonous acid generate oxidative stress response in human bladder cell culture. Toxicology and Applied Pharmacology, 217(1), 7-14.
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  PMID: 16930658;Abstract: Arsenicals have commonly been seen to induce reactive oxygen species (ROS) which can lead to DNA damage and oxidative stress. At low levels, arsenicals still induce the formation of ROS, leading to DNA damage and protein alterations. UROtsa cells, an immortalized human urothelial cell line, were used to study the effects of arsenicals on the human bladder, a site of arsenical bioconcentration and carcinogenesis. Biotransformation of As(III) by UROtsa cells has been shown to produce methylated species, namely monomethylarsonous acid [MMA(III)], which has been shown to be 20 times more cytotoxic. Confocal fluorescence images of UROtsa cells treated with arsenicals and the ROS sensing probe, DCFDA, showed an increase of intracellular ROS within five min after 1 μM and 10 μM As(III) treatments. In contrast, 50 and 500 nM MMA(III) required pretreatment for 30 min before inducing ROS. The increase in ROS was ameliorated by preincubation with either SOD or catalase. An interesting aspect of these ROS detection studies is the noticeable difference between concentrations of As(III) and MMA(III) used, further supporting the increased cytotoxicity of MMA(III), as well as the increased amount of time required for MMA(III) to cause oxidative stress. These arsenical-induced ROS produced oxidative DNA damage as evidenced by an increase in 8-hydroxyl-2'-deoxyguanosine (8-oxo-dG) with either 50 nM or 5 μM MMA(III) exposure. These findings provide support that MMA(III) cause a genotoxic response upon generation of ROS. Both As(III) and MMA(III) were also able to induce Hsp70 and MT protein levels above control, showing that the cells recognize the ROS and respond. As(III) rapidly induces the formation of ROS, possibly through it oxidation to As(V) and further metabolism to MMA(III)/(V). These studies provide evidence for a different mechanism of MMA(III) toxicity, one that MMA(III) first interacts with cellular components before an ROS response is generated, taking longer to produce the effect, but with more substantial harm to the cell. © 2006 Elsevier Inc. All rights reserved.
• Jean-Louis, S., Akare, S., Ali, M. A., Mash Jr., E. A., Meuillet, E., & Martinez, J. D. (2006). Deoxycholic acid induces intracellular signaling through membrane perturbations. Journal of Biological Chemistry, 281(21), 14948-14960.
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  PMID: 16547009;Abstract: Secondary bile acids have long been postulated to be tumor promoters in the colon; however, their mechanism of action remains unclear. In this study, we examined the actions of bile acids at the cell membrane and found that they can perturb membrane structure by alteration of membrane microdomains. Depletion of membrane cholesterol by treating with methyl-β-cyclodextrin suppressed deoxycholic acid (DCA)-induced apoptosis, and staining for cholesterol with filipin showed that DCA caused a marked rearrangement of this lipid in the membrane. Likewise, DCA was found to affect membrane distribution of caveolin-1, a marker protein that is enriched in caveolae membrane microdomains. Additionally, fluorescence anisotropy revealed that DCA causes a decrease in membrane fluidity consistent with the increase in membrane cholesterol content observed after 4 h of DCA treatment of HCT116 cells. Significantly, by using radiolabeled bile acids, we found that bile acids are able to interact with and localize to microdomains differently depending on their physicochemical properties. DCA was also found to induce tyrosine phosphorylation and activate the receptor tyrosine kinase epidermal growth factor receptor in a ligand-independent manner. In contrast, ursodeoxycholic acid did not exhibit any of these effects even though it interacted significantly with the microdomains. Collectively, these data suggest that bile acid-induced signaling is initiated through alterations of the plasma membrane structure and the redistribution of cholesterol. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.
• Mash, E. A. (2006). Preface. Studies in Natural Products Chemistry, 33(PART M), vii.
• Mash, E., Raghunand, N., Jagadish, B., Trouard, T. P., Galons, J., Gillies, R. J., & Mash, E. A. (2006). Redox-sensitive contrast agents for MRI based on reversible binding of thiols to serum albumin. Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine, 55(6).
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  DOTA-based complexes of gadolinium (Gd) bearing a thiol moiety on a propyl or hexyl arm were synthesized. It was hypothesized that these complexes would form reversible covalent linkages with human serum albumin (HSA), which contains a reactive thiol at cysteine-34. The binding constant of the hexyl complex to HSA was measured to be 64 mM(-1) and decreased to 17, 6.1, and 3.6 mM(-1) in the presence of 0.5, 1, and 2 mM homocysteine, respectively. The binding constant of the propyl complex to HSA was significantly lower (5.0 mM(-1)) and decreased to 2.0, 1.5, and 0.87 mM(-1) in the presence of 0.5, 1, and 2 mM homocysteine, respectively. The longitudinal water-proton relaxivities of the hexyl and propyl complexes at 37 degrees C and 4.7 T were 2.3 and 2.9 mM(-1) s(-1), respectively, in saline. The relaxivities of the HSA-bound forms of the hexyl and propyl complexes were calculated to be 5.3 and 4.5 mM(-1) s(-1), respectively. The in vivo pharmacokinetics of both thiol complexes were altered by a chase of homocysteine but not saline, while the washout of GdDTPA was unaffected by either chase. Such redox-sensitive reversible binding of Gd complexes to plasma albumin can be exploited for imaging tissue redox and the blood-pool by MRI.
• Jagadish, B., Iyengar, B. S., Sólyom, A. M., Remers, W. A., Dorr, R. T., Yu, J. S., Gupta, S., & Mash, E. A. (2005). Synthesis of [¹⁴C]-imexon. Journal of Labelled Compounds and Radiopharmaceuticals, 48(3), 165-170.
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  Abstract: A four-step synthesis of [14C]-imexon is described, starting from [14C]-phosgene. The overall yield is 27% and the specific activity is 55 mCi/mmol. Copyright © 2005 John Wiley & Sons, Ltd.
• Jones, I. W., Monguchi, Y., Dawson, A., Carducci, M. D., & Mash, E. A. (2005). Synthesis of 1,10-dimethylbicyclo[8.8.8]hexacosane and 1,10- dihydroxybicyclo[8.8.8]hexacosane. Organic Letters, 7(14), 2841-2843.
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  PMID: 15987150;Abstract: (Chemical Equation Presented) 1,10-Dimethylbicyclo[8.8.8]hexacosane (1) and 1,10-dihydroxybicyclo[8.8.8]hexacosane (2) were prepared in 4% yield over seven steps and in 18% yield over three steps, respectively, starting from 1,10-cyclooctadecanedione. The identities and out,out conformations of these compounds were established by single-crystal X-ray analysis. © 2005 American Chemical Society.
• Weatherhead-Kloster, R. A., Selby, H. D., B., W., & Mash, E. A. (2005). Organic crystal engineering with 1,4-piperazine-2,5-diones. 6. Studies of the hydrogen-bond association of cyclo[(2-methylamino-4,7-dimethoxyindan-2- carboxylic acid)(2-amino-4,7-dimethoxyindan-2-carboxylic acid)]. Journal of Organic Chemistry, 70(22), 8693-8702.
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  PMID: 16238297;Abstract: The title 1,4-piperazine-2,5-dione was synthesized in 23% yield over six steps from ethyl 2-amino-4,7-dimethoxyindan-2-carboxylate. Crystallization by slow diffusion of ether into a chloroform solution and by slow evaporation of an ethanol-chloroform-benzene solution produced polymorphic crystalline forms as determined by single-crystal X-ray analysis. The polymorphs exhibited different hydrogen-bonding networks. The association of this piperazinedione in solution was studied using mass spectrometric and nuclear magnetic resonance spectroscopic techniques. The MS and NMR data were interpreted using the solid-state structures as models for solution aggregation. Association constants extracted from the NMR data are in line with those of other cyclic cis amides in chloroform solvent. © 2005 American Chemical Society.
• Dawson, A., Wang, J., Carducci, M. D., & Mash, E. A. (2004). Tris[2-(2-oxidophenyl)-5-phenyl-1,3,4-oxadiazole-κ²O ²,N³]aluminium 0.167-hydrate. Acta Crystallographica Section E: Structure Reports Online, 60(11), m1644-m1646.
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  Abstract: The title compound, [Al(C14H9N2O 2)3]·0.167H2O, crystallizes with three crystallographically independent molecules in the asymmetric unit. The Al atom is coordinated by one O atom and one N atom from each ligand. One half molecule of water is incorporated into the structure per three A1(C14H 9N2O2)3 units. © 2004 International Union of Crystallography Printed in Great Britain - all rights reserved.
• Jagadish, B., Aposhian, H. V., & Mash, E. A. (2003). An efficient synthesis of sodium dimethylarsinate-¹⁴C. Journal of Labelled Compounds and Radiopharmaceuticals, 46(4), 373-377.
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  Abstract: A short and efficient synthesis of sodium dimethylarsinate-14 is described. Incorporation of the label has been achieved by methylation of methyldiiodoarsine with iodomethane-14C. Product was precipitated and separated from sodium iodide by washing with acetone. Copyright © 2003 John Wiley & Sons, Ltd.
• Jagadish, B., Carducci, M. D., Bosshard, C., Günter, P., Margolis, J. I., Williams, L. J., & Mash, E. A. (2003). Organic crystal engineering with piperazine-2,5-diones. 4. Crystal packing of piperazinediones derived from 2-amino-7-cyano-4-methoxyindan-2-carboxylic acid. Crystal Growth and Design, 3(5), 811-821.
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  Abstract: Piperazine-2,5-diones derived from 2-amino-7-cyano-4-methoxyindan-2-carboxylic acid were prepared in meso, racemic, and enantiomerically pure forms, crystallized from dimethyl sulfoxide (DMSO), and the supramolecular organization in the crystals determined by X-ray crystallography. These molecules were designed to bear two strongly polar p-methoxybenzonitrile moieties either aligned or opposed. In contrast with nonpolar or weakly polar piperazinediones of similar size and shape, which exclude DMSO to form ladder-like tapes by reciprocal intermolecular amide-to-amide hydrogen bonding, these more strongly polar piperazinediones participate in hydrogen bonding with included DMSO. In cocrystals of the enantiomerically pure compounds, the p-methoxybenzonitrile dipoles were aligned in the three-dimensional lattice but opposed by the dipoles of included DMSO. These cocrystals exhibited second harmonic properties comparable to urea. A second cocrystal possessing aligned p-methoxybenzonitrile dipoles was observed when the enantiomerically pure compound was crystallized from dipropylsulfoxide. Compensating dipropylsulfoxide dipoles were absent in this cocrystal.
• Kloster, R. A., Carducci, M. D., & Mash, E. A. (2003). Crystal engineering of a liquid crystalline piperazinedione. Organic Letters, 5(20), 3683-3686.
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  PMID: 14507204;Abstract: (Matrix presented) A molecule designed to self-assemble via hydrogen bonding, arene-arene, and van der Waals interactions and expected to possess thermotropic liquid crystalline properties has been synthesized and characterized. Results support the validity of an assembly paradigm based on incorporation of chemically orthogonal and spatially independent recognition elements in the molecular building blocks.
• Bowen, M. E., Aavula, B. R., & Mash, E. A. (2002). Use of 9-methylfluorene as an indicator in the titration of common group IA and group IIA organometallic reagents. Journal of Organic Chemistry, 67(25), 9087-9088.
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  PMID: 12467435;Abstract: 9-Methylfluorene was tested as an indicator in the titration of commonly used organometallic reagents. This indicator is readily prepared in three steps from fluorenone. In THF solution the deprotonated indicator is red and exhibits a sharp endpoint. The highly basic reagents secbutyllithium and tert-butyllithium can be titrated in ether solution, where the color of the deprotonated indicator is yellow.
• Yushun, L. i., Carter, D. E., & Mash, E. A. (2002). Synthesis and structure of the glutathione conjugate of chloroacetaldehyde. Synthetic Communications, 32(10), 1579-1583.
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  Abstract: A synthesis and the structure of the title compound are presented. The sodium salt of N-BOC glutathione dimethyl ester was S-alkylated with chloroacetaldehyde. Following a protection/deprotection sequence, condensation of the aldehyde moiety with the nitrogen of the cysteine residue and subsequent dehydration produced a glutathione derivative that contains a 2,3-dihydro-4H-1,4-thiazine ring.
• Fontaine, S. M., Mash, E. A., Hoyer, P. B., & Sipes, I. G. (2001). Stereochemical aspects of vinylcyclohexene bioactivation in rodent hepatic microsomes and purified human cytochrome P450 enzyme systems. Drug Metabolism and Disposition, 29(2), 179-184.
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  PMID: 11159809;Abstract: The racemic mixture of 4-vinylcyclohexene (VCH) forms ovotoxic epoxides [VCH-1,2-epoxide, VCH-7,8-epoxide, and vinylcyclohexene diepoxide (VCD)] by cytochrome P450 (CYP) in B6C3F1 female mice. These epoxides deplete primordial and primary follicles. The current studies compared in vitro epoxidation of (R)-VCH with that of (S)-VCH in hepatic microsomes prepared from adult female B6C3F1 mice and Fischer 344 rats. Bioactivation of VCH in the rat was significantly less compared with that in the mouse. (R)-VCH formed significantly more VCH-1,2-epoxide as compared with (S)-VCH in both species, and less VCH-7,8-epoxide in the mouse. Neither of the enantiomers formed detectable amounts of VCD in the mouse or rat. Hepatic microsomes prepared from mice and rats pretreated with CYP-inducing agents (phenobarbital and acetone) were also incubated with (R)-VCH or (S)-VCH. Although monoepoxide formation was not increased enantioselectively in the mouse, VCD was formed preferentially from (R)-VCH as compared with (S)-VCH. Pretreatment with VCH resulted in nonstereoselective increases in both monoepoxide and diepoxide formation. In the rat, these pretreatments resulted in nonstereoselective increases in monoepoxide formation, but VCD formation was not detectable. Incubations with human CYP2E1 enzyme revealed that (R)-VCH formed significantly more VCH-1,2-epoxide and less VCH-7,8-epoxide than (S)-VCH. Human CYP2A6 was limited in its ability to form epoxides from either enantiomer of VCH. Human CYP2B6 preferentially formed VCH-7,8-epoxide compared with VCH-1,2-epoxide, and to a greater extent from (R)-VCH than from (S)-VCH. These results demonstrate regioselectivity and enantioselectivity in the bioactivation of VCH in rodent hepatic microsomes as well as in expressed human CYP enzymes.
• Petrick, J. S., Jagadish, B., Mash, E. A., & Aposhian, H. V. (2001). Monomethylarsonous acid (MMA^III) and arsenite: LD₅₀ in hamsters and in vitro inhibition of pyruvate dehydrogenase. Chemical Research in Toxicology, 14(6), 651-656.
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  PMID: 11409934;Abstract: Monomethylarsonous acid (MMAIII), a metabolite of inorganic arsenic, has received very little attention from investigators of arsenic metabolism in humans. MMAIII, like sodium arsenite, contains arsenic in the +3 oxidation state. Although we have previously demonstrated that it is more toxic than arsenite in cultured Chang human hepatocytes, there are no data showing in vivo toxicity of MMAIII. When MMAIII sodium arsenite was administered intraperitoneally to hamsters, the LD50s were 29.3 and 112.0 μmol/kg of body wt, respectively. In addition, inhibition of hamster kidney or purified porcine heart pyruvate dehydrogenase (PDH) activity by MMAIII or arsenite was determined. To inhibit hamster kidney PDH activity by 50%, the concentrations (mean ± SE) of MMAIII as methylarsine oxide, MMAIII as diiodomethylarsine, and arsenite were 59.9 ± 6.5, 62.0 ± 1.8, and 115.7 ± 2.3 μM, respectively. To inhibit activity of purified porcine heart PDH activity by 50%, the concentrations (mean ± SE) of MMAIII as methylarsine oxide and arsenite were 17.6 ± 4.1 and 106.1 ± 19.8 μM, respectively. These data demonstrate that MMAIII is more toxic than inorganic arsenite, both in vivo and in vitro, and call into question the hypothesis that methylation of inorganic arsenic is a detoxication process.
• Aavula, B. R., Cui, Q., & Mash, E. A. (2000). Synthesis of (S)-(-)-β-cuparenone and (S)-(-)-cuparene. Tetrahedron Asymmetry, 11(23), 4681-4686.
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  Abstract: A short and efficient synthesis of the title compounds is described. (S)-(-)-β-Cuparenone was prepared in 31% yield from p-tolualdehyde and mesityl oxide in eight steps. Absolute stereochemistry was established by means of a diastereoselective cyclopropanation using (R,R)-hydrobenzoin as a recoverable auxiliary. © 2001 Elsevier Science Ltd.
• Bednarczyk, D., Mash, E. A., Aavula, B. R., & Wright, S. H. (2000). NBD-TMA: A novel fluorescent substrate of the peritubular organic cation transporter of renal proximal tubules. Pflugers Archiv European Journal of Physiology, 440(1), 184-192.
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  PMID: 10864014;Abstract: Traditionally, the measurement of transport activity has employed radiolabeled compounds. The resulting experimental procedures do not measure transport in real time and are limited in temporal and spatial resolution. The use of epifluorescence microscopy provides the ability to measure transport activity in real time with high temporal and spatial resolution. Using epifluorescence microscopy we characterized the transport of the fluorescent organic cation, [2-(4-nitro-2,1,3-benzoxadiazol-7- yl)aminoethyl]trimethylammonium (NBD-TMA+, MW 266). NBD-TMA+ has structural characteristics common to other secreted organic cations and is fluorescent (λ(ex)=458 nm; λ(em)=530 nm). The excitation and emission spectra are insensitive to changes in [Cl-] and minimally sensitive to pH in the physiologically relevant range (pH 5.0-7.4). A microscope equipped with a photon-detection system was used to measure accumulation of NBD-TMA+ by isolated rabbit renal proximal tubules. Accumulation of NBD-TMA+ by proximal tubules was time dependent and saturable (Michaelis-Menten constant K(m) 12 μM). Proximal tubule accumulation of NBD-TMA+ was inhibited by the organic cations tetraethylammonium (TEA+) (apparent inhibitory constant K(app) (TEA) 134 μM), cimetidine, and N1-methylnicotinamide (NMN). Our experimental results provide strong evidence that NBD-TMA+ is transported by one or more of the basolateral organic cation transporters involved in the renal secretion of this chemical class of compound. This fluorescent substrate provides a sensitive means of investigating organic cation transport.
• Jagadish, B., Williams, L. J., Carducci, M. D., Bosshard, C., & Mash, E. A. (2000). The crystal packing of a strongly dipolar piperazinedione. Tetrahedron Letters, 41(49), 9483-9487.
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  Abstract: A strongly dipolar piperazine-2,5-dione was synthesized in enantiomerically pure form, crystallized from DMSO, and the supramolecular organization of the crystals determined by X-ray crystallography. In contrast with non-polar or weakly polar piperazinediones of similar molecular topography, which form tapes by reciprocal intermolecular amide-to-amide hydrogen bonding, the strongly dipolar piperazinedione participated in hydrogen bonding with occluded DMSO. The dipoles of the piperazinedione molecules were aligned and were opposed by the dipoles of the DMSO molecules. The cocrystals exhibited second harmonic generation when subjected to pulsed irradiation. (C) 2000 Elsevier Science Ltd.
• Mash, E. A., & Aavula, B. R. (2000). Synthesis of 7-alkoxyquinolines, coumarins, and resorufins. Synthetic Communications, 30(2), 367-375.
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  Abstract: Synthesis of the title compounds by treatment of the sodium salts of 7- quinolinol, 7-hydroxycoumarin, and resorufin with alkyl halides is described.
• Nimkar, K. S., & Mash, E. A. (2000). Intermolecular and intramolecular reactions of resolved 2-alkoxytetrahydrofuran-3-yl and 2-alkoxytetrahydropyran-3-yl radicals. Tetrahedron, 56(32), 5793-5800.
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  Abstract: Diastereomeric trans-2-alkoxy-3-phenylselenenyltetrahydrofuranyl acetals and trans-2-alkoxy-3-phenyl-selenenyltetrahydropyranyl acetals were prepared from dihydrofuran, dihydropyran, phenylselenenyl bromide, and the alcohols (S)-methyl lactate, (S)-methyl hexahydromandelate, and (R)-pantolactone. The diastereomers were chromatographically separated and were subjected to intermolecular alkylation via generation and trapping of free radicals. Observed diastereoselectivity was higher for 2-alkoxytetrahydrofuran-3-yl radicals than for 2-alkoxytetrahydropyran-3-yl radicals, and highest for acetals involving (R)-pantolactone. Alcohol exchanges at the anomeric carbon were highly stereocontrolled, and permitted introduction of alkenes for intramolecular trapping of free radical intermediates. (C) 2000 Elsevier Science Ltd.
• Mash, E. A., & Baron, J. A. (1999). Diastereoselective manipulations of bicyclo[m.1.0]alkane derivatives. 6. Stereocontrolled synthesis of tricyclo[m.n.0.0]alkenones. Journal of Organic Chemistry, 64(20), 7412-7418.
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  Abstract: Enolates derived from bicyclo[m.1.0]alkan-2-ones possessing 5-, 6-, and 7-membered rings were sequentially alkylated with iodomethane and with precursors to 2-oxopropyl or 3-oxobutyl substituents. High diastereoselectivities were observed. Product yields for more active electrophiles were generally good to very good and were fair for less active electrophiles. Following unmasking of the 2-oxopropyl or 3-oxobutyl substituents, ring closure and dehydration under basic conditions provided the corresponding tricyclic γ,δ-cyclopropyl-α,β-enones. Reversal of the order of alkylation switched the configuration of the angular methyl substituent relative to the stereogenic cyclopropane in the tricyclo[m.n.0.0]alkenone product.
• Waller, S. C., He, Y. A., Harlow, G. R., He, Y. Q., Mash, E. A., & Halpert, J. R. (1999). 2,2',3,3',6,6'-Hexachlorobiphenyl hydroxylation by active site mutants of cytochrome P450 2B1 and 2B11. Chemical Research in Toxicology, 12(8), 690-699.
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  PMID: 10458702;Abstract: The structural basis of species differences in cytochrome P450 2B- mediated hydroxylation of 2,2',3,3',6,6'-hexachlorobiphenyl (236HCB) was evaluated by using 14 site-directed mutants of cytochrome P450 2B1 and three point mutants of 2B11 expressed in Escherichia coli. To facilitate metabolite identification, seven possible products, including three hydroxylated and four dihydroxylated hexachlorobiphenyls, were synthesized by direct functionalization of precursors and Ullmann and crossed Ullmann reactions. HPLC and GCfMS analysis and comparison with authentic standards revealed that 2B1, 2B11, and all their mutants produced 4,5-dihydroxy-236HCB and 5-hydroxy- 236HCB, while 2B11 L363V and 2B1 I114V mutants also catalyzed hydroxylation at the 4-position. The amount of products formed by 2B1 mutants I114V, F206L, L209A, T302S, V363A, V363L, V367A, I477A, I477L, G478S, I480A, and I480L was smaller than that of the wild type. I477V exhibited unaltered 236HCB metabolism, and I480V produced twice as much dihydroxy product as the wild type. For 2B11, substitution of Val-114 or Asp-290 with Ile decreased the product yields. Replacement of Leu-363 with Val dramatically altered the profile of 236HCB metabolites. In addition to an increase in the overall level of hydroxylation, the mutant mainly catalyzed hydroxylation at the 4- position. Incubation of P450 2B1 with 5-hydroxy-236HCB produced 4,5- dihydroxy-236HCB, which indicates that 4,5-dihydroxy-236HCB may be formed by a direct hydroxylation of 5-hydroxy-236HCB. The findings from this study demonstrate the importance of residues 114, 206, 209, 302, 363, 367, 477, 478, and 480 in 2B1 and 114, 290, and 363 in 2B11 for 236HCB metabolism.
• Williams, L. J., Jagadish, B., Lansdown, M. G., Carducci, M. D., & Mash, E. A. (1999). Organic crystal engineering with piperazine-2,5-diones. 2. Crystal packing of weakly dipolar piperazinediones derived from 2-amino-4-bromo-7- methoxyindan-2-carboxylic acid. Tetrahedron, 55(50), 14301-14322.
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  Abstract: Piperazine-2,5-diones with the potential to manifest three chemically distinct and linearly independent intermolecular interactions were synthesized from the enantiomers of 2-amino-4-bromo-7-methoxyindan-2- carboxylic acid. Samples of enantiomerically pure, racemic, and meso piperazinediones were characterized in the solid state by X-ray crystallography. 'Ladder-like' intermolecular amide-to-amide hydrogen bonding interactions were observed in each case, establishing tape structures parallel to one crystallographic axis. The observed tape morphologies and crystal packing closely resemble that previously observed for a topographically similar tetramethoxy-piperazinedione. The results obtained demonstrate that the weak dipoles associated with the p-bromoanisole moiety play no role in determining order in the crystalline state.
• Williams, L. J., Jagadish, B., Lyon, S. R., Kloster, R. A., Carducci, M. D., & Mash, E. A. (1999). Organic crystal engineering with piperazine-2,5-diones. 1. Crystal packing of piperazinediones derived from substituted 2-aminoindan-2- carboxylic acids. Tetrahedron, 55(50), 14281-14300.
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  Abstract: We have postulated that molecules engineered to participate in three chemically distinct and linearly independent intermolecular interactions will self-assemble in a predictable fashion. Six prototypes for molecules capable of manifesting such interactions were synthesized from 2-aminoindan-2- carboxylic acid, 2-amino-5,6-dimethylindan-2-carboxylic acid, and 2-amino- 4,7-dimethoxyindan-2-carboxylic acid. These piperazinediones were characterized in solution by NMR spectroscopy and in the solid state by X-ray crystallography. 'Ladder-like' intermolecular amide-to-amide hydrogen bonding interactions were observed in each case, establishing tape structures parallel to one crystallographic axis. Tape morphology varied depending on the arene substitution pattern and was governed by the development of arene and/or van der Waals contact interactions.
• Hendrickx, E., Wang, J. F., Maldonado, J. L., Volodin, B. L., Sandalphon, ., Mash, E. A., Persoons, A., Kippelen, B., & Peyghambarian, N. (1998). Synthesis and characterization of highly efficient photorefractive polymer composites with long phase stability. Macromolecules, 31(3), 734-739.
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  Abstract: We have synthesized the chromophores 4-[(4′-nitrophenyl)azo]-1,3-bis[(3″- or 4″-vinylbenzyl)-oxy]benzene (NPADVBB) and 4-[(4′-nitrophenyl)azo]-1,3-bis(benzyloxy)benzene (NPADB). New polymer composites based on the photoconductor poly(9-vinylcarbazole), the plasticizer 9-ethylcarbazole, NPAD-VBB, and the sensitizers 2,4,7-trinitro-9-fluorenone and (2,4,7-trinitro-9-fluorenylidene)malonitrile were prepared. Ellipsometric measurements and degenerate four-wave mixing experiments were performed at 633 and 830 nm. The composites showed excellent phase stability, and nearly complete diffraction was observed at 633 nm. The two-beam coupling gain was limited by the small phase shift between the interference pattern and the index grating.
• Kawabe, Y., Spiegelberg, C., Schülzgen, A., Nabor, M. F., Kippelen, B., Mash, E. A., Allemand, P. M., Kuwata-Gonokami, M., Takeda, K., & Peyghambarian, N. (1998). Whispering-gallery-mode microring laser using a conjugated polymer. Applied Physics Letters, 72(2), 141-143.
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  Abstract: We observed laser emission in whispering gallery modes using a microring composed of a semiconducting polymer poly[2,5-bis-(2′-ethylhexyloxy)-p-phenylenevinylene coated on an etched fiber under transient and quasisteady-state pumping conditions. The threshold for laser oscillation was 1 mJ/cm2 (0.1 MW/cm2) and 30 μJ/cm2 (300 MW/cm2) for nanosecond and femtosecond excitation, respectively. The laser output showed superlinear dependence on the excitation energy above the threshold. The demonstration of lasing under quasisteady-state pumping shows the possibility to develop electrically pumped polymer lasers. © 1998 American Institute of Physics.
• Kawabe, Y., Spiegelberg, C., Schülzgen, A., Nabor, M., Jabbour, G. E., Kippelen, B., Mash, E. A., Allemand, P. M., Peyghambarian, N., Kuwata-Gonokami, M., & Takeda, K. (1998). Whispering-gallery-mode oscillation in a polymer microring laser. Proceedings of SPIE - The International Society for Optical Engineering, 3281, 211-216.
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  Abstract: We observed laser emission in whispering gallery modes using a microring composed of a light-emitting semiconducting polymer poly[2,5-bis-(2′-ethylhexyloxy)-p-phenylenevinylene] (BEH-PPV) coated on an etched fiber under transient and quasi steady-state pumping conditions. The threshold for laser oscillation was 1 mJ/cm2 (0.1 MW/cm2) and 30 μJ/cm2 (300 MW/cm2) for nanosecond and femtosecond excitation, respectively. The laser output showed superlinear dependence on the excitation energy above the threshold. The demonstration of lasing under quasi steady-state pumping shows the possibility to develop electrically pumped polymer lasers. Preliminary results on the line narrowing in tripheny dilamine (TPD) films under nanosecond optical pumping are also presented.
• Mash, E. A., Baron, J. A., Gregg, T. M., & Nimkar, S. K. (1998). Diastereoselective manipulations of bicyclo[m.1.0]alkane derivatives. 5. α'-Alkylations of bicycle[m.1.0]alkan-2-ones. Tetrahedron, 54(12), 2669-2682.
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  Abstract: α'-Alkylations of bicyclo[m.1.0]alkan-2-ones were shown to proceed with high diastereoselectivity under conditions which favor kinetic control of the product distribution. Product yields for active electrophiles were good to very good. In sequential α'-alkylations with different electrophiles, reversal of the order of alkylation switches the configuration of the newly formed quaternary center.
• Schulzgen, A., Spiegelberg, C., Morrell, M. M., Mendes, S. B., Nabor, M. F., Mash, E. A., Allemand, P. M., & Kippelen, B. (1998). Vertical-cavity surface-emitting polymer laser. Conference on Lasers and Electro-Optics Europe - Technical Digest, 6-7.
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  Abstract: Electroluminescence from conjugated polymers allows the application of organic materials in electrically pumped light-emitting devices. In this paper, a vertical-cavity surface-emitting polymer laser is characterized. The application of this laser is presented and its emission spectra are compared with other lasers without a cavity.
• Schülzgen, A., Spiegelberg, C., Morrell, M. M., Mendes, S. B., Kippelen, B., Peyghambarian, N., Nabor, M. F., Mash, E. A., & Allemand, P. M. (1998). Near diffraction-limited laser emission from a polymer in a high finesse planar cavity. Applied Physics Letters, 72(3), 269-271.
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  Abstract: We report near diffraction-limited laser emission from the conjugated polymer BEH:PPV in a cavity made with two dielectric mirrors providing a high finesse planar cavity. The laser has a sharp intensity threshold, a strong directionality, and a high degree of polarization. These emission characteristics are compared with those of a single polymer layer without optical feedback. © 1998 American Institute of Physics.
• Sutherland, T. D., Unnithan, G. C., Andersen, J. F., Evans, P. H., Murataliev, M. B., Szabo, L. Z., Mash, E. A., Bowers, W. S., & Feyereisen, R. (1998). A cytochrome P450 terpenoid hydroxylase linked to the suppression of insect juvenile hormone synthesis. Proceedings of the National Academy of Sciences of the United States of America, 95(22), 12884-12889.
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  PMID: 9789009;PMCID: PMC23641;Abstract: A cDNA encoding a cytochrome P450 enzyme was isolated from a cDNA library of the corpora allata (CA) from reproductively active Diploptera punctata cockroaches. This P450 from the endocrine glands that produce the insect juvenile hormone (JH) is most closely related to P450 proteins of family 4 and was named CYP4C7. The CYP4C7 gene is expressed selectively in the CA; its message could not be detected in the fat body, corpora cardiaca, or brain, but trace levels of expression were found in the midgut and caeca. The levels of CYP4C7 mRNA in the CA, measured by ribonuclease protection assays, were linked to the activity cycle of the glands. In adult females, CYP4C7 expression increased immediately after the peak of JH synthesis, reaching a maximum on day 7, just before oviposition. mRNA levels then declined after oviposition and during pregnancy. The CYP4C7 protein was produced in Escherichia coli as a C-terminal His-tagged recombinant protein. In a reconstituted system with insect NADPH cytochrome P450 reductase, cytochrome b(s), and NADPH, the purified CYP4C7 metabolized (2E,6E)-farnesol to a more polar product that was identified by GC-MS and by NMR as (10E)-12- hydroxyfarnesol, CYP4C7 converted JH III to 12-trans-hydroxy JH HI and metabolized other JH-like sesquiterpenoids as well. This ω-hydroxylation of sesquiterpenoids appears to be a metabolic pathway in the corpora allata that may play a role in the suppression of JH biosynthesis at the end of the gonotrophic cycle.
• Yushun, L. i., Carter, D. E., & Mash, E. A. (1998). Synthesis of the mono-cysteine disulfide of meso-2,3-dimercaptosuccinic acid. Synthetic Communications, 28(11), 2057-2062.
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  Abstract: A synthesis of the title compound from dimethyl meso-2,3- dimemaptosuccinate and a protected, activated cysteine derivative is described.
• Kippelen, B., Hendrickx, E., Wang, J. F., Golemme, A., Volodin, B. L., Rivera, J. M., Mash, E. A., & Peyghambarian, N. (1997). Recent advances in photorefractive polymers and liquid crystals. American Chemical Society, Polymer Preprints, Division of Polymer Chemistry, 38(2), 506-507.
• Mash, E. A., Gregg, T. M., & Baron, J. A. (1997). Diastereoselective Manipulations of Bicyclo[m.1.0]alkane Derivatives. 4. Reactions of Nucleophiles with Bicyclo[m.1.0]alk-3-en-2-ones. Journal of Organic Chemistry, 62(24), 8513-8521.
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  Abstract: Enantiomerically enriched bicyclo[m.1.0]alk-3-en-2-ones possessing 8-, 12-, and 15-membered rings were prepared and subjected to additions of nucleophiles. 1,2-Additions of n-butyllithium were highly diastereoselective for all cyclopropyl enones examined. Reactions of (Z)-bicyclo[6.1.0]non-3-en-2-one and (E)-bicyclo[13.1.0]hexadec-3-en-2-one with dimethyloxosulfonium methylide were highly diastereoselective, while reaction of (E)-bicyclo[10.1.0]tridec-3-en-2-one with this reagent was not diastereoselective. In contrast, 1,4-additions of lithium diorganocuprates were highly diastereoselective for the 8- and 12-membered enones but were not diastereoselective for the 15-membered enone. All reactions were chemically efficient. The diastereoselectivities observed for 1,2-additions, which are thought to involve early transition states, can be rationalized by consideration of the low-energy conformations of each cyclopropyl enone. The diastereoselectivities observed for 1,4-additions, which may involve late transition states, do not correlate simply with the lowest energy conformations of these enones.
• Mash, E. A., Gregg, T. M., & Stahl, M. T. (1997). Development of Molecular Mechanics Torsion Parameters for α,β-Cyclopropyl α′,β′-Enones and Conformational Analysis of Bicyclo[m.1.0]alk-3-en-2-ones. Journal of Organic Chemistry, 62(11), 3715-3721.
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  Abstract: Conformations of cyclopropyl vinyl ketone have been studied using ab initio methods in an effort to quantify the effects of conjugative overlap between the cyclopropane ring and adjacent enone carbonyl. With respect to the cyclopropyl carbonyl torsion, cyclopropyl vinyl ketone exhibits a global energy minimum in the s-cis conformer and a local energy minimum in the s-trans conformer. The potential energy curve obtained was used to derive torsion parameters which were employed in molecular mechanics studies of the conformations of the set of bicyclo[m.1.0]alk-3-en-2-ones having larger ring sizes from 5- to 16-membered.
• Mash, E. A., Korth, H., & DeMoss, S. M. (1997). On the reported intermediacy of vinyl radicals in spontaneous polymerization: An ESR-spin trapping study and its significance for the bond forming initiation theory. Tetrahedron, 53(45), 15297-15320.
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  Abstract: Deuterated isopropyl vinyl sulfides and diethyl fumarate were synthesized and employed in a re-investigation of the mechanism of initiation of spontaneous polymerization of these comonomers by means of spin- trapping/ESR spectroscopy. Previous radical spin-trapping studies had been interpreted as indicating the involvement of vinyl radicals. While our studies produced data substantially in agreement with the previous study, it must be noted that the date are not consistent with literature data for other vinyl radicals. Accordingly, results from both spin-trapping/ESR studies me inconsistent with involvement of vinyl radical intermediates, but are consistent with initiation by tetramethylene diradicals.
• Mash, E. A., Nimkar, K. S., & Baron, J. A. (1997). Diastereoselective manipulations of bicyclo[m.1.0] alkane derivatives. 3. Nucleophilic additions to the carbonyl carbon of (1R,8R)-Bicyclo[6.1.0]nonan-2,6-dione 2-(2S,3S)-1,4-Di-O-methyl-1,2,3,4-butane ketal. Tetrahedron, 53(27), 9043-9056.
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  Abstract: Conformations of the title compound were studied using a Monte Carlo search technique. Two principal conformational motifs were observed for the bicyclic carbocycle in which both faces of the carbonyl appear susceptible to nucleophilic attack. The title compound was synthesized in eight steps from cis-1,5-cyclooctanediol. Additions of nucleophiles (e.g., CH3Li) to the title compound gave adducts in good yields, but with low levels of diastereoselectivity, in agreement with computational prediction.
• Mash, E. A., T., L., & Waller, S. C. (1997). Monobenzylation of 1,n-diols via dibutylstannylene intermediates. Synthetic Communications, 27(3), 507-514.
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  Abstract: Symmetrical primary 1,n-diols, HO(CH2)(n)OH, of any chain length from n = 2-10, can be selectively monobenzylated via sequential treatment with dibutyltin oxide and benzyl bromide.
• Mash, E. A., Williams, L. J., & Pfeiffer, S. S. (1997). Synthesis of ethyl N-(diphenyl)methyl-1,2,3,4- tetrahydroisoquinoline-3-carboxylates. Tetrahedron Letters, 38(40), 6977-6980.
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  Abstract: A concise method for the synthesis of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives from α,α'-dibromo-o-xylenes via sequential C-alkylation and N-alkylation of a glycine anion is described.
• Waller, S. C., & Mash, E. A. (1997). Improved syntheses of 2,2',3,3',6,6'-hexachlorobiphenyl. Organic Preparations and Procedures International, 29(6), 679-685.
• Mash, E. A., & Waller, S. C. (1996). Syntheses and spectroscopic characterizations of oxidative metabolites of 4-vinylcyclohexene II diol-epoxides. Toxicological and Environmental Chemistry, 57(1-4), 153-162.
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  Abstract: Several possible diol-epoxide derivatives of 4-vinylcyclohexene were prepared and characterized spectroscopically for use as standards in toxicological studies of the oxidative metabolism of the parent hydrocarbon.
• Mash, E. A., & Williams, L. J. (1996). Engineering molecular solids. American Chemical Society, Polymer Preprints, Division of Polymer Chemistry, 37(1), 207-.
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  Abstract: A new type of organic crystalline was synthesized and was characterized by X-ray crystallography to be highly ordered at the molecular level. The structure of the material supports the contention that diketopeperazines, ordered in the crystalline state, can be designed considering orthogonal interactions.
• Mash, E. A., Gregg, T. M., & Kaczynski, M. A. (1996). Diastereoselective manipulations of bicyclo[m.1.0]alkane derivatives. 2. Nucleophilic additions to the carbonyl carbons of bicyclot[m.1.0]alkan-2-ones. Journal of Organic Chemistry, 61(8), 2743-2752.
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  Abstract: Enantiomerically enriched bicyclo[m.1.0]alkan-2-ones having larger ring sizes between five and 16 members were prepared and subjected to additions of nucleophiles to the carbonyl carbon. Such additions were efficient and highly diastereoselective for all nucleophiles for bicycles with ring sizes greater than seven. Diastereoselectivity for these additions is rationalized by assuming early transition states and exposure of the same carbonyl face to the ring exterior in the vast majority of populated conformers for each bicyclic ketone.
• Mash, E. A., Gregg, T. M., Stahl, M. T., & Walters, W. P. (1996). Development of molecular mechanics torsion parameters for α,β-cyclopropyl ketones and conformational analysis of bicyclo[m.1.0]alkan-2-ones. Journal of Organic Chemistry, 61(8), 2738-2742.
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  Abstract: Conformations of cyclopropyl methyl ketone have been studied using ab initio methods in an effort to quantify the effects of conjugative overlap between the cyclopropane ring and an adjacent ketone carbonyl. Results were comparable with previous experimental and theoretical studies. Cyclopropyl methyl ketone exhibits a global energy minimum in the s-cis conformer and a local energy minimum near the s-trans conformer. The potential energy curve obtained was used to derive torsion parameters which were employed in molecular mechanics studies of the conformations of the set of bicyclo[m.1.0]alkan-2-ones having larger ring sizes from five- to 16-membered. Similar conformations for the cyclopropyl ketone substructure are observed for all the medium and large ring systems examined. Possible synthetic ramifications of local conformational anchoring by this functional group array are discussed.
• Mash, E. A., & Gregg, T. M. (1995). Synthesis of the enantiomers of 4-vinylcyclohexene. Journal of Organic Chemistry, 60(19), 6180-6182.
• Mash, E. A., Gregg, T. M., & Sipes, I. G. (1994). Syntheses and spectroscopic characterizations of oxidative metabolites of 4-vinylcyclohexene. Toxicological and Environmental Chemistry, 42(3-4), 235-239.
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  Abstract: The 7,8-epoxide and 7,8-diol derivatives of 4-vinylcyclohexene were prepared and characterized spectroscopically for use as standards in toxicological studies of the oxidative metabolism of the parent hydrocarbon.
• Mash, E. A., & Nimkar, S. K. (1993). An efficient stereoconvergent synthesis of the 4-ethylamino-2,4-dideoxy-l-threo-pentopyranose component of the calicheamicins and esperamicins. Tetrahedron Letters, 34(3), 385-388.
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  Abstract: A stereconvergent synthesis of the 4-ethylamino-2,4-dideoxy-L-threo-pentopyranose coonponent of calicheamicins γ1, γ1I, α2I, and esperamicin A1b from methyl 2-deoxy-β-D-ribopyranoside is described. The synthesis requires eight steps in each branch. The overall yield is 54%. This synthesis should be adaptable for syntheses of the corresponding 4-methylamino)-2,4-dideoxy- L-threo- and 4-isopropylamino-2.4- dideoxy-L-threo- pentopyranose components of other calicheamicin and esperamicin antibiotics. © 1993.
• Dolata, D. P., Spina, D. R., & Mash, E. A. (1992). Systematic search of transition state conformations. Tetrahedron Letters, 33(44), 6571-6574.
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  Abstract: Structural axioms for modeling transition states (TSs) for the addition of nucleophiles to carbonyl compounds have been added to WIZARD. These axioms are largely based on Houk's studies and MM2 parameters. With these axioms WIZARD is capable of rapidly and systematically searching the conformational space of TSs for such reactions. The resulting TS conformations were validated by MM2 and MOPAC. The theoretical results and experimental observations are in good agreement. © 1992.
• Ito, H., Sooriyakumaran, R., Maekawa, Y., & Mash, E. A. (1992). Acid-catalyzed dehydration for the design of chemical amplification resists. Polymeric Materials Science and Engineering, Proceedings of the ACS Division of Polymeric Materials Science and Engineering, 66, 45-46.
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  Abstract: Chemical amplification (3) based on radiation-induced acidolysis is a very attractive approach to dramatically increasing radiation sensitivities of resist systems for use in short wavelength lithographic technologies. Polarity reversal has been also utilized in the chemical amplification scheme. In this paper is reported another approach to achieving the reverse polarity change. The chemical amplification resists described in this paper are based on acid-catalyzed dehydration of alcohols to olefins.
• Ito, H., Schildknegt, K., & Mash, E. A. (1991). Negative chemical amplification resist systems based on polyhydroxystyrenes and N-substituted imides or aldehydes. Proceedings of SPIE - The International Society for Optical Engineering, 1466, 408-418.
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  Abstract: Aqueous base developable negative deep UV resist systems composed of phenolic resins, monofunctional latent olectrophiles, and a sulfonium salt photochemical acid generator are described. This study was carried out to see whether attachment of a bulky substituent onto the phenolic group via C- or O-alkylation reduces the dissolution rate of the phenolic resin in aqueous base to provide negative images even when no crosslinking is involved in the mechanism. The latent electrophiles selected are N-hydroxymethyl and N-aceotxymethylimides as well as high-boiling aldehydes. Our matrix resins are para-, meta-, and ortho-isomers of polyvinylphenol and copolymers of p-hydroxystyrene.
• Mash, E. A., & Arterburn, J. B. (1991). Enantiomerically pure acetals in organic synthesis. 3. A synthesis of (R)-mevalonic acid lactone. Journal of Organic Chemistry, 56(2), 885-888.
• Mash, E. A., & Fryling, J. A. (1991). Enantiomerically pure acetals in organic synthesis. 2. Diastereoselective alkylation of enantiomeric lithio alkyl lactyl tetrahydropyranosides and related enolates. Journal of Organic Chemistry, 56(3), 1094-1098.
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  Abstract: A concise approach for the rapid synthesis of enantiomerically pure α-alkylated derivatives of lactate esters and of other enantiomerically pure α-hydroxy esters is presented. This methodology, which makes use of enantiomeric lithium enolates prepared from diastereomeric tetrahydropyranyl ethers derived from alkyl lactates and other α-hydroxy esters, is used to prepare both enantiomers of frontalin from (S)-(-)-methyl lactate. © 1991 American Chemical Society.
• Mash, E. A., Arterburn, J. B., Fryling, J. A., & Mitchell, S. H. (1991). Enantiomerically pure acetals in organic synthesis. 1. Chromatographic separability of furanoside and pyranoside acetals derived from α-hydroxy esters. Journal of Organic Chemistry, 56(3), 1088-1093.
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  Abstract: A general chromatographic separation of diastereomeric furanoside and pyranoside acetals derived from α-hydroxy esters is described. Application of this separation methodology is made to rapid syntheses of the diastereomers of (S)-methyl lactyl 4-deoxy-β-erythro-pentopyranoside. © 1991 American Chemical Society.
• Mash, E. A., Fryling, J. A., & Wexler, P. A. (1991). Structure of an enantiomerically pure tetrahydropyranyl ether. Acta Crystallographica Section C: Crystal Structure Communications, 47(12), 2708-2709.
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  Abstract: (2S)-Methyl 2-phenyl-2-[(2S)tetrahydro-2(2H)-pyranyloxy]acetate, C 14H18O4, Mr = 250.29, orthorhombic, P212121, a = 7.850(1), b = 8.211(1), c = 21.123 (3) Å, V= 1361.5 (3) Å3, Z = 4, Dx = 1.22 g cm-3, Mo Kα, λ = 0.71073 Å, μ=0.8 cm -1, F(000) = 536, T=296K, R = 0.039 for 973 unique reflections with Fo2 > 3σ(Fo2). In this diastereomer the anomeric alkoxy substituent is axially oriented. The absolute stereochemistry at the anomeric carbon is assigned as S based upon the known stereochemistry of the mandelate ester. © 1991 International Union of Crystallography.
• Sooriyakumaran, R., Ito, H., & Mash, E. A. (1991). Acid-catalyzed pinacol rearrangement. Chemically amplified reverse polarity change. Proceedings of SPIE - The International Society for Optical Engineering, 1466, 419-428.
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  Abstract: The reverse polarity change from a polar to a nonpolar state has been successfully incorporated in the design of chemical amplification resists. The imaging mechanism is based on the pinacol-pinacolone rearrangement wherein vic-diols (pinacols) are converted to ketones or aldehydes with photochemically generated acid as a catalyst. In addition to a polymeric pinacol which undergoes the rearrangement very cleanly in the solid state, aqueous base developable three-component negative deep UV resist systems are described, which are based on phenolic resins, small pinacols, and triphenylsulfonium hexafluoroantimonate as the acid generator.
• Kilama, J. J., Iyengar, B. S., Remers, W. A., & Mash, E. A. (1990). A new synthetic approach to the C-D ring portion of streptonigrin analogues. Journal of Heterocyclic Chemistry, 27(5), 1437-1440.
• Mash, E. A., & Hemperly, S. B. (1990). Mechanistic studies of diastereoselective cyclopropanation via homochiral ketals. 2. Studies with conformationally restricted 2-cyclohexen-1-one ketals. Journal of Organic Chemistry, 55(7), 2055-2060.
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  Abstract: The effect of cyclohexene ring conformation on the diastereoselectivity observed for Simmons-Smith cyclopropanation of 2-cyclohexen-1-one ethylene ketals was examined by using (5S)-5-tert-butyl-2-cyclohexen-1-one 1,2-ethanediol, (2R,3R)-2,3-butanediol, and (2S,3S)-2,3-butanediol ketals. Reagent chelation by the pseudoequatorial dioxolane oxygen atom was shown to result in more effective methylene transfer. This regiochemical preference can either antagonize or reinforce diastereoselectivity due to steric hindrance of the dioxolane oxygen atoms from dissymmetric, placement of methyl appendages on the dioxolane ring. © 1990 American Chemical Society.
• Mash, E. A., Hemperly, S. B., Nelson, K. A., Heidt, P. C., & Deusen, S. V. (1990). Mechanistic studies of diastereoselective cyclopropanation via homochiral ketals. 1. Dioxolane structural effects. Journal of Organic Chemistry, 55(7), 2045-2055.
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  Abstract: Compounds structurally related to 2-cyclohexen-1-one 1,4-di-O-benzyl-L-threitol ketal were prepared and subjected to the Simmons-Smith cyclopropanation. From these experiments a mechanistic model for diastereoselective cyclopropanation of common ring systems (five-, six-, and seven-membered) has been formulated. Diastereoselectivity is thought to result from preferential chelation of the Simmons-Smith reagent at the least sterically hindered lone pair of electrons on the dioxolane oxygen proximal to the alkene. It is found that the presence of oxygen atoms in the dioxolane appendages provide sites for competitive chelation of the reagent, which can antagonize the diastereoselection due to chelation at dioxolane oxygen. That chelation by dioxolane oxygen does occur and is responsible for diastereoselectivity is inferred from studies with a hydrocarbon model system. Surprisingly, both dioxolane appendages are shown to be necessary for optimum diastereoselection since, under the conditions of the Simmons-Smith cyclopropanation, 2-cycloalken-1-one ethylene ketals are reversibly ring opened to zwitterionic intermediates. © 1990 American Chemical Society.
• Mash, E. A., Kaczynski, M. A., & Dolata, D. P. (1990). Diastereoselective manipulations of conformationally restricted enantiomerically pure bicyclo[m.1.0]alkanes. 1. Nucleophilic additions to the carbonyl carbons of bicyclo[m.1.0]alkan-2-ones. Tetrahedron Letters, 31(32), 4565-4568.
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  Abstract: Additions of nucleophiles to the carbonyls of several enantiomerically pure bicyclo[m.1.0]alkan-2-ones were found to be highly diastereoselective. © 1990.
• Halpert, J., Jaw, J. -., Cornfield, L. J., Balfour, C., & Mash, E. A. (1989). Selective inactivation of rat liver cytochromes P-450 by 21-chlorinated steroids. Drug Metabolism and Disposition, 17(1), 26-31.
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  PMID: 2566465;Abstract: The inactivation by 21-chlorinated steroids of rat liver cytochromes P-450 involved in the hydroxylation of progesterone and androstenedione has been investigated. Preincubation of intact liver microsomes from phenobarbital-treated rats with 21-chloropregnenolone, 21,21-dichloropregnenolone, or 21,21-dichloroprogesterone in the presence of NADPH caused a time-dependent decrease in progesterone 21-hydroxylase and in progesterone or androstenedione 6β-hydroxylase activity but had negligible or only minor effects on five other steroid hydroxylases. The compounds differed, however, with regard to the relative rate constants for inactivation of the 21- and 6β-hydroxylases. For example, 21,21-dichloroprogesterone and 21,21-dichloropregnenolone inactivated the progesterone 6β-hydroxylase at similar rates, but the dichloroprogesterone was a more effective inactivator of the 21-hydroxylase. The results indicate that the introduction of a dichloromethyl group into a substrate bearing a methyl group normally hydroxylated by only one or a few isozymes of cytochrome P-450 may be a rational means of designing isozyme-selective inhibitors but that target and nontarget enzymes may not totally retain the regioselectivity they exhibit towards the underivatized substrate.
• Mash, E. A., & Torok, D. S. (1989). Homochiral ketals in organic synthesis. Diastereoselective cyclopropanation of α,β-unsaturated ketals derived from (S,S)-(-)-hydrobenzoin. Journal of Organic Chemistry, 54(1), 250-253.
• Mash, E. A., Arterburn, J. B., & Fryling, J. A. (1989). Homochiral acetals in organic synthesis. A general enantioselective entry to carbohydrate derivatives from non-carbohydrate precursors. Tetrahedron Letters, 30(51), 7145-7148.
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  Abstract: A general chromatographic separation of furanosides and pyranosides derived from esters of lactic acid is disclosed. Application of this separation methodology to rapid syntheses of the diastereomers of (S)-methyl lactyl 4-deoxyribopyranose is described. © 1989.
• Mash, E. A., Math, S. K., & Arterburn, J. B. (1989). Homochiral ketals in organic synthesis. Diastereoselective cyclopropanation of medium and large ring α,α-unsaturated ketals derived from 1,4-di-O-benzyl-L-threitol. Journal of Organic Chemistry, 54(20), 4951-4953.
• Mash, E. A., Math, S. K., & Flann, C. J. (1989). Homochiral ketals in organic synthesis. Enantioselective synthesis and absolute configuration of (-)-modhephene. Tetrahedron, 45(16), 4945-4950.
• Halpert, J., Jaw, J., Balfour, C., Mash, E. A., & Johnson, E. F. (1988). Selective inactivation by 21-chlorinated steroids of rabbit liver and adrenal microsomal cytochromes P-450 involved in progesterone hydroxylation. Archives of Biochemistry and Biophysics, 264(2), 462-471.
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  PMID: 3261153;Abstract: The inactivation by 21-chlorinated steroids of rabbit liver cytochromes P-450 involved in the hydroxylation of progesterone has been investigated in intact microsomes encompassing two phenotypes of 21-hydroxylase activity, two phenotypes of 16α-hydroxylase activity, and three phenotypes of 6β-hydroxylase activity. In liver microsomes from outbred New Zealand White male rabbits exhibiting a high content of cytochrome P-450 1,21,21-dichloropregnenolone caused a time- and NADPH-dependent loss of 21-hydroxylase activity. This loss of activity exhibited a number of characteristics of mechanism-based inactivation, including irreversibility, saturation with increasing inhibitor concentrations, and protection by substrate, and was also documented with purified P-450 1 in a reconstituted system. 21,21-Dichloropregnenolone caused no time-dependent loss of 6β-hydroxylase activity in microsomes from the New Zealand White rabbits or from control or rifampicin-treated rabbits of the inbred B J strain. In contrast, in the microsomes from the B J rabbits, some inactivation of the 16α-hydroxylase was observed (k = 0.04 min-1), regardless of the rifampicin treatment. The other two compounds tested, 21-chloropregnenolone and 21,21-dichloroprogesterone, were less effective than the dichloropregnenolone as inactivators of cytochrome P-450 1. On the other hand, 21,21-dichloroprogesterone, but not 21,21-dichloropregnenolone, caused a rapid time-dependent loss of 21-hydroxylase activity in rabbit adrenal microsomes. The results indicate that the introduction of a dichloromethyl group into a substrate bearing a methyl group normally hydroxylated by only one or a few forms of cytochrome P-450 may be a rational means of designing selective inhibitors of the enzyme. © 1988.
• Mash, E. A., & Hemperly, S. B. (1988). Homochiral ketals in organic sythesis. Simple chromatographic resolution of diastereomeric α-hydroxycycloalkanone ketals. Tetrahedron Letters, 29(33), 4035-4038.
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  Abstract: A general method for the chromatographic resolution of diastereomeric α-hydroxycycloalkanone ketals derived from 1,4-di-O-benzyl-L-threitol is reported. Separability is thought to result from differences in intramolecular hydrogen bonding for the two diastereomeric forms. © 1988.
• Mash, E. A., Math, S. K., & Flann, C. J. (1988). Homochiral ketals in organic synthesis. Enantioselective preparation of (+)-modhephene. Tetrahedron Letters, 29(18), 2147-2150.
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  Abstract: Abstract: An efficient, enantioselective synthesis of the title compound 1 via diastereoselective cyclopropanation is described. © 1988 Pergamon Press plc.
• Mash, E. A. (1987). Homochiral ketals in organic synthesis. Enantioselective synthesis and absolute configuration of (-)-chokol A. Journal of Organic Chemistry, 52(18), 4142-4143.
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  Abstract: An enantioselective synthesis of (-)-chokol A from 2-methyl-2-cyclopenten-1-one is described. © 1987 American Chemical Society.
• Mash, E. A., & Fryling, J. A. (1987). Homochiral ketals in organic synthesis. Enantioselective synthesis of (+)-β-eudesmol. Journal of Organic Chemistry, 52(14), 3000-3003.
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  Abstract: An enantioselective preparation of (+)-β-eudesmol employing a diastereoselective Simmons-Smith cyclopropanation is described. Cyclopropanation of a bicyclic enone precursor is directed by use of the corresponding (2S,3S)-2,3-butanediol ketal. The overall yield of (+)-β-eudesmol (75% ee) from racemic 7-carbomethoxy-3,4,5,6,7,8-hexahydronaphthalen-1(2H)-one is 25% over eight steps. © 1987 American Chemical Society.
• Mash, E. A., & Nelson, K. A. (1987). Homochiral ketals in organic synthesis. Diastereoselective cyclopropanation of α,β-unsaturated ketals derived from 1,4-D1-O-benzyl-l-threitol. Tetrahedron, 43(4), 679-692.
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  Abstract: 2-Cycloalken-1-one 1,4-di -O-benzyl -L-threitol ketals undergo efficient and diastereoselective cyclopropanation when treated with an excess of the Simmons-Smith reagent. For example, 2-cyclohexen-1-one 1,4-di -O-benzyl -L-threitol ketal gave in 90-98% yield a 9:1 mixture of diastereomeric cyclopropanes as established by 62.9 MHz 13C NMR spectroscopy and by hydrolysis of the mixture to (1R,6S)-bicyclo[4.1.0] heptan-2-one. Sixteen other examples are presented which demonstrate the generality and predictability of the process for 2-cycloalken-1-one ketals, as wall as an unfortunate lack of diastereoselectivity for α,β-unsaturated 1,4-di-O-benzyl-L-threitol acetals. © 1987.
• Mash, E. A., Nelson, K. A., & Heidt, P. C. (1987). Diastereoselective cyclopropanation via homochiral ketals. Dioxolane structural effects. Tetrahedron Letters, 28(17), 1865-1868.
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  Abstract: A series of 2-cyclohexen-1-one ketals related to 2-cyclohexen-1-one 1,4-di- O-benzyl-L-threitol ketal but possesing different dioxolane appendages was prepared and subjected to Simmons-Smith cycloproponation. The observed diastereoselectivity decreased when oxygen was present in the appendages. In the absence of appendage oxygen, the sense of the observed diastereoselectivity was found to depend upon dioxolane chirality. The amount of diastereoselectivity observed was remarkably independent of the nature of the appendages. © 1987.
• Mash, E. A., & Nelson, K. A. (1986). Homochiral ketals in organic synthesis. Enantioselective synthesis of [m.n.1] Propellanones. Tetrahedron Letters, 27(13), 1441-1444.
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  Abstract: Optically active [m.n.1]propellanones have been prepared by diastereoselective cyclopropanation of homochiral one ketals derived from 1,4-di-O-benzyl-L-threitol and readily available bicyclic enones. © 1986.
• Nelson, K. A., & Mash, E. A. (1986). Homochiral ketals in organic synthesis. Enantioselective synthesis of (R)-muscone. Journal of Organic Chemistry, 51(14), 2721-2724.
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  Abstract: An efficient, enantioselective preparation of (R)-muscone employing a diastereoselective Simmons-Smith cyclopropanation is described. Cyclopropanation is directed via chelation control by a homochiral ketal protecting group derived from unnatural tartaric acid. The overall yield of (R)-muscone (>95% R) from commercially available cyclopentadecanone is 60% over seven steps. © 1986 American Chemical Society.
• Mash, E. A., & Nelson, K. A. (1985). Homochiral ketals in organic synthesis. Diastereoselective cyclopropanation. Journal of the American Chemical Society, 107(26), 8256-8258.
• Mash, E. A., Gurria, G. M., & Poulter, C. D. (1981). Farnesylpyrophosphate synthetase. Evidence for a rigid geranyl cation-pyrophosphate anion pair. Journal of the American Chemical Society, 103(13), 3927-3929.
• Poulter, C. D., Mash, E. A., Argyle, J. C., Muscio, O. J., & Rilling, H. C. (1979). Farnesyl pyrophosphate synthetase. Mechanistic studies of the 1′-4 coupling reaction in the terpene biosynthetic pathway [13]. Journal of the American Chemical Society, 101(22), 6761-6763.
• Poulter, C. D., Argyle, J. C., & Mash, E. A. (1978). Farnesyl pyrophosphate synthetase. Mechanistic studies of the 1'-4 coupling reaction with 2-fluorogeranyl pyrophosphate.. Journal of Biological Chemistry, 253(20), 7227-7233.
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  PMID: 701246;Abstract: The mechanism of the 1'-4 coupling reaction between isopentenyl pyrophosphate and geranyl pyrophosphate catalyzed by farnesyl pyrophosphate synthetase from porcine liver was studied with the allylic substrate analogue 2-fluorogeranyl pyrophosphate. 2-Fluorogeranyl pyrophosphate is an alternate substrate for the enzyme, yielding 6-fluorofarnesyl pyrophosphate upon condensation with isopentenyl pyrophosphate. The Michaelis constant for the fluoroanalogue, Km = 1.1 micron, is similar to that measured for geranyl pyrophosphate, Km = 0.7 micron. However, the rate of condensation with the fluoroanalogue was only 8.4 X 10(-4) that of the normal reaction. A similar rate of depression (4.4 X 10(-3)) was found for solvolysis of geranyl methanesulfonate and the corresponding 2-fluoro derivative, reactions known to proceed via cationic intermediates. In contrast, displacement of chlorine from geranyl chloride and 2-fluorogeranyl chloride by cyanide showed a small (2-fold) rate enhancement for the fluoro compound. Finally, 2-fluorogeranyl pyrophosphate is a competitive inhibitor against geranyl pyrophosphate. These data are interpreted in terms of an ionization-condensation-elimination mechanism for the 1'-4 coupling reaction.
• Poulter, C. D., Argyle, J. C., & Mash, E. A. (1977). Prenyltransferase. New evidence for an ionization-condensation-elimination mechanism with 2-fluorogeranyl pyrophosphate [15]. Journal of the American Chemical Society, 99(3), 957-959.
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  PMID: 833388;

Poster Presentations

• Elshan, N., Jayasundera, T., Vagner, J., Lynch, R., & Mash, E. (2013). Development of Multivalent Scaffolds Displaying Biologically Active Ligands. 245st ACS National Meeting. New Orleans, LA.
• Moses, S. A., Jandova, J., Zhang, S., Mash, E. A., & Meuillet, E. J. (2013). Targeting the PH domain of TIAM1 to inhibit prostate cancer metastasis.. American Association for Cancer Research Meeting, Tumor metastasis and invasion. San Diego: AACR.
• Dehigaspitiya, D., Navath, S., Elshan, N., Weber, C., Lynch, R., & Mash, E. (2012). Design and Synthesis of Multivalent Compounds for Imaging of Cancer. 244th ACS National Meeting. Philadelphia, PA.
• Mash, E. (2012). GI-Specific Imaging and Drug Delivery. C. D. Poulter Symposium. Salt Lake City, UT.