Christopher Hulme

Interests

Research

Drug Discovery, Medicinal Chemistry, DOS, Multicomponent Reactions

Teaching

Medicinal Chemistry, Organic Chemistry, Drug Discovery

Courses

Scholarly Contributions

Books

• Hulme, C., Ayaz, M., Martinez-Ariza, G., Medda, F., & Shaw, A. Y. (2015). Recent Advances in Multi-component Reaction Chemistry: Applications in Small Molecule Drug Discovery. Chapter 6: Wiley-VCH.

Chapters

• Hulme, C. (2022).

  Recent Applications of Multicomponent Reactions Toward Heterocyclic Drug Discovery.

  . In Multicomponent Reactions towards Heterocycles, Wiley-VCH Ed.,(pp 339-409).

Journals/Publications

• Hulme, C., & Dunckley, T. (2022). The Omnipresence of DYRK1A in Human Diseases. Int. J. Mol. Sci, 23, 9355.
• Hulme, C., & Hodge, J. (2022). DYRK1a antagonists rescue degeneration and behavioral deficits of in vivo models of Alzheimer’s disease and Down’s Syndrome. Nature Scientific Reports, 12, 1-14.
• Hulme, C., & Hooshmand, S. (2022). Six-Component Reactions and Beyond: The Nuts and Bolts.. Eur. J. Org. Chem.
• Hulme, C., Branca, C., Shaw, D., Belfiore, R., Gokhale, V., Shaw, A., Foley, C., Dunckley, T., Cacomol, A., & Oddo, S. (2016). Dyrk1 inhibition improves Alzheimer’s disease-like pathology.. Molecular Degeneration.
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  Note: this paper required a year long legal agreement as the in vivo pharmacologist refused to release the data unless we agreed to give him 10% equity in any value creation and sole starred authorship on the first paper. Under any normal circumstances I would have been lead author on this paper. A revision was requested as the structure of the molecule is not being revealed at this stage.
• Hulme, C., Foley, C., & Shaw, A. (2018). Aza-Riley Oxidation of Ugi-Azide and Ugi-3CR Products toward Vicinal Tricarbonyl Amides: Two step MCR-Oxidation Methodology Accessing Functionalized α,β-diketoamides and α,β-diketotetrazoles.. Organic Letters, 20(5), 1275-1278.
• Hulme, C., Foley, C., & Wang, J. (2018). Exploring Ugi-Azide Four-Component Reaction Products for Broad-Spectrum Influenza Antivirals with a High Genetic Barrier to Drug Resistance. Scientific Reports, 8, 4653.
• Hulme, C., Pinho, L., Martinez-Arisa, G., & Day, K. (2016). Synthesis of Fluorescent Heterocycles via a Knoevenagel/ [4+1]-Cycloaddition Cascade Using Acetyl Cyanide.. Organic and Bio-molecular Chemistry.
• Hulme, C., Vanden Eynde, J., Mangoni, A., Rautio, J., Leprince, J., Azuma, Y., & Muñoz-Torrero, D. (2020). Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–6.. Molecules, 25, 119.
• Schofield, K., Foley, C., & Hulme, C. (2021). 5- Trig Oxidative Radical Cyclizations of Ugi-3CR Products toward 1,4-Imidazolidinones. Organic letters, 23(1), 107-112.
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  A 5- trig oxidative radical cyclization of benzylamine-derived Ugi three-component reaction products rapidly affords imidazolidinones with three diversity elements. This adaptation of our previously described multicomponent reaction-oxidation methodology further showcases manipulation of the diversity elements in multicomponent reaction products via oxidative radical cyclizations, which generates highly decorated privileged heterocycles.
• Mangoni, A. A., Eynde, J. J., Jampilek, J., Hadjipavlou-Litina, D., Liu, H., Reynisson, J., Sousa, M. E., Gomes, P. A., Prokai-Tatrai, K., Tuccinardi, T., Sabatier, J. M., Luque, F. J., Rautio, J., Karaman, R., Vasconcelos, M. H., Gemma, S., Galdiero, S., Hulme, C., Collina, S., , Gütschow, M., et al. (2019). Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-5. Molecules (Basel, Switzerland), 24(13).
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  Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials which is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal [...].
• Vanden Eynde, J. J., Mangoni, A. A., Rautio, J., Leprince, J., Azuma, Y. T., García-Sosa, A. T., Hulme, C., Jampilek, J., Karaman, R., Li, W., Gomes, P. A., Hadjipavlou-Litina, D., Capasso, R., Geronikaki, A., Cerchia, L., Sabatier, J. M., Ragno, R., Tuccinardi, T., Trabocchi, A., , Winum, J. Y., et al. (2019). Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-6. Molecules (Basel, Switzerland), 25(1).
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  Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials that is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal [...].
• Velazquez, R., Meechoovet, B., Ow, A., Foley, C., Shaw, A., Smith, B., Oddo, S., Hulme, C., & Dunckley, T. (2019). Chronic Dyrk1 Inhibition Delays the Onset of AD-Like Pathology in 3xTg-AD Mice. Molecular Neurobiology, 1-12.
• Mangoni, A. A., Guillou, C., Vanden Eynde, J. J., Hulme, C., Jampilek, J., Li, W., Prokai-Tatrai, K., Rautio, J., Collina, S., Tuccinardi, T., Sousa, M. E., Sabatier, J. M., Galdiero, S., Karaman, R., Kokotos, G., Torri, G., Luque, F. J., Vasconcelos, M. H., Hadjipavlou-Litina, D., , Siciliano, C., et al. (2018). Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes⁻4. Molecules (Basel, Switzerland), 24(1).
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  Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials, which is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal . [...].
• Mangoni, A. A., Tuccinardi, T., Collina, S., Vanden Eynde, J. J., Muñoz-Torrero, D., Karaman, R., Siciliano, C., de Sousa, M. E., Prokai-Tatrai, K., Rautio, J., Guillou, C., Gütschow, M., Galdiero, S., Liu, H., Agrofoglio, L. A., Sabatier, J. M., Hulme, C., Kokotos, G., You, Q., & Gomes, P. A. (2018). Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-3. Molecules (Basel, Switzerland), 23(7).
• Zhang, J., Hu, Y., Foley, C., Wang, Y., Musharrafieh, R., Xu, S., Zhang, Y., Ma, C., Hulme, C., & Wang, J. (2018). Exploring Ugi-Azide Four-Component Reaction Products for Broad-Spectrum Influenza Antivirals with a High Genetic Barrier to Drug Resistance. Scientific reports, 8(1), 4653.
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  Influenza viruses are respiratory pathogens that are responsible for seasonal influenza and sporadic influenza pandemic. The therapeutic efficacy of current influenza vaccines and small molecule antiviral drugs is limited due to the emergence of multidrug-resistant influenza viruses. In response to the urgent need for the next generation of influenza antivirals, we utilized a fast-track drug discovery platform by exploring multi-component reaction products for antiviral drug candidates. Specifically, molecular docking was applied to screen a small molecule library derived from the Ugi-azide four-component reaction methodology for inhibitors that target the influenza polymerase PA-PB1 interactions. One hit compound 5 was confirmed to inhibit PA-PB1 interactions in an ELISA assay and had potent antiviral activity in an antiviral plaque assay. Subsequent structure-activity relationship studies led to the discovery of compound 12a, which had broad-spectrum antiviral activity and a higher in vitro genetic barrier to drug resistance than oseltamivir. Overall, the discovery of compound 12a as a broad-spectrum influenza antiviral with a high in vitro genetic barrier to drug resistance is significant, as it offers a second line of defense to combat the next influenza epidemics and pandemics if vaccines and oseltamivir fail to confine the disease outbreak.
• Branca, C., Shaw, D. M., Belfiore, R., Gokhale, V., Shaw, A. Y., Foley, C., Smith, B., Hulme, C., Dunckley, T., Meechoovet, B., Caccamo, A., & Oddo, S. (2017). Dyrk1 inhibition improves Alzheimer's disease-like pathology. Aging cell, 16(5), 1146-1154.
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  There is an urgent need for the development of new therapeutic strategies for Alzheimer's disease (AD). The dual-specificity tyrosine phosphorylation-regulated kinase-1A (Dyrk1a) is a protein kinase that phosphorylates the amyloid precursor protein (APP) and tau and thus represents a link between two key proteins involved in AD pathogenesis. Furthermore, Dyrk1a is upregulated in postmortem human brains, and high levels of Dyrk1a are associated with mental retardation. Here, we sought to determine the effects of Dyrk1 inhibition on AD-like pathology developed by 3xTg-AD mice, a widely used animal model of AD. We dosed 10-month-old 3xTg-AD and nontransgenic (NonTg) mice with a Dyrk1 inhibitor (Dyrk1-inh) or vehicle for eight weeks. During the last three weeks of treatment, we tested the mice in a battery of behavioral tests. The brains were then analyzed for the pathological markers of AD. We found that chronic Dyrk1 inhibition reversed cognitive deficits in 3xTg-AD mice. These effects were associated with a reduction in amyloid-β (Aβ) and tau pathology. Mechanistically, Dyrk1 inhibition reduced APP and insoluble tau phosphorylation. The reduction in APP phosphorylation increased its turnover and decreased Aβ levels. These results suggest that targeting Dyrk1 could represent a new viable therapeutic approach for AD.
• Collet, J. W., Foley, C., Shaw, A. Y., Orru, R. V., Ruijter, E., & Hulme, C. (2017). Copper(i) catalyzed oxidative hydrolysis of Ugi 3-component and Ugi-azide reaction products towards 2° α-ketoamides and α-ketotetrazoles. Organic & biomolecular chemistry, 15(29), 6132-6135.
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  Herein, a two-step MCR-oxidation methodology accessing decorated 2° α-ketoamides and α-ketotetrazoles is described via a catalytic copper(i)-mediated C-N oxidation/acidic hydrolysis of Ugi-three-component and Ugi-azide reaction products. The ability to install diversity from aldehyde and isocyanide synthons allows rapid complexity generation. Of note, (1) 2° α-ketoamides are traditionally difficult to access and more so reminiscent of the endogenous peptide bonds. (2) The route to α-keto-tetrazoles is significantly shorter than that in previous reports.
• Foley, C., Shaw, A., & Hulme, C. (2017). Oxidative Deaminations and Deisatinylations of Ugi-Azide and Ugi-3CR Products: A Two-Step MCR-Oxidation Protocol toward Functionalized α-Ketoamides and α-Ketotetrazoles. Organic letters, 19(9), 2238-2241.
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  A new postcondensation multicomponent reaction (MCR) methodology, comprising oxidative deaminations enabling access to multiple privileged carbonyl-containing scaffolds in two steps, is described. These protocols allow facile access to functionalized α-ketoamide and α-ketotetrazole small-molecule peptidomimetic-like building blocks from prototypical synthons with two points of diversity. Incorporation of chalcone and alkynyl moieties with further ring-forming reactions enables access to additional novel heterocyclic ring systems, including a unique and potentially highly pharmacologically relevant scaffold, a 1,2-selenazol-3(2H)-one.
• Martinez-Ariza, G., Mehari, B. T., Pinho, L. A., Foley, C., Day, K., Jewett, J. C., & Hulme, C. (2017). Synthesis of fluorescent heterocycles via a Knoevenagel/[4 + 1]-cycloaddition cascade using acetyl cyanide. Organic & biomolecular chemistry, 15(29), 6076-6079.
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  A concise one-pot three-component reaction that affords fluorescent indolizines, benzo[d]pyrrolo[2,1-b]thiazoles, and pyrrolo[1,2-a]pyrazines is reported. The methodology involves the formation of a heterocyclic 1-aza-1,3-diene derived from a Knoevenagel condensation between an aldehyde and 2-methyl-ene-cyano aza-heterocycles, followed by [4 + 1] cycloaddition of acetyl cyanide behaving as a non-classical isocyanide replacement.
• Muñoz-Torrero, D., Mangoni, A. A., Guillou, C., Collina, S., Vanden Eynde, J. J., Rautio, J., Keserű, G. M., Hulme, C., Chibale, K., Luque, F. J., Karaman, R., Gütschow, M., Liu, H., & Ragno, R. (2017). Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes. Molecules (Basel, Switzerland), 22(5).
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• Muñoz-Torrero, D., Mangoni, A. A., Liu, H., Hulme, C., Rautio, J., Karaman, R., de Sousa, M. E., Prokai-Tatrai, K., Sabatier, J. M., Siciliano, C., Luque, F. J., Kokotos, G., Ragno, R., Collina, S., Guillou, C., Gütschow, M., & Agrofoglio, L. A. (2017). Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-2. Molecules (Basel, Switzerland), 23(1).
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  Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials, which are published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules [...].
• Foley, C., Shaw, A., & Hulme, C. (2016). Two-Step Route to Diverse N-Functionalized Peptidomimetic-like Isatins through an Oxidation/Intramolecular Oxidative-Amidation Cascade of Ugi Azide and Ugi Three-Component Reaction Products. Organic letters, 18(19), 4904-4907.
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  Two-step methodology described herein showcases the first example of an oxidation/oxidative amidation cyclization cascade of MCR products toward diverse N-functionalized isatins. Products of both the Ugi 3CR and the Ugi azide reactions are oxidatively cyclized through a postcondensation process utilizing selenium dioxide. This methodology was found to be applicable for the generation of bis-peptidomimetic-like isatins containing multiple points of diversification.
• Hulme, C., Foley, C., & Shaw, A. (2016). Two step route to diverse N-functionalized peptidomimetic-like Isatins through an oxidation/intramolecular oxidative-amidation cascade of Ugi-azide and Ugi-3CR reaction products.. Organic Letters, 18, 4904-4907.
• Hulme, C., Martinez-Arisa, G., & McConnell, N. (2016). One-pot, Two-step Multicomponent process of Indole and other Nitrogenous heterocycles or amines toward -Oxo-acetamidines. Organic Letters, 18, 4904-4907.
• Martinez-Ariza, G., McConnell, N., & Hulme, C. (2016). One-Pot Two-Step Multicomponent Process of Indole and Other Nitrogenous Heterocycles or Amines toward α-Oxo-acetamidines. Organic letters, 18(8), 1864-7.
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  A cesium carbonate promoted three-component reaction of N-H containing heterocycles, primary or secondary amines, arylglyoxaldehydes, and anilines is reported. The key step involves a tandem sequence of N-1 addition of a heterocycle or an amine to preformed α-iminoketones, followed by an air- or oxygen-mediated oxidation to form α-oxo-acetamidines. The scope of the reaction is enticingly broad, and this novel methodology is applied toward the synthesis of various polycyclic heterocycles.
• Hulme, C., Martinez-Ariza, G., Lee, Y., & Nunez-Rios, J. (2015). Acetyl cyanide as a cyanide source in a tandem catalyst-free [4+1] cycloaddition-Strecker cascade.. Tetrahderon Letters, 56, 1038-1040.
• Hulme, C., Medda, F., & Martinez-Ariza, G. (2015). A facile and rapid route toward the synthesis of novel imidazo-tetrazolodiazepinones via post-condensation modifications of the Ugi-azide adduct.. Tetrahedron Letters, 56, 5295-5298.
• Martinez-Ariza, G., & Hulme, C. (2015). Recent advances in allosteric androgen receptor inhibitors for the potential treatment of castration-resistant prostate cancer. Pharmaceutical patent analyst, 4(5), 387-402.
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  Prostate cancer (PC) is the second most frequent cause of male cancer death in the USA. As such, the androgen receptor (AR) plays a crucial role in PC, making AR the major therapeutic target for PC. Current antiandrogen chemotherapy prevents androgen binding to the ligand-binding pocket (LBP) of AR. However, PC frequently recurs despite treatment and it progresses to castration-resistant prostate cancer. Behind this regression is renewed AR signaling initiated via mutations in the LBP. Hence, there is a critical need to improve the therapeutic options to regulate AR activity in sites other than the LBP. Herein, recently disclosed (2010-2015) allosteric AR inhibitors are summarized and a perspective on the potential pharmaceutical intervention at these sites is provided.
• Martinez-Ariza, G., Ayaz, M., Roberts, S. A., Rabanal-León, W. A., Arratia-Pérez, R., & Hulme, C. (2015). The Synthesis of Stable, Complex Organocesium Tetramic Acids through the Ugi Reaction and Cesium-Carbonate-Promoted Cascades. Angewandte Chemie (International ed. in English), 54(40), 11672-6.
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  Two structurally unique organocesium carbanionic tetramic acids have been synthesized through expeditious and novel cascade reactions of strategically functionalized Ugi skeletons delivering products with two points of potential diversification. This is the first report of the use of multicomponent reactions and subsequent cascades to access complex, unprecedented organocesium architectures. Moreover, this article also highlights the first use of mild cesium carbonate as a cesium source for the construction of cesium organometallic scaffolds. Relativistic DFT calculations provide an insight into the electronic structure of the reported compounds.
• Rabanal-Leon, W. A., Martinez-Ariza, G., Roberts, S. A., Hulme, C., & Arratia-Perez, R. (2015). Computational Study of Organo-Cesium Complexes and the Possibility of Lanthanide/Actinide ions Substitution. Chemical Physical Letters, 641, 181-186.
• Roberts, S. A., Martinez-Ariza, G., & Hulme, C. (2015). Crystal structures of N-tert-butyl-3-(4-fluoro-phenyl)-5-oxo-4-[2-(tri-fluoro-meth-oxy)phen-yl]-2,5-di-hydro-furan-2-carboxamide and 4-(2H-1,3-benzodioxol-5-yl)-N-cyclo-hexyl-5-oxo-3-[4-(tri-fluoro-meth-yl)phen-yl]-2,5-di-hydro-furan-2-carboxamide. Acta crystallographica. Section E, Crystallographic communications, 71(Pt 2), 199-202.
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  The title compounds, C22H19F4NO4, (I), and C25H22F3NO5, (II), each contain a central nearly planar di-hydro-furan-one ring. The r.m.s. deviation from planarity of these rings is 0.015 Å in (I) and 0.027 Å in (II). The mol-ecules are T-shaped, with the major conformational difference being the O-C-C-O torsion angle [-178.9 (1) in (I) and 37.7 (2)° in (II)]. In the crystal of (I), mol-ecules are linked by N-H⋯O hydrogen bonds, forming chains along [001] while in (II) mol-ecules are linked by N-H⋯O hydrogen bonds, forming chains along [010]. In (II), the tri-fluoro-methyl substituent is disordered over two sets of sites, with refined occupancies of 0.751 (3) and 0.249 (3).
• Tsai, L. L., Xie, L., Dore, K., Xie, L., Del Rio, J. C., King, C. C., Martinez-Ariza, G., Hulme, C., Malinow, R., Bourne, P. E., & Newton, A. C. (2015). Zeta Inhibitory Peptide Disrupts Electrostatic Interactions That Maintain Atypical Protein Kinase C in Its Active Conformation on the Scaffold p62. The Journal of biological chemistry, 290(36), 21845-56.
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  Atypical protein kinase C (aPKC) enzymes signal on protein scaffolds, yet how they are maintained in an active conformation on scaffolds is unclear. A myristoylated peptide based on the autoinhibitory pseudosubstrate fragment of the atypical PKCζ, zeta inhibitory peptide (ZIP), has been extensively used to inhibit aPKC activity; however, we have previously shown that ZIP does not inhibit the catalytic activity of aPKC isozymes in cells (Wu-Zhang, A. X., Schramm, C. L., Nabavi, S., Malinow, R., and Newton, A. C. (2012) J. Biol. Chem. 287, 12879-12885). Here we sought to identify a bona fide target of ZIP and, in so doing, unveiled a novel mechanism by which aPKCs are maintained in an active conformation on a protein scaffold. Specifically, we used protein-protein interaction network analysis, structural modeling, and protein-protein docking to predict that ZIP binds an acidic surface on the Phox and Bem1 (PB1) domain of p62, an interaction validated by peptide array analysis. Using a genetically encoded reporter for PKC activity fused to the p62 scaffold, we show that ZIP inhibits the activity of wild-type aPKC, but not a construct lacking the pseudosubstrate. These data support a model in which the pseudosubstrate of aPKCs is tethered to the acidic surface on p62, locking aPKC in an open, signaling-competent conformation. ZIP competes for binding to the acidic surface, resulting in displacement of the pseudosubstrate of aPKC and re-engagement in the substrate-binding cavity. This study not only identifies a cellular target for ZIP, but also unveils a novel mechanism by which scaffolded aPKC is maintained in an active conformation.
• Xu, Z., Martinez-Ariza, G., Cappelli, A. P., Roberts, S. A., & Hulme, C. (2015). (Z)-Stereoselective Synthesis of Mono- and Bis-heterocyclic Benzimidazol-2-ones via Cascade Processes Coupled with the Ugi Multicomponent Reaction. The Journal of organic chemistry, 80(18), 9007-15.
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  Several novel cascade reactions are herein reported that enable access to a variety of unique mono- and bis-heterocyclic scaffolds. The sequence of cascade events are mediated through acid treatment of an Ugi adduct that affords 1,5-benzodiazepines which subsequently undergo an elegant rearrangement to deliver (E)-benzimidazolones, which through acid-promoted tautomerization convert to their corresponding (Z)-isomers. Moreover, a variety of heterocycles tethered to (Z)-benzimidazole-2-ones are also accessible through similar domino-like processes, demonstrating a general strategy to access significantly new scaffold diversity, each containing four points of potential diversification. Final structures of five scaffolds have been definitively proven by X-ray crystallography.
• Ayaz, M., Xu, Z., & Hulme, C. (2014). Novel succinct routes to Quinoxalines and 2-Benzimidazolylquinoxalines via the Ugi reaction. Tetrahedron letters, 55(23), 3406-3409.
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  This communication reveals a unique, user-friendly, concise two-step, one-pot protocol for the synthesis of highly substituted quinoxalines. Conducting the Ugi reaction with appropriately functionalized classical Ugi reagents with subsequent acid treatment of the Ugi adduct affords collections of diversified quinoxalines in good to excellent yields. The methodology exploits what may be viewed as a 'convertible carboxylic acid', which in addition may be captured in an intramolecular sense to generate structurally complex 2-benzimidazolylquinoxalines in a mere two steps.
• Bell, C. E., Shaw, A. Y., De Moliner, F., & Hulme, C. (2014). MCRs reshaped into a switchable microwave-assisted protocol toward 5-aminoimidazoles and dihydrotriazines. Tetrahedron, 7(1), 54-59.
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  A tunable microwave-assisted protocol for the synthesis of two biologically relevant families of heterocycles has been designed. Via a simple switch of reaction conditions, the same starting materials can be engaged in either an improved synthesis of the dihydrotriazine scaffold or a novel, first-in-class MCR to render the challenging 5-aminoimidazole nucleus in a single step. An additional first in class MCR is also reported utilizing guanidines to afford 2,5-aminoimidazoles.
• Bell, C. E., Shaw, A. Y., Moliner, F. D., & Hulme, C. (2014). MCRs reshaped into a switchable microwave-assisted protocol toward 5-aminoimidazoles and dihydrotriazines. Tetrahedron, 70(1), 54-59.
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  Abstract: A tunable microwave-assisted protocol for the synthesis of two biologically relevant families of heterocycles has been designed. Via a simple switch of reaction conditions, the same starting materials can be engaged in either an improved synthesis of the dihydrotriazine scaffold or a novel, first-in-class MCR to render the challenging 5-aminoimidazole nucleus in a single step. An additional first-in-class MCR is also reported utilizing guanidines to afford 2,5-aminoimidazoles. © 2013 Elsevier Ltd. All rights reserved.
• Chen, Y., Lu, P., Hulme, C., & Shaw, A. Y. (2014). Synthesis of (E)-5-methoxy-2-styryl-4-pyrones as potent growth-inhibitory agents against hepatocellular carcinoma cells. Journal of Heterocyclic Chemistry, 51(1), 56-61.
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  Abstract: The present study a series of (E)-5-methoxy-2-styryl-4H-pyran-4-ones 6a, 6b, 6c, 6d, 6e, 6f, 6g, 6h, 6i, 6j was synthesized and evaluated for growth inhibitory inhibition against carcinoma cells. The growth inhibition study of eight carcinoma cell lines was examined and demonstrated that SKHep cells exhibit significant structure-activity relationship in response to the tested compounds. Among them, 6f showed the most potent activity against SKHep, A549, AGS, and H460 cell lines with GI50 values of 0.17, 8.3, 3.6, 8.0 μM, respectively. © 2013 HeteroCorporation.
• Kusne, Y., Carrera-Silva, E. A., Perry, A. S., Rushing, E. J., Mandell, E. K., Dietrich, J. D., Errasti, A. E., Gibbs, D., Berens, M. E., Loftus, J. C., Hulme, C., Yang, W., Lu, Z., Aldape, K., Sanai, N., Rothlin, C. V., & Ghosh, S. (2014). Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNFα in glioblastoma. Science signaling, 7(338), ra75.
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  Grade IV glioblastoma is characterized by increased kinase activity of epidermal growth factor receptor (EGFR); however, EGFR kinase inhibitors have failed to improve survival in individuals with this cancer because resistance to these drugs often develops. We showed that tumor necrosis factor-α (TNFα) produced in the glioblastoma microenvironment activated atypical protein kinase C (aPKC), thereby producing resistance to EGFR kinase inhibitors. Additionally, we identified that aPKC was required both for paracrine TNFα-dependent activation of the transcription factor nuclear factor κB (NF-κB) and for tumor cell-intrinsic receptor tyrosine kinase signaling. Targeting aPKC decreased tumor growth in mouse models of glioblastoma, including models of EGFR kinase inhibitor-resistant glioblastoma. Furthermore, aPKC abundance and activity were increased in human glioblastoma tumor cells, and high aPKC abundance correlated with poor prognosis. Thus, targeting aPKC might provide an improved molecular approach for glioblastoma therapy.
• Martinez-Ariza, G., Ayaz, M., Medda, F., & Hulme, C. (2014). Synthesis of diverse nitrogen-enriched heterocyclic scaffolds using a suite of tunable one-pot multicomponent reactions. The Journal of organic chemistry, 79(11), 5153-62.
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  Five elegant and switchable three-component reactions which enable access to a new series of nitrogen-containing heterocycles are reported. A novel one-step addition of an isocyanide to a hydrazine derived Schiff base affords unique six-membered pyridotriazine scaffolds (A and E). With slight modification of reaction conditions and replacement of the nucleophilic isocyanide moiety with different electrophiles (i.e., isocyanates, isothiocyanates, cyclic anhydrides, and acyl chlorides) five-membered triazolopyridine scaffolds (B, D, F, G) are generated in a single step. Furthermore, the use of phenyl hydrazine enables access to dihydroindazole-carboxamides, devoid of a bridge-head nitrogen (C). All protocols are robust and tolerate a diverse collection of reactants, and as such, it is expected that the new scaffolds and associated chemistry will garner high interest from medicinal chemists involved in either file enhancement or specific target-related drug discovery campaigns.
• Medda, F., & Hulme, C. (2014). Exploiting the Divalent Nature of Isonitriles: a novel Pictet-Spengler Amidination process. Tetrahedron letters, 55(22), 3328-3331.
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  An isocyanide-based multicomponent reaction (IMCR) utilized for the rapid assembly of novel, biologically relevant dihydropyrrolo[1,2-a]quinoxalines-amidines is herein presented. Starting from 1-(2-aminophenyl)pyrroles, aldehydes, and isonitriles, the target heterocyclic scaffold is assembled in a one-pot, operationally friendly process. With three points of diversity and formation of three chemical bonds in one step, this strategy proves to be very general. Novel, mild methodology for the generation of amidines from secondary amine anilines and isonitriles is also introduced.
• Zhigang, X. u., Moliner, F. D., Cappelli, A. P., Ayaz, M., & Hulme, C. (2014). Expeditious routes to polycyclic molecular frameworks via one-pot, two-step Ugi ring-closing sequences. Synlett, 25(2), 225-228.
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  Abstract: A very general and robust multicomponent-reaction protocol involving an Ugi condensation between ethyl glyoxylate, isonitriles, N-Boc-α-amino acids, and mono-N-Boc-protected diamines followed by a series of acid-promoted cyclization steps in a one-pot fashion is reported. This process allows for the assembly of complex polycyclic structures by means of just two simple synthetic operations and a single chromatographic purification in high overall yields. Of note, the first scaffolds derived from a highly Âselective sequence of ring-closing events involving three internal amino nucleophiles is reported. © Georg Thieme Verlag Stuttgart New York.
• Chen, Y., Lu, P., Hulme, C., & Shaw, A. Y. (2013). Synthesis of kojic acid-derived copper-chelating apoptosis inducing agents. Medicinal Chemistry Research, 22(2), 995-1003.
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  Abstract: Three classes of kojic acid derivatives were synthesized and examined for their antiproliferative activity against HeLa cells. Both 8b and 11 co-treated with copper ion exhibited synergistic effect on the HeLa cell growth inhibition with GI50 values of 11.9 and 7.1 μM, respectively. Flow cytometric analysis of HeLa cells revealed that 11-Cu co-treatment induced the sub-G1 arrest in a dose-dependent manner, suggesting that the growth-inhibitory effect is attributed to DNA fragmentation. Moreover, western blot of HeLa cells cytosolic extracts displayed the cleavage of the 116-kDa protein poly(ADP-ribose) polymerase and activation of caspase-3 by the reduced level of the 32-kDa proenzyme, indicating that the caspase-dependent apoptotic pathway was involved. We further demonstrated that MAPK pathway regulators such as ERK and p38 were activated in response to 11-Cu co-treatment, suggesting that the intracellular oxidative stress was dramatically stimulated by the copper ion. Taken together, we have successfully synthesized kojic acid-derived copper-induced apoptotic agents. © 2012 Springer Science+Business Media, LLC.
• Gunawan, S., & Hulme, C. (2013). Bifunctional building blocks in the Ugi-azide condensation reaction: A general strategy toward exploration of new molecular diversity. Organic and Biomolecular Chemistry, 11(36), 6036-6046.
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  PMID: 23912086;PMCID: PMC3795786;Abstract: 1,5-Disubstituted tetrazoles are an important drug-like scaffold known for their ability to mimic the cis-amide bond conformation. The scaffold is readily accessible via substitution of the carboxylic acid component of the Ugi multi-component reaction (MCR) with TMSN3 in what is herein denoted the Ugi-azide reaction. This full paper presents a concise, novel, general strategy to access a plethora of new heterocylic scaffolds utilizing tethered aldo/keto-acids/esters in the Ugi-azide reaction followed by a ring closing event that generates novel highly complex bis-heterocyclic lactam-tetrazoles. This journal is © The Royal Society of Chemistry.
• Gunawan, S., & Hulme, C. (2013). Construction of functionalized tricyclic dihydropyrazino-quinazolinedione chemotypes via an Ugi/N-acyliminium ion cyclization cascade. Tetrahedron Letters, 54(33), 4467-4470.
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  Abstract: Dihydropyrazino-quinazolinedione chemotypes are complex and structurally challenging structures of biological interest, being found in the marine alkaloids such as brevianamide M-N and fumiquinazolines A-C. Herein we report the synthesis of this tricyclic system in three synthetic operations by means of an Ugi multi-component reaction (MCR) followed by a tandem N-acyliminium ion cyclization-intramolecular nucleophilic addition reaction sequence. Additional structural diversification for further library enrichment was also accomplished via sequential N-alkylation and N-acylation/sulfonation. © 2013 Elsevier Ltd. All rights reserved.
• Hall, G. B., Medda, F., Roberts, S. A., & Hulme, C. (2013). 3-(4-Bromophenyl)-1-butyl-5-[1-(2-chloro-6-methylphenyl)-1H-tetrazol-5-yl] imidazolidine-2,4-dione. Acta Crystallographica Section E: Structure Reports Online, 69(7), o1102-o1103.
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  PMID: 24046663;PMCID: PMC3770378;Abstract: In the title molecule, C21H20BrClN6O2, the chloro-substituted benzene ring forms a dihedral angle of 77.84 (7)° with the tetrazole ring and the bromo-substituted ring forms a dihedral angle of 43.95 (6)° with the imidazole ring. The dihedral angle between the tetrazole and imidazole rings is 67.42 (8)°. The terminal methyl group of the butyl substituent is disordered over two sets of sites, with refined occupancies 0.67 (3) and 0.33 (3). In the crystal, there is a short Br...N contact of 3.183 (2) Å.
• Hsu, M., Dietrich, J., Hulme, C., & Shaw, A. Y. (2013). Synthesis of di- and tri-substituted imidazole-4-carboxylates via PBu3-mediated [3+2] cycloaddition. Synthetic Communications, 43(11), 1538-1542.
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  Abstract: Some new di- and trisubstituted imidazole-4-carboxylates were prepared from amidoacetic acids 3 in the present report. The key step to establish such imidazole- 4-carboxylates stemmed from the PBu3-mediated [3+2] cycloaddition between in situ-generated Δ2-oxazolinone 4 and ethyl cyanoformate6. Our results indicated that trisubstituted imidazoles 7-20 were afforded in better yields than those of disubstituted imidazoles 21-27. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications1 to view the free supplemental file. Copyright © Taylor & Francis Group, LLC.
• Hulme, C., Gunawan, S., & Hulme, C. -. (2013). Bifunctional building blocks in the Ugi-azide condensation reaction: a general strategy toward exploration of new molecular diversity. Organic & biomolecular chemistry, 11(36).
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  1,5-Disubstituted tetrazoles are an important drug-like scaffold known for their ability to mimic the cis-amide bond conformation. The scaffold is readily accessible via substitution of the carboxylic acid component of the Ugi multi-component reaction (MCR) with TMSN3 in what is herein denoted the Ugi-azide reaction. This full paper presents a concise, novel, general strategy to access a plethora of new heterocylic scaffolds utilizing tethered aldo/keto-acids/esters in the Ugi-azide reaction followed by a ring closing event that generates novel highly complex bis-heterocyclic lactam-tetrazoles.
• Hulme, C., Gunawan, S., & Hulme, C. -. (2013). Construction of functionalized tricyclic dihydropyrazino-quinazolinedione chemotypes via an Ugi/N-acyliminium ion cyclization cascade. Tetrahedron letters, 54(33).
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  Dihydropyrazino-quinazolinedione chemotypes are complex and structurally challenging structures of biological interest, being found in the marine alkaloids such as brevianamide M-N and fumiquinazolines A-C. Herein we report the synthesis of this tricyclic system in three synthetic operations by means of an Ugi multi-component reaction (MCR) followed by a tandem N-acyliminium ion cyclization-intramolecular nucleophilic addition reaction sequence. Additional structural diversification for further library enrichment was also accomplished via sequential N-alkylation and N-acylation/sulfonation.
• Hulme, C., Hall, G. B., Medda, F., Roberts, S. A., & Hulme, C. -. (2013). 3-(4-Bromo-phen-yl)-1-butyl-5-[1-(2-chloro-6-methyl-phen-yl)-1H-tetra-zol-5-yl]imidazolidine-2,4-dione. Acta crystallographica. Section E, Structure reports online, 69(Pt 7).
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  In the title mol-ecule, C21H20BrClN6O2, the chloro-substituted benzene ring forms a dihedral angle of 77.84 (7)° with the tetra-zole ring and the bromo-substituted ring forms a dihedral angle of 43.95 (6)° with the imidazole ring. The dihedral angle between the tetra-zole and imidazole rings is 67.42 (8)°. The terminal methyl group of the butyl substituent is disordered over two sets of sites, with refined occupancies 0.67 (3) and 0.33 (3). In the crystal, there is a short Br⋯N contact of 3.183 (2) Å.
• Hulme, C., Medda, F., Sells, E., Chang, H., Dietrich, J., Chappeta, S., Smith, B., Gokhale, V., Meuillet, E. J., & Hulme, C. -. (2013). Synthesis and biological activity of aminophthalazines and aminopyridazines as novel inhibitors of PGE2 production in cells. Bioorganic & medicinal chemistry letters, 23(2).
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  This Letter reports the synthesis and biological evaluation of a collection of aminophthalazines as a novel class of compounds capable of reducing production of PGE(2) in HCA-7 human adenocarcinoma cells. A total of 28 analogs were synthesized, assayed for PGE(2) reduction, and selected active compounds were evaluated for inhibitory activity against COX-2 in a cell free assay. Compound 2xxiv (R(1)=H, R(2)=p-CH(3)O) exhibited the most potent activity in cells (EC(50)=0.02 μM) and minimal inhibition of COX-2 activity (3% at 5 μM). Furthermore, the anti-tumor activity of analog 2vii was analyzed in xenograft mouse models exhibiting good anti-cancer activity.
• Hulme, C., Xu, Z., De Moliner, F., Cappelli, A. P., & Hulme, C. -. (2013). Aldol reactions in multicomponent reaction based domino pathways: a multipurpose enabling tool in heterocyclic chemistry. Organic letters, 15(11).
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  The aldol reaction has been evaluated in combination with the Ugi multicomponent reaction to assemble richly decorated mono- and polycyclic systems via expeditious cascade pathways. A small collection of pyrrolinones was generated thereof, and the scarcely accessible pyridoquinoxalinedione scaffold was also prepared by designing an additional nucleophilic substitution step in this domino sequence requiring minimal operational effort.
• Lin, C., Lu, P., Yang, C., Hulme, C., & Shaw, A. Y. (2013). Structure-activity relationship study of growth inhibitory 2-styrylchromones against carcinoma cells. Medicinal Chemistry Research, 22(5), 2385-2394.
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  Abstract: The structure-activity relationship study of 2-styrylchromones against carcinoma cell growth is discussed in the present report. Taking advantage of 2-styrylchromone as a molecular template, a series of structural modifications was carried out and examined on several carcinoma cell lines. Interestingly, AGS cells exhibited more sensitivity in response to methoxy-bearing compounds, of which compound 23 (3,4,5-trimethoxy group on ring B) showed the most potent activity with a GI50 value of 1.3 μM. Surprisingly, as methoxy groups in 12 and 24-27 were demethylated to generate their hydroxyl counterparts 28-32, none of them displayed appreciable activity against all carcinoma cells. We further confirmed the pivotal role of rigidity for growth inhibitory activity between the rigid 12 and its flexible counterpart 33. Taken together, in the present report, we have clearly demonstrated the structure-activity relationship study of 2-styrylchromones targeting carcinoma cell growth. © 2012 Springer Science+Business Media, LLC.
• Martinez-Ariza, G., Ayaz, M., & Hulme, C. (2013). A simple one-pot 2-step N-1-alkylation of indoles with α-iminoketones toward the expeditious 3-step synthesis of N-1-quinoxaline-indoles. Tetrahedron Letters, 54(49), 6719-6721.
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  Abstract: A straightforward procedure for the preparation of N-quinoxaline-indoles is presented. A base-catalyzed one-pot addition of indoles to a preformed α-iminoketone proceeds on the N-1 indole and the subsequent adduct undergoes an acid-mediated deprotection of an internal amino nucleophile, intramolecular cyclization, and final oxidation generating N-1-quinoxaline- indoles in good yield. © 2013 Elsevier Ltd. All rights reserved.
• Martinez-Ariza, G., Ayaz, M., & Hulme, C. (2013). A simple one-pot 2-step N-1-alkylation of indoles with α-iminoketones toward the expeditious 3-step synthesis of N-1-quinoxaline-indoles. Tetrahedron letters, 54(49).
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  A straightforward procedure for the preparation of N-quinoxaline-indoles is presented. A base-catalyzed one-pot addition of indoles to a preformed α-iminoketone proceeds on the N-1 indole and the subsequent adduct undergoes an acid-mediated deprotection of an internal amino nucleophile, intramolecular cyclization and final oxidation generating N-1-quinoxaline-indoles in good yield.
• Martinez-Ariza, G., Dietrich, J., Moliner, F. D., & Hulme, C. (2013). A tandem [3+2] cycloaddition-elimination cascade reaction to generate pyrrolo-[3,4-c]pyrrole-1,3-diones. Synlett, 24(14), 1801-1804.
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  Abstract: An efficient tandem [3+2] cycloaddition-elimination cascade sequence has been developed enabling assembly of the pharmacologically relevant pyrrolo-[3,4-c]pyrrole-1,3-dione chemotype. The strategy involves simple mixing of readily accessible oxazolin-2-ones and pyrrole-2,5-diones in the presence of base under mild conditions, rendering the title compounds in typically excellent yields. Of note, this route allows for installation of three points of diversity and is ideal for combinatorial applications and parallel synthesis production campaigns. © Georg Thieme Verlag Stuttgart · New York.
• Medda, F., Smith, B., Gokhale, V., Shaw, A. Y., Dunckley, T., & Hulme, C. (2013). Beyond secretases: Kinase inhibitors for the treatment of Alzheimer's disease. Annual Reports in Medicinal Chemistry, 48, 57-71.
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  Abstract: Alzheimer's disease (AD) is the most prevalent form of dementia in old age. Recent data indicate that 24.3 million people worldwide suffer from AD. Hyperphosphorylation of tau, a protein normally involved in microtubule stabilization, has been identified as an important pathological contributor to AD development. In AD brains, hyperphosphorylation of tau leads to its aggregation, misfolding, and formation of neurofibrillary tangles, one common hallmark of AD. Specific protein kinases, such as GSK-3β, CDK5, and DYRK1A, are involved in tau hyperphosphorylation and have been identified as potential targets for the development of novel therapeutic agents for the treatment of AD cognitive deficits. We herein review the current state of the art in the development of small molecule inhibitors of GSK-3β, CDK5, DYRK1A, and other protein kinases involved in tau phosphorylation. Only recently developed compounds with cellular and/or in vivo activity will be discussed. © 2013 Elsevier Inc.
• Shaw, A. Y., Denning, C. R., & Hulme, C. (2013). One-pot two-step synthesis of quinoxalinones and diazepinones via a tandem oxidative amidation-deprotection-cyclization sequence. Synthesis (Germany), 45(4), 459-462.
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  Abstract: This report discloses novel concise syntheses of quinoxalinones and diazepinones via a tandem oxidative amidation-deprotection-cyclization sequence. A selenium dioxide mediated oxidative amidation of arylglyoxals with secondary amines was carried out under microwave irradiation to give the corresponding α-keto amides, followed by an acid-promoted deprotection and cyclization to afford the desired products in moderate to good yields. © Georg Thieme Verlag Stuttgart · New York.
• Zhigang, X. u., Moliner, F. D., Cappelli, A. P., & Hulme, C. (2013). Aldol reactions in multicomponent reaction based domino pathways: A multipurpose enabling tool in heterocyclic chemistry. Organic Letters, 15(11), 2738-2741.
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  PMID: 23718233;PMCID: PMC3727662;Abstract: The aldol reaction has been evaluated in combination with the Ugi multicomponent reaction to assemble richly decorated mono- and polycyclic systems via expeditious cascade pathways. A small collection of pyrrolinones was generated thereof, and the scarcely accessible pyridoquinoxalinedione scaffold was also prepared by designing an additional nucleophilic substitution step in this domino sequence requiring minimal operational effort. © 2013 American Chemical Society.
• Ayaz, M., Moliner, F. D., Dietrich, J., & Hulme, C. (2012). Applications of Isocyanides in IMCRs for the Rapid Generation of Molecular Diversity. Isocyanide Chemistry: Applications in Synthesis and Material Science, 335-384.
• Gunawan, S., Ayaz, M., Moliner, F. D., Frett, B., Kaiser, C., Patrick, N., Zhigang, X. u., & Hulme, C. (2012). Synthesis of tetrazolo-fused benzodiazepines and benzodiazepinones by a two-step protocol using an Ugi-azide reaction for initial diversity generation. Tetrahedron, 68(27-28), 5606-5611.
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  Abstract: A two-step strategy for the synthesis of arrays of tricyclic tetrazolo-fused benzodiazepines and benzodiazepinones has been investigated. The protocol uses ortho-N-Boc phenylisocyanides and phenylglyoxaldehydes or ethyl glyoxylate in the four-component Ugi-azide reaction to afford MCR (MultiComponent Reactions) derived adducts equipped with the desired diversity inputs. A subsequent acidic treatment (TFA/DCE) allows a simultaneous deprotection-cyclization leading to the final products. © 2012 Elsevier Ltd. All rights reserved.
• Gunawan, S., Keck, K., Laetsch, A., & Hulme, C. (2012). Synthesis of peptidomimetics, δ- And ε-lactam tetrazoles. Molecular Diversity, 16(3), 601-606.
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  PMID: 22622388;Abstract: A concise two-step procedure for the synthesis of novel δ-lactam tetrazoles has been established via the Ugi-azide reaction using 5-oxohexanoic acid along with primary amines, isocyanides, and azidotrimethylsilane followed by 1,1′-carbonyldiimidazole-mediated intramolecular amide formation. Expansion to ε-lactam tetrazole scaffolds was accomplished using methyl 6-oxoheptanoate via the same Ugi-azide reaction followed by basic hydrolysis and SOCl2 activation to enable lactam formation. © Springer Science+Business Media B.V. 2012.
• Gunawan, S., Nichol, G., & Hulme, C. (2012). Concise route to a series of novel 3-(tetrazol-5-yl)quinoxalin-2(1H)-ones. Tetrahedron Letters, 53(13), 1664-1667.
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  Abstract: This Letter presents a novel three step solution phase protocol to synthesize 3-(tetrazol-5-yl)quinoxalin-2(1H)-ones. The strategy utilizes ethyl glyoxalate and mono-N-Boc-protected-o-phenylenediamine derivatives in the Ugi-Azide multi-component reaction (MCR) to generate a unique 1,5-disubstituted tetrazole. Subsequent acid treatment stimulates a simultaneous Boc deprotection and intramolecular cyclization leading to bis-3,4-dihydroquinoxalinone tetrazoles. Direct oxidation using a stable solid-phase radical catalyst (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) with ceric ammonium nitrate (CAN) in catalytic fashion initiating aerobic oxidation, completes the entire procedure to generate a series of original unique bis-quinoxalinone tetrazoles. The method was also expanded to produce a bis-benzodiazepine tetrazole. © 2011 Elsevier Ltd. All rights reserved.
• Gunawan, S., Petit, J., & Hulme, C. (2012). Concise one-pot preparation of unique bis-pyrrolidinone tetrazoles. ACS Combinatorial Science, 14(3), 160-163.
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  PMID: 22330239;PMCID: PMC3299871;Abstract: A one-pot, two-step synthesis of bis-pyrrolidinone tetrazoles has been established via the Ugi-Azide reaction using methyl levulinate, primary amines, isocyanides and azidotrimethylsilane with subsequent acid treatment to catalyze the lactam formation. The efficiency of the protocol was established followed by a successful transition to library production in four 24-well plates. © 2012 American Chemical Society.
• Hulme, C., De Moliner, F., & Hulme, C. -. (2012). A Van Leusen deprotection-cyclization strategy as a fast entry into two imidazoquinoxaline families. Tetrahedron letters, 53(43).
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  A concise synthesis of two pharmacologically relevant classes of molecules possessing the imidazoquinoxaline core is reported. The protocol involves use of 1,2-phenylenediamines and glyoxylic acid derivatives, namely ethyl glyoxylate or benzylglyoxamide, along with tosylmethylisocyanides in a microwave-assisted Van Leusen three-component condensation. Subsequent unmasking (Boc removal) of an internal amino-nucleophile promotes deprotection and cyclization that take place either spontaneously in a one-pot fashion to give 8 or upon acidic treatment under microwave irradiation after isolation of the imidazole intermediate to give 11. Of note, a tricyclic framework is hence assembled by means of a rapid and straightforward method with a high bond-forming efficiency.
• Hulme, C., De Moliner, F., & Hulme, C. -. (2012). Straightforward assembly of phenylimidazoquinoxalines via a one-pot two-step MCR process. Organic letters, 14(5).
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  An efficient multicomponent-based methodology providing a new entry into a medicinally important complex heterocyclic core is presented. The strategy is very general and able to endow target compounds with the highest possible number of diversity points. Notably, four new chemical bonds and two aromatic rings are formed in a one-pot fashion.
• Hulme, C., Gunawan, S., Ayaz, M., De Moliner, F., Frett, B., Kaiser, C., Patrick, N., Xu, Z., & Hulme, C. -. (2012). Synthesis of Tetrazolo-Fused Benzodiazepines and Benzodiazepinones by a Two-Step Protocol Using an Ugi-Azide Reaction for Initial Diversity Generation. Tetrahedron, 68(27-28).
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  A two-step strategy for the synthesis of arrays of tricyclic tetrazolo-fused benzodiazepines and benzodiazepinones has been investigated. The protocol uses ortho-N-Boc phenylisocyanides and phenylglyoxaldehydes or ethyl glyoxylate in the 4-component Ugi-Azide reaction to afford MCR (Multi Component Reactions) derived adducts equipped with the desired diversity inputs. A subsequent acidic treatment (TFA/DCE) allows a simultaneous deprotection-cyclization leading to the final products.
• Hulme, C., Gunawan, S., Keck, K., Laetsch, A., & Hulme, C. -. (2012). Synthesis of peptidomimetics, δ- and ε-lactam tetrazoles. Molecular diversity, 16(3).
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  A concise two-step procedure for the synthesis of novel δ-lactam tetrazoles has been established via the Ugi-azide reaction using 5-oxohexanoic acid along with primary amines, isocyanides, and azidotrimethylsilane followed by 1,1'-carbonyldiimidazole-mediated intramolecular amide formation. Expansion to ε-lactam tetrazole scaffolds was accomplished using methyl 6-oxoheptanoate via the same Ugi-azide reaction followed by basic hydrolysis and SOCl(2) activation to enable lactam formation.
• Hulme, C., Gunawan, S., Nichol, G., & Hulme, C. -. (2012). Concise route to a series of novel 3-(tetrazol-5-yl)quinoxalin-2(1H)-ones. Tetrahedron letters, 53(13).
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  This report presents a novel three step solution phase protocol to synthesize 3-(tetrazol-5-yl)quinoxalin-2(1H)-ones. The strategy utilizes ethyl glyoxalate and mono-N-Boc-protected-o-phenylenediamine derivatives in the Ugi-Azide multi-component reaction (MCR) to generate a unique 1,5-disubstituted tetrazole. Subsequent acid treatment stimulates a simultaneous Boc deprotection and intramolecular cyclization leading to bis-3,4-dihydroquinoxalinone tetrazoles. Direct oxidation using a stable solid-phase radical catalyst (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) with ceric ammonium nitrate (CAN) in catalytic fashion initiating aerobic oxidation, completes the entire procedure to generate a series of original unique bis-quinoxalinone tetrazoles. The method was also expanded to produce a bis-benzodiazepine tetrazole.
• Hulme, C., Shaw, A. Y., Denning, C. R., & Hulme, C. -. (2012). Selenium dioxide-mediated synthesis of α-ketoamides from arylglyoxals and secondary amines. Tetrahedron letters, 53(32).
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  A facile and expeditious synthetic approach to α-ketoamides 3 is described. A series of α-ketoamides 3 was synthesized via reaction of selenium dioxide-mediated oxidative amidation between arylglyoxals 1 and secondary amines 2, and accelerated with microwave irradiation. Our findings indicate that constrained amines, such as piperazine and piperidine exhibit higher conversions for this transformation. This reaction was explored by synthesizing a series of α-ketoamides 3 from various arylglyoxals with cyclic and acyclic secondary amines.
• Hulme, C., Shaw, A. Y., McLaren, J. A., Nichol, G. S., & Hulme, C. -. (2012). Hydrazine-mediated cyclization of Ugi products to synthesize novel 3-hydroxypyrazoles. Tetrahedron letters, 53(21).
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  This report discloses a novel concise synthesis of a series of 3-hydroxypyrazoles 5 via a tandem Ugi/debenzylation /hydrazine-mediated cyclization sequence. Herein, n-butyl isocyanide 4b was utilized as an alternative to classical convertible isocyanides enabling high yielding hydrazine-mediated cyclization. Taken together, a novel class of 3-hydroxypyrazoles 5a-5i was synthesized with potential to be of interest in future library enrichment strategies.
• Hulme, C., Shaw, A. Y., Medda, F., & Hulme, C. -. (2012). Facile and rapid route for the synthesis of novel conformationally constrained norstatine analogs via PADAM-cyclization methodology. Tetrahedron letters, 53(11).
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  The following report describes novel methodology for the rapid synthesis of unique conformationally constrained norstatine analogs of potential biological relevance. A PADAM (Passerini reaction - Amine Deprotection - Acyl Migration reaction) sequence is followed by a TFA-mediated microwave-assisted cyclization to generate the final benzimidazole isostere of the norstatine scaffold in moderate to good yields. The applicability of this solution phase methodology to the preparation of a small collection of compounds is discussed.
• Hulme, C., Shaw, A. Y., Xu, Z., & Hulme, C. -. (2012). Ugi/Robinson-Gabriel reactions directed toward the synthesis of 2,4,5-trisubstituted oxazoles. Tetrahedron letters, 53(15).
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  This Letter discloses a novel concise synthesis of a series of 2,4,5-trisubstituted oxazoles via a tandem Ugi/Robinson-Gabriel sequence. Herein, 2,4-dimethoxybenzylamine 1 was used as an ammonia equivalent in combination with arylglyoxal 3 and supporting Ugi reagents, an isonitrile and carboxylic acid. As such the product of the acid treated Ugi intermediate is ideally configured to undergo a Robinson-Gabriel cyclodehydration reaction to yield the desired oxazole scaffold 5.
• Hulme, C., Smith, B., Chang, H., Medda, F., Gokhale, V., Dietrich, J., Davis, A., Meuillet, E. J., & Hulme, C. -. (2012). Synthesis and biological activity of 2-aminothiazoles as novel inhibitors of PGE2 production in cells. Bioorganic & medicinal chemistry letters, 22(10).
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  This Letter presents the synthesis and biological evaluation of a collection of 2-aminothiazoles as a novel class of compounds with the capability to reduce the production of PGE(2) in HCA-7 human adenocarcinoma cells. A total of 36 analogs were synthesized and assayed for PGE(2) reduction, and those with potent cellular activity were counter screened for inhibitory activity against COX-2 in a cell free assay. In general, analogs bearing a 4-phenoxyphenyl substituent in the R(2) position were highly active in cells while maintaining negligible COX-2 inhibition. Specifically, compound 5l (R(1)=Me, R(2)=4-OPh-Ph, R(3)=CH(OH)Me) exhibited the most potent cellular PGE(2) reducing activity of the entire series (EC(50)=90 nM) with an IC(50) value for COX-2 inhibition of >5 μM in vitro. Furthermore, the anti-tumor activity of analog 1a was analyzed in xenograft mouse models exhibiting promising anti-cancer activity.
• Hulme, C., Smith, B., Medda, F., Gokhale, V., Dunckley, T., & Hulme, C. -. (2012). Recent advances in the design, synthesis, and biological evaluation of selective DYRK1A inhibitors: a new avenue for a disease modifying treatment of Alzheimer's?. ACS chemical neuroscience, 3(11).
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  With 24.3 million people affected in 2005 and an estimated rise to 42.3 million in 2020, dementia is currently a leading unmet medical need and costly burden on public health. Seventy percent of these cases have been attributed to Alzheimer's disease (AD), a neurodegenerative pathology whose most evident symptom is a progressive decline in cognitive functions. Dual specificity tyrosine phosphorylation regulated kinase-1A (DYRK1A) is important in neuronal development and plays a variety of functional roles within the adult central nervous system. The DYRK1A gene is located within the Down syndrome critical region (DSCR) on human chromosome 21 and current research suggests that overexpression of DYRK1A may be a significant factor leading to cognitive deficits in people with Alzheimer's disease (AD) and Down syndrome (DS). Currently, treatment options for cognitive deficiencies associated with Down syndrome, as well as Alzheimer's disease, are extremely limited and represent a major unmet therapeutic need. Small molecule inhibition of DYRK1A activity in the brain may provide an avenue for pharmaceutical intervention of mental impairment associated with AD and other neurodegenerative diseases. We herein review the current state of the art in the development of DYRK1A inhibitors.
• Hulme, C., Xu, Z., Ayaz, M., Cappelli, A. A., & Hulme, C. -. (2012). General one-pot, two-step protocol accessing a range of novel polycyclic heterocycles with high skeletal diversity. ACS combinatorial science, 14(8).
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  An Ugi one-pot three-component four-center reaction was coupled with a subsequent acid mediated cyclodehydration step to furnish a multitude of unique scaffolds having in common an embedded or attached benzimidazole and often a ring system formed through lactamization. Using combinations of tethered Ugi inputs typically via tethered acid-ketone inputs and supporting reagents containing masked internal nucleophiles, such scaffolds were produced in good to excellent yields in an operationally friendly manner.
• Hulme, C., Xu, Z., De Moliner, F., Cappelli, A. P., & Hulme, C. -. (2012). Ugi/aldol sequence: expeditious entry to several families of densely substituted nitrogen heterocycles. Angewandte Chemie (International ed. in English), 51(32).
• Hulme, C., Xu, Z., Shaw, A. Y., Dietrich, J., Cappelli, A. P., Nichol, G., & Hulme, C. -. (2012). Facile, novel two-step syntheses of benzimidazoles, bis-benzimidazoles, and bis-benzimidazole-dihydroquinoxalines. Molecular diversity, 16(1).
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  Three scaffolds of benzimidazoles, bis-benzimidazoles, and bis-benzimidazole-dihydroquinoxalines were synthesized via Ugi/de-protection/cyclization methodology. Benzimidazole forming ring closure was enabled under microwave irradiation in the presence of 10% TFA/DCE. The methodology demonstrates the utility of 2-(N-Boc-amino)-phenyl-isocyanide for the generation of new molecular diversity.
• Hulme, C., Xu, Z., Shaw, A. Y., Nichol, G. S., Cappelli, A. P., & Hulme, C. -. (2012). Applications of ortho-phenylisonitrile and ortho-N-Boc aniline for the two-step preparation of novel bis-heterocyclic chemotypes. Molecular diversity, 16(3).
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  Concise routes to five pharmacologically relevant bis-heterocyclic scaffolds are described. Significant molecular complexity is generated in a mere two synthetic operations enabling access to each scaffold. Routes are often improved by microwave irradiation and all utilize isocyanide-based multi-component reaction methods to incorporate the required diversity elements. Common reagents in all initial condensation reactions include 2-(N-Boc-amino)-phenyl-isocyanide 1, mono-Boc-phenylenediamine 2 and ethyl glyoxalate 3.
• Medda, F., & Hulme, C. (2012). A facile and rapid route for the synthesis of novel 1,5-substituted tetrazole hydantoins and thiohydantoins via a TMSN ₃-Ugi/RNCX cyclization. Tetrahedron Letters, 53(42), 5593-5596.
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  Abstract: This Letter describes novel methodology for the rapid assembly of new and biologically appealing 1,5-substituted tetrazole-hydantoins and thiohydantoins. The product of a TMSN 3-Ugi multi-component reaction is treated with an excess of isocyanate or isothiocyanate to generate the final scaffold in moderate to good yields. The applicability of this solution phase methodology to the preparation of a small collection of compounds is discussed. © 2012 Elsevier Ltd. All rights reserved.
• Moliner, F. D., & Hulme, C. (2012). A Van Leusen deprotection-cyclization strategy as a fast entry into two imidazoquinoxaline families. Tetrahedron Letters, 53(43), 5787-5790.
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  Abstract: A concise synthesis of two pharmacologically relevant classes of molecules possessing the imidazoquinoxaline core is reported. The protocol involves use of 1,2-phenylenediamines and glyoxylic acid derivatives, namely ethyl glyoxylate or benzylglyoxamide, along with tosylmethylisocyanides in a microwave-assisted Van Leusen three-component condensation. Subsequent unmasking (Boc removal) of an internal amino-nucleophile promotes deprotection and cyclization that take place either spontaneously in a one-pot fashion to give 8 or upon acidic treatment under microwave irradiation after isolation of the imidazole intermediate to give 11. Of note, a tricyclic framework is hence assembled by means of a rapid and straightforward method with a high bond-forming efficiency. © 2012 Elsevier Ltd. All rights reserved.
• Moliner, F. D., & Hulme, C. (2012). Straightforward assembly of phenylimidazoquinoxalines via a one-pot two-step MCR process. Organic Letters, 14(5), 1354-1357.
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  PMID: 22356134;PMCID: PMC3311158;Abstract: An efficient multicomponent-based methodology providing a new entry into a medicinally important complex heterocyclic core is presented. The strategy is very general and able to endow target compounds with the highest possible number of diversity points. Notably, four new chemical bonds and two aromatic rings are formed in a one-pot fashion. © 2012 American Chemical Society.
• Roberts, S. A., Martinez-Ariza, G., Dietrich, J., & Hulme, C. (2012). 2,4-Diphenyl-6-trifluoromethyl-2,3-dihydro-1H,5H-pyrrolo-[3,4-c]pyrrole-1, 3-dione. Acta Crystallographica Section E: Structure Reports Online, 68(2), o496-o497.
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  PMID: 22347098;PMCID: PMC3275242;Abstract: The asymmetric unit of the title compound, C 19H 11F 3N 2O 2, contains two crystallographically unique mol-ecules which differ in the rotation of a phenyl ring and a -CF3 substituent. The dihedral angles involving the pyrrole ring and the attached phenyl ring are 62.82 (8) and 71.54 (7)° in the two molecules. The difference in the rotation of the CF3 groups with respect to the pyrrolo rings to which they are attached is 23.5(1)°. For one mol-ecule, there is a close contact between an H atom and the centroid of the phenyl ring of an adjacent mol-ecule (2.572 Å). A similar contact is lacking in the second mol-ecule. In the crystal, N - H⋯O inter-actions connect adjacent mol-ecules into a chain normal to (01 ). Crystallographically unique mol-ecules alternate along the hydrogen-bonded chains.
• Shaw, A. Y., Denning, C. R., & Hulme, C. (2012). Selenium dioxide-mediated synthesis of α-ketoamides from arylglyoxals and secondary amines. Tetrahedron Letters, 53(32), 4151-4153.
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  Abstract: A facile and expeditious synthetic approach for the synthesis of α-ketoamides 3 is described. A series of α-ketoamides 3 was synthesized via reaction of selenium dioxide-mediated oxidative amidation between arylglyoxals 1 and secondary amines 2, and accelerated with microwave irradiation. Our findings indicate that constrained amines, such as piperazine and piperidine exhibit higher conversions for this transformation. This reaction was explored by synthesizing a series of α-ketoamides 3 from various arylglyoxals 1 with cyclic and acyclic secondary amines 2. © 2012 Elsevier Ltd. All rights reserved.
• Shaw, A. Y., McLaren, J. A., Nichol, G. S., & Hulme, C. (2012). Hydrazine-mediated cyclization of Ugi products to synthesize novel 3-hydroxypyrazoles. Tetrahedron Letters, 53(21), 2592-2594.
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  Abstract: This report discloses a novel concise synthesis of a series of 3-hydroxypyrazoles 5 via a tandem Ugi/debenzylation /hydrazine-mediated cyclization sequence. Herein, n-butyl isocyanide 4b was utilized as an alternative to classical convertible isocyanides enabling high yielding hydrazine-mediated cyclization. Taken together, a novel class of 3-hydroxypyrazoles 5a-5i was synthesized with a potential to be of interest in future library enrichment strategies. © 2012 Elsevier Ltd. All rights reserved.
• Shaw, A. Y., Medda, F., & Hulme, C. (2012). Facile and rapid route for the synthesis of novel norstatine analogs via PADAM-cyclization methodology. Tetrahedron Letters, 53(11), 1313-1315.
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  Abstract: The following report describes novel methodology for the rapid synthesis of unique conformationally constrained norstatine analogs of potential biological relevance. A PADAM (Passerini reaction-Amine Deprotection-Acyl Migration reaction) sequence is followed by a TFA-mediated microwave-assisted cyclization to generate the final benzimidazole isostere of the norstatine scaffold in moderate to good yields. The applicability of this solution phase methodology to the preparation of a small collection of compounds is discussed. © 2012 Elsevier Ltd. All rights reserved.
• Shaw, A. Y., Zhigang, X. u., & Hulme, C. (2012). Ugi/Robinson-Gabriel reactions directed toward the synthesis of 2,4,5-trisubstituted oxazoles. Tetrahedron Letters, 53(15), 1998-2000.
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  Abstract: This Letter discloses a novel concise synthesis of a series of 2,4,5-trisubstituted oxazoles via a tandem Ugi/Robinson-Gabriel sequence. Herein, 2,4-dimethoxybenzylamine 1 was used as an ammonia equivalent in combination with arylglyoxal 3 and supporting Ugi reagents, an isonitrile and carboxylic acid. As such the product of the acid treated Ugi intermediate is ideally configured to undergo a Robinson-Gabriel cyclodehydration reaction to yield the desired oxazole scaffold 5. © 2011 Elsevier Inc. All rights reserved.
• Smith, B., Medda, F., Gokhale, V., Dunckley, T., & Hulme, C. (2012). Recent advances in the design, synthesis, and biological evaluation of selective DYRK1A inhibitors: A new avenue for a disease modifying treatment of Alzheimers?. ACS Chemical Neuroscience, 3(11), 857-872.
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  PMID: 23173067;PMCID: PMC3503344;Abstract: With 24.3 million people affected in 2005 and an estimated rise to 42.3 million in 2020, dementia is currently a leading unmet medical need and costly burden on public health. Seventy percent of these cases have been attributed to Alzheimers disease (AD), a neurodegenerative pathology whose most evident symptom is a progressive decline in cognitive functions. Dual specificity tyrosine phosphorylation regulated kinase-1A (DYRK1A) is important in neuronal development and plays a variety of functional roles within the adult central nervous system. The DYRK1A gene is located within the Down syndrome critical region (DSCR) on human chromosome 21 and current research suggests that overexpression of DYRK1A may be a significant factor leading to cognitive deficits in people with Alzheimers disease (AD) and Down syndrome (DS). Currently, treatment options for cognitive deficiencies associated with Down syndrome, as well as Alzheimers disease, are extremely limited and represent a major unmet therapeutic need. Small molecule inhibition of DYRK1A activity in the brain may provide an avenue for pharmaceutical intervention of mental impairment associated with AD and other neurodegenerative diseases. We herein review the current state of the art in the development of DYRK1A inhibitors. © 2012 American Chemical Society.
• Zhigang, X. u., Ayaz, M., Cappelli, A. A., & Hulme, C. (2012). General one-pot, two-step protocol accessing a range of novel polycyclic heterocycles with high skeletal diversity. ACS Combinatorial Science, 14(8), 460-464.
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  PMID: 22746181;PMCID: PMC3426865;Abstract: An Ugi one-pot three-component four-center reaction was coupled with a subsequent acid mediated cyclodehydration step to furnish a multitude of unique scaffolds having in common an embedded or attached benzimidazole and often a ring system formed through lactamization. Using combinations of tethered Ugi inputs typically via tethered acid-ketone inputs and supporting reagents containing masked internal nucleophiles, such scaffolds were produced in good to excellent yields in an operationally friendly manner. © 2012 American Chemical Society.
• Zhigang, X. u., Moliner, F. D., Cappelli, A. P., & Hulme, C. (2012). Ugi/Aldol sequence: Expeditious entry to several families of densely substituted nitrogen heterocycles. Angewandte Chemie - International Edition, 51(32), 8037-8040.
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  PMID: 22753341;PMCID: PMC3517102;Abstract: Complexity from simplicity: Nitrogen-containing heterocycles have been assembled by means of unprecedented domino processes designed to take advantage of diversity assembly using strategically decorated Ugi products (see scheme). The aldol reaction is the second common denominator which enables sequences of up to five steps in one pot, thus producing unique molecular architectures in rapid fashion. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
• Zhigang, X. u., Shaw, A. Y., Dietrich, J., Cappelli, A. P., Nichol, G., & Hulme, C. (2012). Facile, novel two-step syntheses of benzimidazoles, bis-benzimidazoles, and bis-benzimidazole-dihydroquinoxalines. Molecular Diversity, 16(1), 73-79.
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  PMID: 22237832;PMCID: PMC3311162;Abstract: Three scaffolds of benzimidazoles, bis-benzimidazoles, and bis-benzimidazole-dihydroquinoxalines were synthesized via Ugi/de-protection/ cyclization methodology. Benzimidazole forming ring closure was enabled under microwave irradiation in the presence of 10% TFA/DCE. The methodology demonstrates the utility of 2-(N-Boc-amino)-phenyl-isocyanide for the generation of new molecular diversity. © 2012 Springer Science+Business Media B.V.
• Zhigang, X. u., Shaw, A. Y., Nichol, G. S., Cappelli, A. P., & Hulme, C. (2012). Applications of ortho-phenylisonitrile and ortho-N-Boc aniline for the two-step preparation of novel bis-heterocyclic chemotypes. Molecular Diversity, 16(3), 607-612.
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  PMID: 22622389;Abstract: Concise routes to five pharmacologically relevant bis-heterocyclic scaffolds are described. Significant molecular complexity is generated in a mere two synthetic operations enabling access to each scaffold. Routes are often improved by microwave irradiation and all utilize isocyanide-based multi-component reaction methods to incorporate the required diversity elements. Common reagents in all initial condensation reactions include 2-(N-Boc-amino)-phenyl-isocyanide 1, mono-Boc-phenylenediamine 2 and ethyl glyoxalate 3. © Springer Science+Business Media B.V. 2012.
• Ayaz, M., Dietrich, J., & Hulme, C. (2011). A novel route to synthesize libraries of quinoxalines via Petasis methodology in two synthetic operations. Tetrahedron Letters, 52(38), 4821-4823.
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  Abstract: This Letter reveals an innovative and facile procedure to prepare quinoxalines in two synthetic steps. The microwave assisted Petasis reaction is followed by the acid mediated unmasking of an internal amino nucleophile, cyclodehydration and oxidation to give collections of quinoxalines in good to excellent yields. © 2011 Elsevier Ltd. All rights reserved.
• Dömling, A., & Hulme, C. (2011). Molecular Diversity: Editorial. Molecular Diversity, 15(1), 1-2.
• Dömling, A., & Hulme, C. (2011). Special issue on Mini-MCR issue and SCS-09--Second International Symposium on Combinatorial Sciences in Biology, Chemistry, Catalysts and Materials. Editorial.. Molecular diversity, 15(1), 1-2.
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  PMID: 21373985;
• Hulme, C., Ayaz, M., Dietrich, J., & Hulme, C. -. (2011). A novel route to synthesize libraries of quinoxalines via Petasis methodology in two synthetic operations. Tetrahedron letters, 52(38).
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  This communication reveals an innovative and facile procedure to prepare quinoxalines in two synthetic steps. The microwave assisted Petasis reaction is followed by the acid mediated unmasking of an internal amino nucleophile, cyclodehydration and oxidation to give collections of quinoxalines in good to excellent yields.
• Nichol, G. S., Zhigang, X. u., Kaiser, C. E., & Hulme, C. (2011). 4-(piperidin-1-yl)-4H-benzo[b]tetrazolo-[1,5-d][1,4]diazepin-5(6H)-one. Acta Crystallographica Section E: Structure Reports Online, 67(1), o23-o24.
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  PMID: 21522729;PMCID: PMC3050344;Abstract: There are two crystallographically unique molecules present in the asymmetric unit of the title compound, C14H16N 6O; in both molecules, the seven-membered diazepinone ring adopts a boat-like conformation and the chair conformation piperidine ring is an axial substituent on the diazepinone ring. In the crystal, each molecule forms hydrogen bonds with its respective symmetry equivalents. Hydrogen bonding between molecule A and symmetry equivalents forms two ring motifs, the first formed by inversion-related n-h ⋯ o interactions and the second formed by c-h ⋯ o and c-h⋯n interactions. The combination of both ring motifs results in the formation of an infinite double tape, which propagates in the a-axis direction. hydrogen bonding between molecule B and symmetry equivalents forms one ring motif by inversion-related n-h ⋯ o interactions and a second ring motif by c-h ⋯ o interactions, which propagate as a single tape parallel with the c axis.
• Dietrich, J., Hulme, C., & Hurley, L. H. (2010). The design, synthesis, and evaluation of 8 hybrid DFG-out allosteric kinase inhibitors: A structural analysis of the binding interactions of Gleevec ^®, Nexavar^®, and BIRB-796. Bioorganic and Medicinal Chemistry, 18(15), 5738-5748.
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  PMID: 20621496;Abstract: The majority of kinase inhibitors developed to date are competitive inhibitors that target the ATP binding site; however, recent crystal structures of Gleevec® (imatinib mesylate, STI571, PDB: 1IEP), Nexavar ® (Sorafenib tosylate, BAY 43-9006, PDB: 1UWJ), and BIRB-796 (PDB: 1KV2) have revealed a secondary binding site adjacent to the ATP binding site known as the DFG-out allosteric binding site. The recent successes of Gleevec® and Nexavar® for the treatment of chronic myeloid leukemia and renal cell carcinoma has generated great interest in the development of other kinase inhibitors that target this secondary binding site. Here, we present a structural comparison of the important and similar interactions necessary for Gleevec®, Nexavar®, and BIRB-796 to bind to their respective DFG-out allosteric binding pockets and the selectivity of each with respect to c-Abl, B-Raf, and p38α. A structural analysis of their selectivity profiles has been generated from the synthesis and evaluation of 8 additional DFG-out allosteric inhibitors that were developed directly from fragments of these successful scaffolds. © 2010 Elsevier Ltd.
• Dietrich, J., Kaiser, C., Meurice, N., & Hulme, C. (2010). Concise two-step solution phase syntheses of four novel dihydroquinazoline scaffolds. Tetrahedron Letters, 51(30), 3951-3955.
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  Abstract: Novel two-step solution phase protocols for the synthesis of dihydroquinazolines and fused dihydroquinazoline-benzodiazepine tetracycles are reported. The methodology employs the Ugi reaction to assemble the desired diversity and acid treatment enables ring-closing transformations. The protocols are further facilitated by the use of microwave irradiation and n-butyl isocyanide to control the rate of each ring-forming transformation.
• Gunawan, S., Nichol, G. S., Chappeta, S., Dietrich, J., & Hulme, C. (2010). Concise preparation of novel tricyclic chemotypes: Fused hydantoin-benzodiazepines. Tetrahedron Letters, 51(36), 4689-4692.
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  Abstract: The following article describes a concise synthesis of a collection of 4,5-dihydro-1H-benzo[e][1,4]diazepines fused to a hydantoin ring. Molecular complexity and biological relevance are high and structures are generated in a mere three steps, employing the Ugi reaction to assemble diversity reagents. The protocol represents a novel UDC (Ugi-deprotect-cyclize) strategy employed in the Ugi-5-component CO2-mediated condensation, followed by further cyclization under basic conditions, to afford the fused hydantoin. Mechanistic caveats, dependent on the aldehydes of choice will be revealed and a facile oxidation of the final products to imidazolidenetriones is briefly discussed. © 2010 Elsevier Ltd. All rights reserved.
• Hulme, C., Dietrich, J., Kaiser, C., Meurice, N., & Hulme, C. -. (2010). Concise Two-Step Solution Phase Syntheses of four novel Dihydroquinazoline scaffolds. Tetrahedron letters, 51(30).
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  Novel two-step solution phase protocols for the synthesis of dihydroquinazolines and fused dihydroquinazoline-benzodiazepine tetracycles are reported. The methodology employs the Ugi reaction to assemble desired diversity and acid treatment enables ring closing transformations. The protocols are further facilitated by the use of microwave irradiation and n-butyl isocyanide to control the rate of each ring forming transformation.
• Hulme, C., Gunawan, S., Nichol, G. S., Chappeta, S., Dietrich, J., & Hulme, C. -. (2010). Concise Preparation of Novel Tricyclic Chemotypes: Fused Hydantoin-benzodiazepines. Tetrahedron letters, 51(36).
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  The following article describes a concise synthesis of a collection of 4,5-dihydro-1H-benzo[e][1,4]diazepines fused to a hydantoin ring. Molecular complexity and biological relevance is high and structures are generated in a mere three steps, employing the Ugi reaction to assemble diversity reagents. The protocol represents a novel UDC (Ugi-deprotect-cyclize) strategy employed in the Ugi-5-component CO(2) mediated condensation, followed by further cyclization under basic conditions, to afford the fused hydantoin. Mechanistic caveats, dependent on aldehydes of choice will be revealed and a facile oxidation of final products to imidazolidenetriones briefly discussed.
• Hulme, C., Xu, Z., Dietrich, J., Shaw, A. Y., & Hulme, C. -. (2010). Two step syntheses of fused quinoxaline-benzodiazepines and bis-benzodiazepines. Tetrahedron letters, 51(34).
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  A two-step solution phase synthesis employing a double UDC (Ugi/Deprotect/Cyclize) strategy has been utilized to obtain fused 6,7,6,6-quinoxalinone-benzodiazepines and 6,7,7,6-bis-benzodiazepines. Optimization of the methodology to produce these tetracyclic scaffolds was enabled by microwave irradiation, incorporation of trifluoroethanol as solvent, and the use of the convertible isocyanide, 4-tert-butyl cyclohexen-1-yl isocyanide.
• Meurice, N., Wang, L., Lipinski, C. A., Yang, Z., Hulme, C., & Loftus, J. C. (2010). Structural conservation in band 4.1, ezrin, radixin, moesin (FERM) domains as a guide to identify inhibitors of the proline-rich tyrosine kinase 2. Journal of Medicinal Chemistry, 53(2), 669-677.
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  PMID: 20017492;PMCID: PMC3178892;Abstract: The nonreceptor focal adhesion kinases FAK and Pyk2 play a central role in the regulation of glioma cell proliferation and migration, making them attractive targets to improve clinical outcome. Noncatalytic targeting represents a novel approach to regulate the activity of these tyrosine kinases. A combination of site directed mutagenesis and molecular modeling was used to identify compounds that target the F3 module of the Pyk2 FERM domain. A protein pharmacophore model for the Pyk2 FERM/F3 module, generated utilizing the structural conservation of ligand-bound FERM domains with known 3D structures, was used to search the LeadQuest compound library. Compounds compliant with the model were tested for their ability to inhibit the binding of a monoclonal antibody that maps to a functional site on the F3 module. The highest scoring compound bound directly to the Pyk2 FERM domain, inhibited Pyk2 stimulated glioma migration, and provides the framework for the development of novel therapeutic agents to target the activity of the focal adhesion kinases. ©2009 American Chemical Society.
• Nichol, G. S., Gunawan, S., Dietrich, J., & Hulme, C. (2010). 2-Butyl-11-phenyl-5,10-dihydro-1H-benzo[e]imidazo[1,5-a][1,4]diazepine-1, 3(2H)-dione. Acta Crystallographica Section E: Structure Reports Online, 66(3), o625.
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  PMID: 21580382;PMCID: PMC2983587;Abstract: The title compound, C21H21N3O2, was obtained following a five-step synthetic procedure yielding weakly diffracting rod and needle-shaped crystals which crystallized concomitantly. Structural analysis of a rod-shaped crystal showed that the central seven-membered heterocyclic ring adopts a conformation that is perhaps best described as a distorted boat, with the H-bearing (CH2 and NH) atoms lying well out of the least-squares mean plane fitted through the other five atoms in the ring (r.m.s. deviation 0.075 Å). In the crystal, the compound packs as a twisted chain, which propagates along the b axis by means of an R 12(6) motif formed by one of the carbonyl O atoms acting as a bifurcated acceptor in an N - H⋯O and C - H⋯O inter-action. No diffraction was observed from the needle-shaped crystals.
• Nichol, G. S., Gunawan, S., Zhigang, X. u., Dietrich, J., & Hulme, C. (2010). 2-Propyl 3,3-dibromo-2-hydroxypyrrolidine-1-carboxylate. Acta Crystallographica Section E: Structure Reports Online, 66(3), o597.
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  PMID: 21580358;PMCID: PMC2983708;Abstract: The title compound, C8H13Br2NO 3, crystallizes as a non-merohedral twin with twin law -0.6 0 0.4/0 - 1 0 /1.6 0 0.6, and the structure has a refined twin domain ratio of 0.546 (5). The structure shows a compact conformation, with the ester unit roughly coplanar with a mean plane fitted through the non-H atoms of the pyrrolidine ring [dihedral angle = 8.23 (9)°]. In the crystal, inversion dimers linked by pairs of O - H⋯O hydrogen bonds generate an R 22(12) motif.
• Zhigang, X. u., Dietrich, J., Shaw, A. Y., & Hulme, C. (2010). Two-step syntheses of fused quinoxaline-benzodiazepines and bis-benzodiazepines. Tetrahedron Letters, 51(34), 4566-4569.
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  Abstract: A two-step solution phase synthesis employing a double UDC (Ugi/Deprotect/Cyclize) strategy has been utilized to obtain fused 6,7,6,6-quinoxalinone-benzodiazepines and 6,7,7,6-bis-benzodiazepines. Optimization of the methodology to produce these tetracyclic scaffolds was enabled by microwave irradiation, incorporation of trifluoroethanol as solvent, and the use of the convertible isocyanide, 4-tert-butyl cyclohexen-1-yl isocyanide.
• Hulme, C., & Dietrich, J. (2009). Emerging molecular diversity from the intra-molecular Ugi reaction: Iterative efficiency in medicinal chemistry. Molecular Diversity, 13(2), 195-207.
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  PMID: 19205916;Abstract: This review details a now established area within the isonitrile multi-component reaction (IMCR) field of study, namely employing bi-functional reagents in the Ugi reaction for the construction of screening sets with the additional element or even possibly 'metric' of enhanced 'iterative efficiency potential'. The concept of 'iterative efficiency' will be briefly introduced, coupled with discussion on new synthetic routes to select bi-functional IMCR precursors and their use in the generation of pharmacologically relevant 'molecular diversity'. © 2009 Springer Science+Business Media B.V.
• Hulme, C., Chappeta, S., & Dietrich, J. (2009). A simple, cheap alternative to 'designer convertible isonitriles' expedited with microwaves. Tetrahedron Letters, 50(28), 4054-4057.
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  Abstract: Interest in designer convertible isonitriles has increased in recent years with the growing recognition that isonitrile-based multi-component reactions (IMCRs) are highly effective in rapidly accessing, new and pharmacologically relevant diversity space. This Letter reports on the novel use of n-butylisonitrile as a cheaper and more atom-economical alternative to currently reported 'designer convertible isonitriles', facilitated by the advent of microwave-assisted organic synthesis (MAOS).
• Hulme, C., Chappeta, S., Griffith, C., Lee, Y., & Dietrich, J. (2009). An efficient solution phase synthesis of triazadibenzoazulenones: 'designer isonitrile free' methodology enabled by microwaves. Tetrahedron Letters, 50(17), 1939-1942.
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  Abstract: A novel two-step solution phase protocol for the synthesis of arrays of triazadibenzoazulenones is reported. The methodology employs the Ugi reaction to assemble desired diversity and acid treatment enables two tandem ring closing transformations. The order of ring closure is shown to be key for optimal conversion to the desired tetra-cyclic product and initially proceeds through a benzimidazole intermediate, followed by second ring closure to give the desired fused benzodiazepine. The two-step protocol is further facilitated by microwave irradiation. Prudent selection of the isonitrile reagent enables the correct order of ring forming events. As such the methodology represents the first example of a post-condensation Ugi modification that employs two internal amino nucleophiles. © 2009 Elsevier Ltd. All rights reserved.
• Hulme, C., & Lee, Y. (2008). Emerging approaches for the syntheses of bicyclic imidazo[1,2-x]- heterocycles. Molecular Diversity, 12(1), 1-15.
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  PMID: 18409015;Abstract: Imidazo-[1,2-x]heterocycles are versatile building blocks for use in both a 'drug hunters' quest to discover new leads and a chemical biologists search for effective molecular tools in 'cell perturbation' studies. At the front end of the drug discovery flow chart, the last 5-10 years have witnessed the discovery of new high-throughput methodologies which very quickly have enabled access to virtual libraries of these chemo-types in the realm of 107 derivatives. Interestingly, these often neglected cores in patent cooperation treaty (PCT) applications appear in several highly effective marketed drugs, completing the medicinal chemists search for clinical success. Such rigid chemo-types, all containing a bridgehead nitrogen atom, are thus poised for an ever increasing impact on the discovery and development of new molecular therapeutics. The following mini-review will briefly cover therapeutic utility, chemical methodologies and automation developed to enable preparation of arrays of these chemo-types in a high-throughput manner. Synthetic emphasis is placed on a 3-component-3-center isocyanide based multi-component reaction (IMCR), which spans solution, solid phase, flourous and microwave assisted organic synthesis. © 2008 Springer Science+Business Media B.V.
• Hulme, C., & Maggiora, G. M. (2008). Molecular diversity: from small to large, emerging to enabling. Current Opinion in Chemical Biology, 12(3), 257-259.
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  PMID: 18498777;
• Umkehrer, M., Ross, G., Jäger, N., Burdack, C., Kolb, J., Hong, H. u., Alvim-Gaston, M., & Hulme, C. (2007). Expeditious synthesis of imidazo[1,2-c]pyrimidines via a [4+1]-cycloaddition. Tetrahedron Letters, 48(12), 2213-2216.
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  Abstract: A new and versatile synthesis of imidazo[1,2-c]pyrimidines via a [4+1]-cycloaddition is described. The reported novel synthetic approach leads to pharmacologically interesting scaffolds containing three points of potential diversity, which previously were not accessible under conventional conditions. In addition, this novel synthetic procedure is amenable to the assembly of libraries with this interesting core structure. © 2007 Elsevier Ltd. All rights reserved.
• Masquelin, T., Bui, H., Brickley, B., Stephenson, G., Schwerkoske, J., & Hulme, C. (2006). Sequential Ugi/Strecker reactions via microwave assisted organic synthesis: Novel 3-center-4-component and 3-center-5-component multi-component reactions. Tetrahedron Letters, 47(17), 2989-2991.
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  Abstract: Two novel one-step microwave mediated syntheses of arrays of 3-iminoaryl-imidazo[1,2-a]pyridines and imidazo[1,2-a]pyridyn-3-ylamino-2- acetonitriles are reported. Reactions are performed under microwave condition in methanol by simply mixing α-amino-pyridines, aldehydes, and trimethylsilylcyanide (TMSCN) with distinct reagent stoichiometries, catalyzed by polymer-bound scandium triflate, to afford either product. Furthermore, functionally different aldehydes were shown to proceed to different end-points, adding an extra caveat to the studies. The new methodology represents examples of both formal 3-center-4-component and 3-center-5-component multi-component reactions. © 2006 Elsevier Ltd. All rights reserved.
• Salamant, W., & Hulme, C. (2006). Unique one step, multicomponent α,β,β-oxidations of carbamates with Willgerodt-like hypervalent iodine reagents - An example of triple C-H bond activation. Tetrahedron Letters, 47(4), 605-609.
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  Abstract: This communication reveals a novel multicomponent oxidation of saturated, urethane protected nitrogen heterocyclic systems. The oxidation is facile, general, high yielding and involves the application of readily-made hypervalent iodine reagents, giving an α,β,β-oxidation pattern relative to the nitrogen of the heterocycle. The oxidation is multicomponent type III, in that the substrate, reagent and solvent provide the three inputs during the reaction. The transformation also represents an example of triple C-H bond activation. A mechanistic rationale for this is proposed. © 2005 Elsevier Ltd. All rights reserved.
• Vu, M. a., Bannon, A. W., Baumgartner, J., Hale, C., Hsieh, F., Hulme, C., Rorrer, K., Salon, J., Staden, C. v., & Tempest, P. (2006). Solid-phase synthesis and structure-activity relationships of novel biarylethers as melanin-concentrating hormone receptor-1 antagonists. Bioorganic and Medicinal Chemistry Letters, 16(19), 5066-5072.
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  PMID: 16887348;Abstract: Melanin-concentrating hormone (MCH) is a cyclic 19 amino acid orexigenic neuropeptide. The action of MCH on feeding is thought to involve the activation of its respective G protein-coupled receptor MCH-R1. Consequently, antagonists that block MCH regulated MCH-R1 activity may provide a viable approach to the treatment of diet-induced obesity. This communication reports the discovery of a novel MCH-R1 receptor antagonist, the biarylether 7, identified through high throughput screening. The solid-phase synthesis and structure-activity relationship of related analogs is described. © 2006 Elsevier Ltd. All rights reserved.
• Hulme, C. (2005). Applications of Multicomponent Reactions in Drug Discovery - Lead Generation to Process Development. Multicomponent Reactions, 311-341.
• Schwerkoske, J., Masquelin, T., Perun, T., & Hulme, C. (2005). New multi-component reaction accessing 3-aminoimidazo[1,2-a]pyridines. Tetrahedron Letters, 46(48), 8355-8357.
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  Abstract: The novel one step solution phase synthesis of an array of 3-aminoimidazo[1,2-a]pyridines is reported. Reactions were performed in methanol by mixing a α-amino-pyridine, aldehyde and trimethylsilylcyanide (TMSCN) to give the desired product. Mediated by microwave irradiation and catalyzed by scandium triflate, the methodology represents the first one pot preparation of 3-aminoimidazo[1,2-a]pyridines that avoids the use of an isonitrile and subsequent de-protection strategy. The reaction is an example of a formal three-centre-three-component multi-component reaction.
• Hulme, C., & Gore, V. (2003). "Multi-component reactions: Emerging chemistry in drug discovery" 'from Xylocain to Crixivan'. Current Medicinal Chemistry, 10(1), 51-80.
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  PMID: 12570721;Abstract: With the recent emergence of combinatorial chemistry and high-speed parallel synthesis for drug discovery applications, the multi-component reaction (MCR) has seen a resurgence of interest. Easily automated one-pot reactions, such as the Ugi and Passerini reactions, are powerful tools for producing diverse arrays of compounds, often in one step and high yield. Despite this synthetic potential, the Ugi reaction is limited by producing products that are flexible and peptide-like, often being classified as 'non drug-like'. This review details developments of new, highly atom-economic MCR derived chemical methods, which enable the fast and efficient production of chemical libraries comprised of a variety of biologically relevant templates. Representative examples will also be given demonstrating the successful impact of MCR combinatorial methods at different stages of the lead discovery, lead optimization and pre-clinical process development arenas. This will include applications spanning biological tools, natural products and natural product-like diversity, traditional small molecule and 'biotech' therapeutics respectively. In particular, this review will focus on applications of isocyanide based MCR (IMCR) reactions.
• Hulme, C., & Nixey, T. (2003). Rapid assembly of molecular diversity via exploitation of isocyanide-based multi-component reactions. Current Opinion in Drug Discovery and Development, 6(6), 921-929.
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  PMID: 14758761;Abstract: Molecular diversity is the variability of physical properties between molecules, viewed in terms of molecular shape, polarity/charge, lipophilicity, polarizability and flexibility. Due to their widespread medicinal properties, natural products were one of the original sources of molecular diversity; however, new developments in the search for novel pharmacological agents over the last decade have focused on the preparation of chemical libraries as the source of new leads for drug discovery. A plethora of personal synthesizers and new automation technologies have emerged to help fuel the lead discovery engines of drug discovery organizations. Multistep solid-phase syntheses of diverse libraries in excess of 10,000 products can now be prepared via split-and-mix techniques. Simultaneously, a multitude of more efficient, diversity- or target-oriented solution-phase chemical methodologies have appeared in the chemical literature, enabling the relatively facile construction of successful lead generation libraries with low full-time equivalent input and little capital expenditure. Isocyanide-related multi-component reactions hold a pre-eminent position in this regard, and are finding increasing applications in the discovery process of new drugs and agrochemicals. This review is the authors' personal assessment of advances in the field over the last two years (2002 to 2003), with little emphasis placed on highly mechanistic details.
• Hulme, C., Bienaymé, H., Nixey, T., Chenera, B., Jones, W., Tempest, P., & Smith, A. L. (2003). Library Generation via Postcondensation Modifications of Isocyanide-Based Multicomponent Reactions. Methods in Enzymology, 369, 469-496.
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  PMID: 14722968;
• Tempest, P., Pettus, L., Gore, V., & Hulme, C. (2003). MCC/S_NAr methodology. Part 2: Novel three-step solution phase access to libraries of benzodiazepines. Tetrahedron Letters, 44(9), 1947-1950.
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  Abstract: New developments in the search for novel pharmacological agents over the last decade have focused on the preparation of chemical libraries as sources for new leads for drug discovery. To aid this search a plethora of personal synthesizers and new automation technologies have emerged to help fuel the lead discovery engines of drug discovery organizations. In fact, multi-step solid-phase syntheses of diverse libraries in excess of 10,000 products are now feasible via split and mix techniques. At the same time, a multitude of more efficient, diversity or target oriented solution phase chemical methodologies have appeared in the chemical literature, which have enabled the relatively facile construction of successful lead generation libraries with low FTE input and little capital expenditure. This communication reveals a further application of N-BOC-α-aminoaldehydes in the Ugi condensation reaction, followed by a secondary SNAr cyclization, accessing arrays of biologically relevant benzodiazepines in good yield and overall purity. © 2003 Elsevier Science Ltd. All rights reserved.
• Vasquez Jr., T. E., Nixey, T., Chenera, B., Gore, V., Bartberger, M. D., Sun, Y., & Hulme, C. (2003). One-pot microwave assisted preparation of pyrazoloquinazolinone libraries. Molecular Diversity, 7(2-4), 161-164.
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  PMID: 14870845;Abstract: The novel solution-phase synthesis of an array of biologically relevant pyrazoloquinazolinones in a simple microwave driven one pot procedure is revelaed. Transformations are carried out in good to excellent yield by condensation of α-cyano-ketones and 2-hydrazino-benzoic acids. Subsequent microwave irradiation affords pyrazoloquinazolinones with six points of potential diversification. The protocol described represents a very attractive solution phase procedure for the rapid generation of arrays of such functionalized cores, further demonstrating the growing importance of economic and enabling complexity generating chemistries in the lead discovery arena.
• Nixey, T., & Hulme, C. (2002). Rapid generation of cis-constrained norstatine analogs using a TMSN₃-modified Passerini MCC/N-capping strategy. Tetrahedron Letters, 43(38), 6833-6835.
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  Abstract: A novel application of the TMSN3-modified Passerini three-component reaction is disclosed for the rapid solution phase synthesis of cis constrained norstatine mimetic libraries. The reaction of an N-BOC-α-amino aldehyde, an isocyanide and trimethylsilylazide in dichloromethane, followed by deprotection and N-capping with TFP esters affords cis constrained norstatine mimetics. This efficient protocol, producing products with three diversity points, can be used to generate arrays of biologically relevant small molecules for protease targeted screening. © 2002 Elsevier Science Ltd. All rights reserved.
• Nixey, T., Kelly, M., Semin, D., & Hulme, C. (2002). Short solution phase preparation of fused azepine-tetrazoles via a UDC (Ugi/de-Boc/cyclize) strategy. Tetrahedron Letters, 43(20), 3681-3684.
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  Abstract: A novel application of the TMSN3 modified Ugi 4-component reaction is disclosed for the solution phase synthesis of fused azepine-tetrazole libraries. The reaction of a N-Boc-α-amino aldehyde, secondary amine, methyl isocyanoacetate and trimethylsilylazide in methanol, followed by acid treatment, proton scavenging and reflux affords bicyclic azepine-tetrazoles. This efficient protocol, producing products with three diversity points, can be used to generate arrays of biologically relevant small molecules for general and targeted screening. © 2002 Elsevier Science Ltd. All rights reserved.
• Nixey, T., Tempest, P., & Hulme, C. (2002). Two-step solution-phase synthesis of novel quinoxalinones utilizing a UDC (Ugi/de-Boc/cyclize) strategy. Tetrahedron Letters, 43(9), 1637-1639.
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  Abstract: The novel solution-phase synthesis of an array of biologically relevant quinoxalinones in a simple two-step procedure is revealed. Transformations are carried out in excellent yield by condensation of mono-Boc protected ortho-phenylene di-amine, glyoxylic acids and supporting Ugi reagents. Subsequent acid treatment and evaporation affords quinoxalinones in good to excellent yields. © 2002 Elsevier Science Ltd. All rights reserved.
• Viswanadhan, V. N., Balan, C., Hulme, C., Cheetham, J. C., & Sun, Y. (2002). Knowledge-based approaches in the design and selection of compound libraries for drug discovery. Current Opinion in Drug Discovery and Development, 5(3), 400-406.
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  PMID: 12058615;Abstract: In the past decade, the pharmaceutical industry has realized the increasing significance of impacting the early phase hit-to-lead development in the drug discovery process. In particular, knowledge-based approaches emerged and evolved to address a multitude of issues such as absorption, distribution, metabolism and excretion (ADME), potency, toxicity and overall drugability. Each of these approaches seeks to bring together all relevant pieces of information and create a knowledge-oriented process to deploy such information in drug discovery. This review focuses on work relating to drugability, which aims at obtaining hits (or leads) that have enhanced likelihoods of leading to successful clinical candidates by medicinal chemistry efforts. The period covered in this review is from 1997 (since the publication of Lipinski's rule of 5) to March 2002.
• Tempest, P., Vu, M. a., Kelly, M. G., Jones, W., & Hulme, C. (2001). MCC/S_NAr methodology. Part 1: Novel access to a range of heterocyclic cores. Tetrahedron Letters, 42(30), 4963-4968.
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  Abstract: The novel solution-phase syntheses of arrays of biologically relevant indazolinones, benzazepines and benzoxazepines, utilizing multi-component condensation (MCC)/SNAr methodology is reported. Reaction of commercially available 2-fluoro-5-nitrobenzoic acid with an aldehyde, isonitrile and a primary amine tethered to a Boc-protected internal amino or hydroxyl nucleophile, affords the Ugi product in good yield. Subsequent acid treatment followed by proton scavenging promotes cyclization of internal amino nucleophiles to a variety of ring sizes. Base treatment alone is sufficient to generate benzoxazepines. Interestingly, this communication also introduces a highly efficient two-step route to benzimidazoles. © 2001 Elsevier Science Ltd.
• Tempest, P., Vu, M. a., Thomas, S., Hua, Z., Kelly, M. G., & Hulme, C. (2001). Two-step solution-phase synthesis of novel benzimidazoles utilizing a UDC (Ugi/de-Boc/cyclize) strategy. Tetrahedron Letters, 42(30), 4959-4962.
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  Abstract: The novel solution-phase synthesis of an array of biologically relevant benzimidazoles in a simple two-step procedure is revealed. Transformations are carried out in excellent yield by condensation of mono-Boc protected ortho-phenylene diamine and supporting Ugi reagents. Subsequent acid treatment and evaporation affords benzimidazoles in good to excellent yield. The described protocol represents a highly attractive solution-phase procedure for the rapid generation of benzimidazole libraries. © 2001 Elsevier Science Ltd.
• Bienaymé, H., Hulme, C., Oddon, G., & Schmitt, P. (2000). Maximizing synthetic efficiency: Multi-component transformations lead the way. Chemistry - A European Journal, 6(18), 3321-3329.
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  Abstract: With the emergence of high-throughput screening in the pharmaceutical industry in the early 1990's, organic chemists were faced with a new challenge: how to prepare large collections of molecules (the libraries) to "feed" the high-throughput screen? The unique exploratory power of some reactions (such as the 40 year-old Ugi four-component condensation) was soon recognized to be extremely valuable to produce libraries in a time-and cost-effective manner. Over the last five years, industrial and academic researchers have made these powerful transformations into one of the most efficient and cost-effective tools for combinatorial and parallel synthesis.
• Hulme, C., Liang, M. a., Cherrier, M., Romano, J. J., Morton, G., Duquenne, C., Salvino, J., & Labaudiniere, R. (2000). Novel applications of convertible isonitriles for the synthesis of mono and bicyclic γ-lactams via a UDC strategy. Tetrahedron Letters, 41(12), 1883-1887.
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  Abstract: This communication reveals a novel application of the so-called convertible isonitriles for the solution/solid phase generation of γ-lactam analogues. Use of tethered N-BOC aldehydes in the Ugi multi-component reaction (MCR), followed by BOC removal and base treatment (a '3-step, 1-pot procedure') affords γ-lactams in good yield. The UDC (Ugi/De-BOC/Cyclize) strategy, coupled with a convertible isonitrile, is now feasible from all three substitution sites of the Ugi product. A conceptually novel approach, combining a bi-functional precursor with a post-condensation modification to give fused lactam-ketopiperazines, is also revealed. (C) 2000 Elsevier Science Ltd.
• Hulme, C., Liang, M. a., Kumar, N. V., Krolikowski, P. H., Allen, A. C., & Labaudiniere, R. (2000). Novel applications of resin bound α-amino acids for the synthesis of benzodiazepines (via Wang resin) and ketopiperazines (via hydroxymethyl resin). Tetrahedron Letters, 41(10), 1509-1514.
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  Abstract: This communication reveals a novel application of resin bound α-amino acids coupled with the UDC (Ugi/DeBOC/cyclize) strategy. Reaction with either N-BOC-α-amino aldehydes or N-BOC anthranilic acids and subsequent acid treatment allows the preparation of highly pure and diverse arrays (approx. 10000 in size) of 1,4-benzodiazepines (Wang resin) and ketopiperazines (hydroxymethyl resin), respectively. Notable for the benzodiazepine series of compounds are the five potential points of diversity available from this two-step protocol. (C) 2000 Elsevier Science Ltd.
• Hulme, C., Liang, M. a., Romano, J. J., Morton, G., Tang, S., Cherrier, M., Choi, S., Salvino, J., & Labaudiniere, R. (2000). Novel applications of carbon dioxide/MeOH for the synthesis of hydantoins and cyclic ureas via the Ugi reaction. Tetrahedron Letters, 41(12), 1889-1893.
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  Abstract: This communication reveals novel applications of the CO2/MeOH reagent combination coupled with the UDC (Ugi/DeBOC/Cyclize) strategy. The Ugi five component condensation (5CC) affords carbamate protected amino-amides in good yield. When one of the supporting reagents employed in the Ugi reaction possesses a tethered amino-BOC protected functional group, subsequent acid treatment and proton scavenging results in rapid cyclization to cyclic ureas. Additionally, treatment of the 5CC product with base affords hydantoins in good yield, representing a novel and short approach to this class of molecule. (C) 2000 Elsevier Science Ltd.
• Nixey, T., Kelly, M., & Hulme, C. (2000). The one-pot solution phase preparation of fused tetrazole-ketopiperazines. Tetrahedron Letters, 41(45), 8729-8733.
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  Abstract: A novel application of the TMSN3 modified Ugi 4-component reaction is disclosed for the solution phase synthesis of fused tetrazole-ketopiperazine libraries. The reaction of an aldehyde, primary amine, methyl isocyanoacetate and trimethylsilylazide in methanol at reflux affords bicyclic tetrazole-ketopiperazines in good yield. This efficient one step protocol, producing products with three potential diversity points, may be used to generate arrays of biologically relevant small molecules for general and targeted screening. (C) 2000 Elsevier Science Ltd.
• Hulme, C., & Cherrier, M. -. (1999). Novel applications of ethyl glyoxalate with the Ugi MCR. Tetrahedron Letters, 40(29), 5295-5299.
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  Abstract: This letter describes novel high-yielding solution phase preparations of 1,4-benzodiazepine-2,5-dione, diketopiperazine, ketopiperazine and dihydroquinoxalinone libraries via a UDC (Ugi/de-Boc/cyclization) strategy in combination with ethylglyoxalate. The methodology represents a 'three step, one-pot procedure', employing the Ugi multi-component reaction (MCR), followed by Boc deprotection and cyclization.
• Hulme, C., Liang, M. a., Romano, J., & Morrissette, M. (1999). Remarkable three-step-one-pot solution phase preparation of novel imidazolines utilizing a UDC (Ugi/de-Boc/cyclize) strategy. Tetrahedron Letters, 40(45), 7925-7928.
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  Abstract: This communication reveals the novel solution phase synthesis of an array of biologically relevant imidazolines in a remarkable 'three-step-one-pot' procedure, utilizing a Ugi/de-Boc/cyclization (UDC) strategy. Transformations are carried out in excellent yield by condensation of N-Boc-α-amino-aldehydes and supporting Ugi reagents. The described protocol represents a highly attractive solution phase procedure for the rapid generation of this class of molecule.
• Mason, J. S., Morize, I., Menard, P. R., Cheney, D. L., Hulme, C., & Labaudiniere, R. F. (1999). New 4-point pharmacophore method for molecular similarity and diversity applications: Overview of the method and applications, including a novel approach to the design of combinatorial libraries containing privileged substructures. Journal of Medicinal Chemistry, 42(17), 3251-3264.
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  PMID: 10464012;Abstract: A new 4-point pharmacophore method for molecular similarity and diversity that rapidly calculates all potential pharmacophores/pharmacophoric shapes for a molecule or a protein site is described. The method, an extension to the ChemDiverse/Chem-X software (Oxford Molecular, Oxford, England), has also been customized to enable a new internally referenced measure of pharmacophore diversity. The 'privileged' substructure concept for the design of high-affinity ligands is presented, and an example of this new method is described for the design of combinatorial libraries for 7- transmembrane G-protein-coupled receptor targets, where 'privileged' substructures are used as special features to internally reference the pharmacophoric shapes. Up to 7 features and 15 distance ranges are considered, giving up to 350 million potential 4-point 3D pharmacophores/molecule. The resultant pharmacophore 'key' ('fingerprint') serves as a powerful measure for diversity or similarity, calculable for both a ligand and a protein site, and provides a consistent frame of reference for comparing molecules, sets of molecules, and protein sites. Explicit 'on-the- fly' conformational sampling is performed for a molecule to enable the calculation of all geometries accessible for all combinations of four features (i.e., 4-point pharmacophores) at any desired sampling resolution. For a protein site, complementary site points to groups displayed in the site are generated and all combinations of four site points are considered. In this paper we report (i) the details of our customized implementation of the method and its modification to systematically measure 4-point pharmacophores relative to a 'special' substructure of interest present in the molecules under study; (ii) comparisons of 3- and 4-point pharmacophore methods, highlighting the much increased resolution of the 4-point method; (iii) applications of the 4-point potential pharmacophore descriptors as a new measure of molecular similarity and diversity and for the design of focused/biased combinatorial libraries.
• McGarry, D. G., Regan, J. R., Volz, F. A., Hulme, C., Moriarty, K. J., Djuric, S. W., Souness, J. E., Miller, B. E., Travis, J. J., & Sweeney, D. M. (1999). Benzofuran based PDE4 inhibitors. Bioorganic and Medicinal Chemistry, 7(6), 1131-1139.
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  PMID: 10428384;Abstract: Replacement of the 3,4-dialkoxyphenyl substructure common to a number of PDE4 inhibitors with a 2-alkyl-7-methoxybenzofuran unit is described. This substitution can result in either enhancement or substantial reductions in PDE4 inhibitory activity depending on the system to which it is applied. An in vitro SAR study of a potent series of 4-(2-heteroaryl-ethyl)-benzofurans 26 is also presented. Copyright (C) 1999 Elsevier Science Ltd.
• Hulme, C., Mathew, R., Moriarty, K., Miller, B., Ramanjulu, M., Cox, P., Souness, J., Page, K. M., Uhl, J., Travis, J., Labaudiniere, R., Huang, F., & Djuric, S. W. (1998). Orally active indole N-oxide PDE4 inhibitors. Bioorganic and Medicinal Chemistry Letters, 8(21), 3053-3058.
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  PMID: 9873675;Abstract: This communication describes the synthesis and in vitro and in vivo evaluation of a novel potent series of phosphodiesterase type (IV) (PDE4) inhibitors. Several of the compounds presented possess low nanomolar IC50's for PDE4 inhibition and excellent in vivo activity for inhibition of TNF-α levels in LPS challenged mice (mouse endotoxemia model). Emesis studies (dog) and efficacy in a SCW arthritis model for the most potent PDE4 inhibitors are presented.
• Hulme, C., Moriarty, K., Huang, F., Mason, J., McGarry, D., Labaudiniere, R., Souness, J., & Djuric, S. (1998). Quaternary substituted PDE IV inhibitors II: The synthesis and in vitro evaluation of a novel series of γ-lactams. Bioorganic and Medicinal Chemistry Letters, 8(4), 399-404.
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  PMID: 9871693;Abstract: This communication describes the synthesis and in vitro evaluation of a novel potent series of phosphodiesterase type (IV) (PDE IV) inhibitors. Several of the quaternary substituted lactams presented possess low nanomolar IC50's for PDE IV inhibition.
• Hulme, C., Moriarty, K., Miller, B., Mathew, R., Ramanjulu, M., Cox, P., Souness, J., Page, K. M., Uhl, J., Travis, J., Huang, F., Labaudiniere, R., & Djuric, S. W. (1998). The synthesis and biological evaluation of a novel series of indole PDE4 inhibitors I. Bioorganic and Medicinal Chemistry Letters, 8(14), 1867-1872.
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  PMID: 9873449;Abstract: This communication describes the synthesis and in vitro evaluation of a novel potent series of phosphodiesterase type (IV) (PDE4) inhibitors. The compounds described contain an indole moiety which replaces the 'rolipram- like' 3-methoxy-4-cyclopentoxy motif. Several of the compounds presented possess low nanomolar IC50's for PDEIV inhibition. In vivo activities determined from measurement of serum TNF-α levels in LPS challenged mice (mouse endotoxemia model) are also reported.
• Hulme, C., Morrissette, M. M., Volz, F. A., & Burns, C. J. (1998). The solution phase synthesis of diketopiperazine libraries via the Ugi reaction: Novel application of Armstrong's convertible isonitrile.. Tetrahedron Letters, 39(10), 1113-1116.
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  Abstract: This communication describes the generation of high-yielding solution phase diketopiperazine libraries via a '3-step, 1-pot' procedure, employing the Ugi multi-component reaction (MCR), followed by BOC deprotection and cyclization to diketopiperazine (DKP). Exploitation of Armstrong's convertible isonitrile in the Ugi reaction utilising an 'internal nucleophile' approach for diketopiperazine formation is presented.
• Hulme, C., Peng, J., Louridas, B., Menard, P., Krolikowski, P., & Kumar, N. V. (1998). Applications of N-BOC-diamines for the solution phase synthesis of ketopiperazine libraries utilizing a Ugi/De-BOC/Cyclization (UDC) strategy. Tetrahedron Letters, 39(44), 8047-8050.
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  Abstract: This communication reveals a novel application of the 'so-called' convertible isonitrile for the solution phase generation of ketopiperazine libraries. Use of mono N-BOC diamines in the Ugi multi-component reaction (MCR), followed by BOC removal and base treatment (a '3 step, 1-pot procedure') affords ketopiperazines in good yield. The generality of this procedure was further explored revealing novel routes to dihydroquinoxalinones and 1,4-benzodiazepines respectively.
• Hulme, C., Peng, J., Morton, G., Salvino, J. M., Herpin, T., & Labaudiniere, R. (1998). Novel safety-catch linker and its application with a Ugi/De- BOC/cyclization (UDC) strategy to access carboxylic acids, 1,4- benzodiazepines, diketopiperazines, ketopiperazines and dihydroquinoxalinones. Tetrahedron Letters, 39(40), 7227-7230.
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  Abstract: This communication reveals the synthesis and application of a novel resin bound isonitrile. The resin is an example of a novel safety-catch linker which upon BOC-activation can be resin cleaved with a variety of nucleophiles. Use of this polymer supported isonitrile in the Ugi multi- component reaction (MCR), followed by resin clipping and cyclization allows access to diverse arrays of 1,4-benzodiazepine-2,5-diones, diketopiperazines and ketopiperazines respectively. The methoxide safety-catch clipping strategy and subsequent solution phase cyclization offers similar advantages to a traceless linker.
• Hulme, C., Peng, J., Tang, S., Burns, C. J., Morize, I., & Labaudiniere, R. (1998). Improved procedure for the solution phase preparation of 1,4- benzodiazepine-2,5-dione libraries via Armstrong's convertible isonitrile and the Ugi reaction. Journal of Organic Chemistry, 63(22), 8021-8023.
• Hulme, C., Poli, G. B., Huang, F., Souness, J. E., & Djuric, S. W. (1998). Quaternary substituted PDE4 inhibitors I: The synthesis and in vitro evaluation of a novel series of oxindoles. Bioorganic and Medicinal Chemistry Letters, 8(2), 175-178.
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  PMID: 9871649;Abstract: The following letter presents the synthesis and in vitro evaluation of a novel quaternary substituted series of phosphodiesterase type (IV) (PDE4) inhibitors. The compounds represent conformationally constrained analogues of the Celltech PDE IV inhibitor, CDP 840. Examples with sub-micromolar IC50's for PDE4 inhibition are reported.
• Myers, M. R., Wei, H. e., & Hulme, C. (1997). Inhibitors of tyrosine kinases involved in inflammation and autoimmune disease. Current Pharmaceutical Design, 3(5), 473-502.
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  Abstract: The study of tyrosine kinases involved in cellular signaling associated with inflammation and autoimmune disease is rapidly progressing. Lessons learned from recent successes in identifying novel, potent, and selective tyrosine kinase inhibitors for the treatment of cancer and cardiovascular disease can be applied toward developing selective tyrosine kinase inhibitors for targets associated with diseases such as rheumatoid arthritis, sepsis and autoimmune disease. The design of new selective tyrosine kinase inhibitors will be aided by the very recent successes in solving X-ray crystal structures of the catalytic domains of several kinases. This paper summarizes the literature on inhibitors of several non-receptor and receptor tyrosine kinases thought to be involved in cellular signaling associated with inflammatory diseases.
• D., T., Hulme, C., Kelly, R. J., Lee, V., Nash, I. A., & Schofield, C. J. (1996). Synthesis and analysis of Leu-enkephalin analogues containing reverse turn peptidomimetics. Bioorganic and Medicinal Chemistry Letters, 6(4), 485-490.
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  Abstract: The synthesis and 1H n.m.r. analysis of peptidomimetics of Leu-enkephalin containing bicyclic lactams is described.
• Lynch, V. M., Hulme, C., Magnus, P., & Davis, B. E. (1995). Novel 2- and 5-azido-N-(diphenylcarbamoyl)proline methyl esters. Examples of a novel proline oxidation.. Acta crystallographica. Section C, Crystal structure communications, 51, Pt 12/-.
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  PMID: 8588859;Abstract: The crystal structures of two azido-substituted proline derivatives are reported. Racemic 2-azido-1-(diphenyl-carbamoyl)proline methyl ester, (I), C19H19N5O3, is resolved upon crystallization from methylene chloride-diethyl ether. The azido moieties are nonlinear with N--N--N angles of 173 (1) and 170.3 (2) degrees for (I) and (II) [cis-5-azido-N-(diphenylcarbamoyl)proline methyl ester, C19H19N5O3], respectively. Close intramolecular contacts between the carbonyl O atom of the amide and the central N atom of the azido group are found. The contact distances between N7 and O14 are 2.780 (14) and 2.815 (2) A for (I) and (II), respectively.
• Magnus, P., Roe, M. B., & Hulme, C. (1995). New trialkylsilyl enol ether chemistry: Direct 1,2-bis-azidonation of triisopropylsilyl enol ethers: An azido-radical addition process promoted by TEMPO. Journal of the Chemical Society, Chemical Communications, 263-265.
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  Abstract: Treatment of triisopropylsilyl enol ethers with PhIO/TMSN3/TEMPO (cat.) -45°C results in 1,2-bis-azidonation, which appears to occur through a radical addition process; the 1-azido group can be replaced by carbon nucleophiles such as allyl, methyl, cyano, acetylene and acetonyl.
• Magnus, P., Roe, M. B., Lynch, V., & Hulme, C. (1995). The structure of a stable new organotellurium azide: Bis- azidodiphenyltellurium(IV) oxide. Journal of the Chemical Society, Chemical Communications, 1609-1610.
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  Abstract: Diphenyltelluroxide reacts with azidotrimethylsilane to give a remarkable stable adduct (Ph2TeN3)2O which was characterised by X-ray crystallography.
• Baldwin, J. E., Claridge, T. D., Hulme, C., Rodger, A., & Schofield, C. J. (1994). Comments on the use of a dichromophoric circular dichroism assay for the identification of β-turns in peptides. International Journal of Peptide and Protein Research, 43(2), 180-184.
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  PMID: 8200737;Abstract: Use of the dichromophoric CD assay for β-turn formation in peptide sequences has been investigated. The assay involves the observation of Cotton effects in CD spectra, originating from the approach of N- and C-terminal aromatic chromophores in tetrapeptides. The approach of the chromophores was believed to be brought about by a β-turn in the peptide structure. Our investigations were paralleled by NMR studies which revealed the presence of a previously unreported hydrogen bond in the β-turn conformers, which appears to play a role in the generation of the observed Cotton effects. This suggests caution in the use of the CD technique alone as an assay for β- turn conformers in peptides.
• Magnus, P., & Hulme, C. (1994). Oxidation of L-Proline methyl ester derivatives with the iodosylbenzene/trimethylsilylazide reagent combination. Tetrahedron Letters, 35(44), 8097-8100.
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  Abstract: Oxidation of a series of L-Proline derivatives with the (PhlO)n/TMSN3 reagent combination is reported. Subsequent utilization of the 5-azido N-acyl functionality as a N-acyl iminium ion precursor is described. © 1994.
• Magnus, P., Hulme, C., & Weber, W. (1994). α-Azidonation of amides, carbamates, and ureas with the iodosylbenzene/trimethylsilyl azide reagent combination: N-acyliminium ion precursors. Journal of the American Chemical Society, 116(10), 4501-4502.
• Baldwin, J. E., Hulme, C., Edwards, A. J., Schofield, C. J., & Parkes, K. E. (1993). Synthesis of a bicyclic γ-lactam dipeptide analogue. Tetrahedron Letters, 34(10), 1665-1668.
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  Abstract: Synthesis of a comformationally restrained bicyclic γ-lactam dipeptide mimetic, involving a diastereoselective bicyclisation reaction is described. © 1993.
• Baldwin, J. E., Hulme, C., Schofield, C. J., & Edwards, A. J. (1993). Synthesis of potential β-turn bicyclic dipeptide mimics. Journal of the Chemical Society - Series Chemical Communications, 935-936.

Presentations

• Hulme, C. (2013, December). ‘Emerging Approaches for Alzheimer’s to Complexity Generating Chemistry'. Rigel Drug Discovery Seminar Series. San Francisco: Rigel Therapeutics.
• Hulme, C. (2022). Discovery of DYR533 and Target Product profile toward Alzheimer’s and Down Syndrome.. DYRKs and related kinases 3rd International Conference. St Malo France, November, 2022,. St Malo France.
• Hulme, C., & Fistrovich, A. (2022). Small molecule kinase inhibitors (SMKIs) as a multi-targeted therapeutic for the treatment of glioblastoma multiforme (GBM).. Head and Neck Translational Research Meeting, Arizona Cancer Center. AZ Cancer Center.
• Hulme, C., & Schofield, K. (2022). Discovery of DYR684, a First-in-class DYRK1A/B PROTAC. Arizona Biology Retreat. Biosphere 2. Biosphere 2 Arizona.
• Hulme, C. (2016, July). Heterocyclic Chemistry: concise routes from MCRs impacting drug discovery’. 27th European Colloquium on Heterocyclic Chemistry, Keynote,. Amsterdam, Holland: Partial Coverage by Conference.
• Hulme, C. (2015, April Spring). ‘Enabling Drug Discovery through Expedited Chemistry’ - Plenary Lecture. MCR2016. Brasilia, Brasil: Brasilian Society for Organic Chemistry.
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  One of 8 Plenary Lectures in MCR conferencce series (held very 3 years)
• Hulme, C. (2015, April). ‘Enabling Drug Discovery through Expedited Chemistry’. UNB seminar series. Brasilia: UNB.
• Hulme, C. (2015, April, Spring). ‘Enabling Drug Discovery through Expedited Chemistry’. Campus Invited Talk: Universidada de Brasilia, Brazil. Brasilia, Brazil: Universidada de Brasilia, Brazil.
• Hulme, C. (2015, March). ‘Enabling Drug Discovery through Expedited Chemistry’, Plenary Lecture. MCR2015. Brasilia, Brasil: MCR2015/UNB.
• Hulme, C. (2015, October Fall). ‘Enabling Drug Discovery through Expedited Chemistry’. Seminar Series, VU Amsterdam. Amsterdam: Vrieje Universiteit, Amsterdam, Holland.
• Hulme, C. (2015, October). Enabling Drug Discovery through Expedited Chemistry. University of Groningen Seminar Series. Groningen, Holland: University of Groningen.
• Hulme, C. (2015, October). Enabling Drug Discovery through Expedited Chemistry. Vrieje Universiteit Seminar Series. Amsterdam, Holland: Vrieje Universiteit.
• Hulme, C. (2015, October). Front load the deck – Enabling chemistry to expedite Drug Discovery. Compound Libraries 2015. Berlin: IQCP.
• Hulme, C. (2015, October, 2015). “Front load the deck – Enabling chemistry to expedite Drug Discovery.”. Compound Libraries 2015, October 2015 Berlin, Germany. Berlin, Germany: IQPC.
• Hulme, C. (2015, October, Fall). ‘Enabling Drug Discovery through Expedited Chemistry’. Invited Talk. University of Groningen, Groningen, Holland: University of Groningen, Groningen, Holland.
• Hulme, C. (2015, September). Expediting Compound Collection Growth: Multi-Component Reaction (MCR) Research and the Molecular Libraries Small Molecule Repository’. 11th Compound Management & Integrity Summit. Boston: IQCP.
• Hulme, C. (2015, September). ‘Expediting Compound Collection Growth: Multi-Component Reaction (MCR) Research and the Molecular Libraries Small Molecule Repository’. 11th Compound Management & Integrity Summit. Boston: IQPC.
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  Invited Talk
• Hulme, C. (2014, September). ‘Enabling Drug Discovery through Expedited Chemistry’. Biogen-Idec Drug Discovery Seminar Series. Boston: Biogen-Idec.
• Hulme, C. (2014, September). ‘From Ultra-high Iteratively Efficient Chemistry to novel Androgen Receptor Antagonists’. Purdue University Inaugural Drug Discovery Center Symposium. Lafayette, IN: Purdue U..
• Hulme, C. (2013, August). 'Multi-component Reaction Driven Molecular Diversity in Drug Discovery’. Sanofi Seminar Series. Oro Valley: Sanofi.
• Hulme, C. (2013, August). 38. ‘Operationally Friendly, complexity generating file enhancement strategies – the exploratory power of MCR methodologies’. DART Neurosciences Seminar Series. San Diego: DART Neurosciences.
• Hulme, C. (2013, August). Operationally Friendly, complexity generating file enhancement strategies – the exploratory power of MCR methodologies’. Invitation to Merck Labs - Talk. Kenilworth, New Jersey: Merck.
• Hulme, C. (2013, December). ‘Operationally Friendly, Complexity Generating Chemistry for rapid Value Chain progression',. Theravance Drug Discovery Seminar Series. San Francisco: Theravance.
• Hulme, C. (2013, March 22nd, 2013.). ‘Drug Discovery at Bio5 Oro Valley’, Arizona Alzheimer’s Consortium, Prescott, March 22nd, 2013.. Arizona Alzheimer’s Consortium. Prescott: Arizona Alzheimer’s Consortium.
• Hulme, C. (2013, September). 41. ‘Novel Biologically Appealing Chemotypes via Post-Condensation Modifications of MCR products: Recent Achievements of Bio5 Oro Valley’. Sanofi Seminar Series. Oro Valley: Sanofi.
• Hulme, C. (2013, September). From Heterocycles to Macrocycles: Applications of an Isocyanide based three component reaction. Sanofi Seminar Series. Oro Valley: Sanofi.

Poster Presentations

• Hulme, C., Foley, C., Dunckley, T., & Shaw, A. (2018, March). DYRK1A inhibition simultaneously targets amyloid-beta and tau pathology.. 255th ACS National Meeting & Exposition, New Orleans, LA, United States, March 18-22. New Orleans: American Chemical Society.
• Hulme, C., & Martinez-Ariza, G. (2015, April Spring). Switchable First-in-class MCRs toward Imidazoles, Dihydrotriazines, Triazolopyridines and Pyridotriazines. MCR2016. Brasilia, Brasil: Brazilian Society of Chemistry.
• Martinez-Ariza, G., Xu, Z., & Hulme, C. (2015, March). Benzimidazol-2-one scaffolds derived from unique domino processes centered upon elegant benzodiazepine ring rearrangements.. Spring ACS. Denver, Colorado: Spring.