Wei Wang

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Scholarly Contributions

Journals/Publications

• Fang, K., Dong, G., Li, Y., He, S., Wu, Y., Wu, S., Wang, W., & Sheng, C. (2018). Discovery of Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) and Histone Deacetylase (HDAC) Dual Inhibitors. ACS medicinal chemistry letters, 9(4), 312-317.
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  In order to take advantage of both immunotherapeutic and epigenetic antitumor agents, the first generation of dual indoleamine 2,3-dioxygenase 1 (IDO1) and histone deacetylase (HDAC) inhibitors were designed. The highly active dual inhibitor showed excellent and balanced activity against both IDO1 (IC = 69.0 nM) and HDAC1 (IC = 66.5 nM), whose dual targeting mechanisms were validated in cancer cells. Compound had good pharmacokinetic profiles as an orally active antitumor agent and significantly reduced the l-kynurenine level in plasma. In particular, it showed excellent antitumor efficacy in the murine LLC tumor model with low toxicity. This proof-of-concept study provided a novel strategy for cancer treatment. Compound represents a promising lead compound for the development of novel antitumor agents and can also be used as a valuable probe to clarify the relationships and mechanisms between cancer immunotherapy and epigenetics.
• Fang, K., Dong, G., Wang, H., He, S., Wu, S., Wang, W., & Sheng, C. (2018). Improving the Potency of Cancer Immunotherapy by Dual Targeting of IDO1 and DNA. ChemMedChem, 13(1), 30-36.
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  Herein we report the first exploration of a dual-targeting drug design strategy to improve the efficacy of small-molecule cancer immunotherapy. New hybrids of indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors and DNA alkylating nitrogen mustards that respectively target IDO1 and DNA were rationally designed. As the first-in-class examples of such molecules, they were found to exhibit significantly enhanced anticancer activity in vitro and in vivo with low toxicity. This proof-of-concept study has established a critical step toward the development of a novel and effective immunotherapy for the treatment of cancers.
• He, S., Dong, G., Wu, S., Fang, K., Miao, Z., Wang, W., & Sheng, C. (2018). Small Molecules Simultaneously Inhibiting p53-Murine Double Minute 2 (MDM2) Interaction and Histone Deacetylases (HDACs): Discovery of Novel Multitargeting Antitumor Agents. Journal of medicinal chemistry, 61(16), 7245-7260.
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  p53-Murine double minute 2 (MDM2) interaction and histone deacetylases (HDACs) are important targets in antitumor drug development. Inspired by the synergistic effects between MDM2 and HDACs, the first MDM2/HDACs dual inhibitors were identified, which showed excellent activities against both targets. In particular, compound 14d was proven to be a potent and orally active MDM2/HDAC dual inhibitor, whose antitumor mechanisms were validated in cancer cells. Compound 14d showed excellent in vivo antitumor potency in the A549 xenograft model, providing a promising lead compound for the development of novel antitumor agents. Also, this proof-of-concept study offers a novel and efficient strategy for multitargeting antitumor drug discovery.
• Huang, X. F., Jiang, W. T., Liu, L., Song, F. C., Zhu, X., Shi, G. L., Ding, S. M., Ke, H. M., Wang, W., O'Donnell, J. M., Zhang, H. T., Luo, H. B., Wan, Y. Q., Song, G. Q., & Xu, Y. (2018). A novel PDE9 inhibitor WYQ-C36D ameliorates corticosterone-induced neurotoxicity and depression-like behaviors by cGMP-CREB-related signaling. CNS neuroscience & therapeutics, 24(10), 889-896.
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  Major depressive disorder (MDD) is a mental disease characterized by depressed mood, lifetime anxiety, and deficits of learning and memory. Inhibition of phosphodiesterase 9 (PDE9) has been reported to improve rodent cognitive and memory function. However, the role of PDE9 in MDD, in particular its manifestations of depression and anxiety, has not been investigated.
• Li, J., Zheng, H., Wang, W., Miao, Y., Sheng, Y., & Feng, C. (2018). Role of an isoform-specific residue at the calmodulin-heme (NO synthase) interface in the FMN - heme electron transfer. FEBS letters, 592(14), 2425-2431.
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  The interface between calmodulin (CaM) and the NO synthase (NOS) heme domain is the least characterized interprotein interface that the NOS isoforms must traverse through during catalysis. Our previous molecular dynamics simulations predicted a salt bridge between K497 in human inducible NOS (iNOS) heme domain and D118(CaM). Herein, the FMN - heme interdomain electron transfer (IET) rate was found to be notably decreased by charge-reversal mutation, while the IET in the iNOS K497D mutant is significantly restored by the CaM D118K mutation. The results of wild-type protein with added synthetic peptides further demonstrate the critical nature of K497 relative to the rest of the peptide sequence in modulating the IET. These data provide definitive evidence supporting the regulatory role of the isoform-specific K497 residue.
• Qin, C., Liu, Y., Yu, Y., Fu, Y., Li, H., & Wang, W. (2018). α-Functionalization of 2-Vinylpyridines via a Chiral Phosphine Catalyzed Enantioselective Cross Rauhut-Currier Reaction. Organic letters, 20(5), 1304-1307.
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  Herein, 2-vinylpyridines as a new type of electron-poor system for the asymmetric cross Rauhut-Currier reaction are reported. 2-Vinylpyridines are chemo- and enantioselectively activated by a newly designed chiral phosphine catalyst. The new reaction provides a powerful synthetic tool for accessing structurally diverse, highly valued chiral pyridine building blocks in good yields and with high enantioselectivities. Preliminary mechanistic studies reveal that two NH protons in the catalyst are critical for the synergistic activation of the substrates and governing the stereoselectivity of this reaction.
• Tong, M., Wang, S., Zhuang, J., Qin, C., Li, H., & Wang, W. (2018). Direct Access of the Chiral Quinolinyl Core of Cinchona Alkaloids via a Brønsted Acid and Chiral Amine Co-catalyzed Chemo- and Enantioselective α-Alkylation of Quinolinylmethanols with Enals. Organic letters, 20(4), 1195-1199.
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  A strategy for the facile construction of the chiral quinolinylmethanolic structure, a core featured in cinchona alkaloids, is reported. A new reactivity is harnessed by TfOH-promoted chemoselective activation of α-C-H over O-H bond in quinolinylmethanols. The new reactivity is successfully engineered with an iminium catalysis in a synergistic manner to create a powerful conjugate addition-cyclization cascade process for synthesis of chiral quinoline derived γ-butyrolactones in good yields and with good to excellent enantioselectivities. The method enables the first total synthesis of natural product broussonetine in three steps.
• Wang, W., Chen, X., Xu, H., Ma, S., Tong, H., & Lou, K. Y. (2018). A Simple Two-photon Turn-on Fluorescent Probe for Selective Detection of Cysteine Based on Dual PeT/ICT Mechanism. RCS Advances, 8, 13388-13392.
• Wang, W., Fan, H., Pan, P., & Zhang, Y. (2018). Facile Synthesis of 2-Quinolinones via Hypervalent Iodine(III)-Mediated Intramolecular Decarboxylative-Heck Reaction at Room Temperature. Organic Letters, 20, 7929-7932.
• Wang, W., Mao, Y., Liu, Y., Hu, W., Wang, L., & Zhang, S. L. (2018). Pd-catalyzed Debenzylation and Deallyation of Ethers and Esters with Sodium Hydride. ACS Catalysis, 8(4), 3016-3020.
• Wang, W., Shao, L. Y., Xing, L. H., Guo, Y., Yu, K. K., Liu, H. W., Liao, D. H., & Ji, Y. F. (2018). Catalytic Cascade Access to Biaryl-2-Methyl Acetates from Pyruvate O-Arylmethyl Ketoximes via the Palladium-Catalyzed C(sp2)-H Bond Arylation and C-O Bond Solvolysis. Advanced Synthesis & Catalysis, 360(15), 2925-2937.
• Wang, W., Tong, M., Zhang, Y., Qin, C., Fu, Y., Liu, Y., & LI, H. (2018). Alkenylazaarenes as Dipolarophiles in 1,3-Dipolar Cycloaddition of Nitrones: Regioselectivity-Switchable and Highly Diastereoselective Synthesis of Multisubstituted Isoxazolidines. Organic Chemical Frontiers, 5(20), 2945-2949.
• Wang, W., Xu, H., & Wang, X. L. (2018). Monomethylarsonous Acid: Induction of DNA Damage and Oxidative Stress in Mouse Natural Killer Cells at Environmentally-relevant Concentrations. Mutation Research - Genetic Toxicology and Environmental Mutagenesis, 832-833, 1-6.
• Xu, H., Xu, H., Ma, S., Chen, X., Huang, L., Chen, J., Gao, F., Wang, R., Lou, K., & Wang, W. (2018). Analyte Regeneration Fluorescent Probes for Formaldehyde Enabled by Regiospecific Formaldehyde-Induced Intramolecularity. Journal of the American Chemical Society.
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  An important challenge for reaction-based fluorescent probes is that they generally require analyte consumption for fluorescence signal generation, thus creating potential perturbation of native analyte homeostasis or change of local concentrations. Herein, we reported two formaldehyde (FA) regeneration fluorescent probes, NAP-FAP-1 and NAP-FAP-2. An unprecedented regiospecific FA-induced intramolecularity strategy is implemented in the probe design, which adopts 3-(benzylamino)-succinimide as the FA-selective reaction group. The probes are able to capture the analyte molecule, induce regiospecific imide bond cleavage, and then release the captured FA molecule with simultaneous fluorescence turn-on response via a unique dual PeT/ICT quenching mechanism. The probes have shown potentials in detection, comparison, and imaging of FA levels intracellularly and inside lysosomes. These features make them useful for the study of FA homeostasis and functions in biological systems with minimal perturbation.
• Zhou, D., Yu, X., Zhang, J., Wang, W., & Xie, H. (2018). Organocatalytic Asymmetric Formal [4 + 2] Cycloaddition of in Situ Oxidation-Generated ortho-Quinone Methides and Aldehydes. Organic letters, 20(1), 174-177.
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  An unprecedented chiral secondary amine-catalyzed formal [4 + 2] annulation of aldehydes and oxidation-generated β-unsubstituted o-QMs is reported. This asymmetric protocol allows direct functionalization of the benzylic C-H bonds and furnishes [4 + 2] cycloadducts, chromanols, with excellent enantioselectivity and in up to 92% yield. The usability of this approach was further demonstrated by the enantioselective synthesis of anticancer Rhinacanthins derivative NKPLS8.

Presentations

• Wang, W. (2018, December). Invited talk - Title not available. Central South University. Changsha, China.
• Wang, W. (2018, December). Invited talk - Title not available. Changzhou University. Changzhou, China.
• Wang, W. (2018, January). Invited talk - Title not available. Wichita State University. Wichita, Kansas.
• Wang, W. (2018, March). Invited talk - Title not available. Old Dominon University. Norfolk, Virginia.
• Wang, W. (2018, May). Invited talk - Title not available. Tsinghua University. Beijing, China.