- Scaffold Diversity Inspired by the Natural Product Evodiamine: Discovery of Highly Potent and Multitargeting Antitumor Agents
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A critical question in natural product-based drug discovery is how to translate the product into drug-like molecules with optimal pharmacological properties. The generation of natural product-inspired scaffold diversity is an effective but challenging strategy to investigate the broader chemical space and identify promising drug leads. Extending our efforts to the natural product evodiamine, a diverse library containing 11 evodiamine-inspired novel scaffolds and their derivatives were designed and synthesized. Most of them showed good to excellent antitumor activity against various human cancer cell lines. In particular, 3-chloro-10-hydroxyl thio-evodiamine (66c) showed excellent in vitro and in vivo antitumor efficacy with good tolerability and low toxicity. Antitumor mechanism and target profiling studies indicate that compound 66c is the first-in-class triple topoisomerase I/topoisomerase II/tubulin inhibitor. Overall, this study provided an effective strategy for natural product-based drug discovery. (Figure Presented).
- Wang, Shengzheng,Fang, Kun,Dong, Guoqiang,Chen, Shuqiang,Liu, Na,Miao, Zhenyuan,Yao, Jianzhong,Li, Jian,Zhang, Wannian,Sheng, Chunquan
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p. 6678 - 6696
(2015/09/07)
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- Design, synthesis and biological evaluation of thienopyridinones as Chk1 inhibitors
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A series of thienopyridinone derivatives was designed and synthesized as inhibitors of checkpoint kinase 1 (Chk1). Most of them exhibited moderate to good Chk1 inhibitory activities. Among them, compounds 8q, 8t, and 8w with excellent Chk1 inhibitory activities (IC50 values of 4.05, 6.23, and 2.33 nM, respectively) displayed strong synergistic effects with melphalan, a DNA-damaging agent in the cell-based assay. Further kinase profiling indicated that compound 8t was highly selective against CDK2/cyclinA, Aurora A, and PKC.
- Song, Pinrao,Peng, Peng,Han, Mengmeng,Cao, Xianchao,Ma, Xiaodong,Liu, Tao,Zhou, Yubo,Hu, Yongzhou
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p. 4882 - 4892
(2014/10/16)
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- THIENOPYRIDINONE DERIVATIVES AS MACROPHAGE MIGRATION INHIBITORY FACTOR INHIBITORS
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Inhibitors of macrophage migration inhibitory factor having a thienopyridinone backbone are provided which have utility in the treatment of a variety of disorders, including the treatment of pathological conditions associated with macrophage migration inhibitory factor activity. The inhibitors of macrophage migration inhibitory factor have the following structures formula (I), (II), (III) including forms such as stereoisomers, free forms, pharmaceutically acceptable salts or esters thereof, solvates, or combinations of such forms, wherein n, R1, R2, R3, X, and Y are as defined herein. Compositions comprising an inhibitor of macrophage migration inhibitory factor in combination with a pharmaceutically acceptable carrier are also provided, as well as methods for use of the same.
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Page/Page column 97-98
(2010/11/24)
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- Anti-infective agents
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Compounds having the formula are hepatitis C (HCV) polymerase inhibitors. Also disclosed are a composition and method for inhibiting hepatitis C (HCV) polymerase, processes for making the compounds, and synthetic intermediates employed in the processes.
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- Thiaisatoic anhydrides: Efficient synthesis under microwave heating conditions and study of their reactivity
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2-thiaisatoic anhydride 1 and 3-thiaisatoic anhydride 2 were synthesized in large scale under microwave heating conditions with 85% and 67% yields respectively. The reactivity of these two compounds was studied towards various nucleophiles and appeared to be generally different from that of isatoic anhydride: many new thiophene-2 and 3-carboxylic acids were isolated with good yields as potential new pharmacological scaffolds.
- Fabis, Frederic,Jolivet-Fouchet, Sandrine,Robba, Max,Landelle, Henriette,Rault, Sylvain
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p. 10789 - 10800
(2007/10/03)
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