3-Thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile (S1) derivatives as pan-Bcl-2-inhibitors of Bcl-2, Bcl-x_L and Mcl-1

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• 作者：Ting Song^a ; ^&dagger ; ; Xiangqian Li^a ; ^&dagger ; ; Xilong Chang^b ; ^c ; ^&dagger ; ; Xiaomeng Liang^a ; Yan Zhao^d ; Guiye Wu^a ; Shenghui Xie^a ; Pengchen Su^a ; Zhiyong Wu^a ; Yingang Feng^e ; Zhichao Zhang^a ; ^{zczhang@dlut.edu.cn}
• 关键词：Bcl-2 ; B-cell lymphoma 2 ; Mcl-1 ; myeloid cell leukemia sequence 1 ; Bcl-xL ; B-cell lymphoma x long ; Bax ; Bcl-2-associated x protein ; Bak ; Bcl-2 homologous antagonist/killer ; BH3 ; Bcl-2 homology domain 3 ; SAR ; Structure&ndash ; activity relationship ; FPA ; flu
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：1 January, 2013
• 年：2013
• 卷：21
• 期：1
• 页码：11-20
• 全文大小：5629 K

文摘

Based on the binding mode of our previously discovered dual inhibitor of Bcl-2 and Mcl-1, 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (3, S1), a library of 9-substituted 3 derivatives was synthesized to further probe the p4 pocket of the two targets. By NMR, structure-activity relationship study, and site-directed mutation, compound 6d (3-(4-aminophenylthio)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-3-phenyl)propylamine) was identified to span p2-p4 pockets of Mcl-1, Bcl-2 and Bcl-x_L, and then exhibited 9- to 35-fold better affinity to the three targets than 3 (IC₅₀ = 10, 20 and 18 nM, respectively), which led to greater activity in induction of apoptosis in multiple cancer cell lines. Different contribution of p4 pocket to binding Bcl-2 and Mcl-1 was also investigated by plotting the potency and the HAC of the derivatives.