کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1355660 | 981055 | 2013 | 10 صفحه PDF | دانلود رایگان |
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-xL, 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.
S1 derivatives spanning p2–p4 pockets of Mcl-1, Bcl-2 and Bcl-xL were synthesized. Compound 6d exhibited 9- to 35-fold improved affinity toward the three targets than S1 (IC50 = 10, 20 and 18 nM, respectively). Different contribution of p4 to binding Bcl-2 and Mcl-1 was investigated by plotting the potency and the HAC of the derivatives.Figure optionsDownload as PowerPoint slide
Journal: Bioorganic & Medicinal Chemistry - Volume 21, Issue 1, 1 January 2013, Pages 11–20