State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian 116012, People's Republic of China.
Bioorg Med Chem. 2013 Jan 1;21(1):11-20. doi: 10.1016/j.bmc.2012.11.008. Epub 2012 Nov 21.
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 (IC(50)=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.
基于我们先前发现的 Bcl-2 和 Mcl-1 的双重抑制剂 3-硫代吗啉-8-氧代-8H-吖萘并[1,2-b]吡啶-9-甲腈（3，S1）的结合模式，我们合成了 9-取代的 3 个衍生物文库，以进一步研究两个靶标的 p4 口袋。通过 NMR、构效关系研究和定点突变，确定化合物 6d（3-（4-氨基苯基硫代）-8-氧代-8H-吖萘并[1,2-b]吡啶-9-3-苯基丙胺）跨越 Mcl-1、Bcl-2 和 Bcl-x（L）的 p2-p4 口袋，与 3 相比，对这三个靶标的亲和力提高了 9 至 35 倍（IC50=10、20 和 18 nM），这导致在多种癌细胞系中诱导凋亡的活性更高。还通过绘制衍生物的效力和 HAC 来研究 p4 口袋对结合 Bcl-2 和 Mcl-1 的不同贡献。
