We have recently reported a new chemotype of a potent topoisomerase I poison with compound 1 as a potential anticancer chemotherapeutic agent. During further optimization, it has been observed that compound 1 suffers from high intrinsic clearance in human liver microsomes. To overcome the metabolic instability of compound 1, we report design and synthesis of metabolically stable Top1 poison 3. Newly identified Top1 poison 3 exhibits t_1/2 of 69.1 min in human liver microsomes in comparison to compound 1 with t_1/2 of 9.9 min. Molecular dynamic study of the newly optimized Top1 poison 3 was performed to get the insight into the stability of the binding pose in the active site. Compound 3 was able to trap DNA-Top1 cleavage complex and found to be less cytotoxic in non-cancerous cell line as compared to compound 1.

我们最近报道了一种强效拓扑异构酶I毒物的新化学型，化合物1作为潜在的抗癌化学治疗剂。在进一步优化过程中，已观察到化合物1在人肝微粒体中具有很高的固有清除率。为了克服化合物1的代谢不稳定性，我们报告了代谢稳定的Top1毒药3的设计和合成。与化合物1相比，新发现的Top1毒物3在人肝微粒体中的t _1/2为69.1分钟，而t _1/2为9.9分钟。新近优化的Top1毒药3的分子动力学研究进行该操作以了解结合位点在活性位点的稳定性。与化合物1相比，化合物3能够捕获DNA-Top1切割复合物，并且发现在非癌细胞系中的细胞毒性较小。