Design,Synthesis,Structure-activity Relationship And Biological Evaluation Of Sophoridine Derivatives

Sophoridine alone was approved by CFDA to cure the cancer patients with malignant trophoblastic tumors in 2005,however its poor biological activity and large side effects make its clinical application limited.Since the base structure is simple and highly soluble,it is considered to be an ideal compound for further structural modification and it is expected to enhance its anti-proliferative activity against tumor cells by this way.In this paper,we took sophoridine as the starting material and introduced various N-substituted pyrrole or indole scaffold at 14 site of sophoridine.Consequently,59 novel sophoridine derivatives bearing ?,?-unsaturrated ketone scaffold were synthesized and the anti-tumor activity of all the derivatives were further studied.All compounds showed better antitumor activity than sophoridine.Among them,the compound 2X showed the most excellent anti-proliferation activity in six human cancer cell lines(HepG2,SMMC-7721,Hela,CNE1,CNE2 and MCF7)with its IC50 value in range of 0.93-1.89 ?M.SAR analysis indicated that the introduction of an N-benzyl indole at 14 site of sophoridine could significantly enhance the antitumor activity.The results of molecular docking and enzyme assay showed that the compound 2X can inhibit the activity of DNA topoisomerase I.Apoptosis assay showed that the compound 2X could induce the apoptosis of HepG2 cells in a dose-dependent manner.Western Blot further showed that the compound 2X can induce apoptosis by increasing the ratio of Bax/bcl-2,activating caspase-3 and increasing the expression of cleaved caspase-3.In addition,the in vivo antitumor assay showed that the compound 2X can inhibit the growth of HepG2 tumors without any obvious toxicity.