Design, Total Synthesis And Antitumor Activity Of Homocamptothecin Derivatives As Topoisomerase Ⅰ Inhibitors

Camptothecin and its derivates as the most important Topoisomerase I inhibitors had been good activity against several tumor cells in vitro and in vivo. Recently three camptothecin derivates had been approved for cancer therapy. Homocamptothecin, a novel CPT analogue which contains an expanded seven-membered β-hydroxylactone replacing six-membered α-hydroxylactone, had shown elevated antitumor activity and improved stability without species difference.Granted by the National Natural Science Foundation of China(No.30371689),we had designed and synthesized three kinds of fifty-three novel homocamptothecins base on a new total synthetic method designed by our group. The result showed that twenty-two compounds had more potent activity than TPT against tumor cells in vitro and some compounds had potent activity of tumor growth inhibition in vivo. The resulting CoMFA and CoMSIA models by computer-aided drug design had a cross validated coeffiecient q~2 of 0.703 and 0.717 respectively, which showed strong predictive ability .