Synthesis And Antitumor Acitivity Of Novel 10-substituted Camptothecin Analogues

In an attempt to improve the antitumor activity, value of biologic assimilation and stability in blood, and decrease the cytotoxicity, 18 novel nitrous heterocyclic CPT analogues which have never been reported were prepared by facile nucleophic substitution, with high production ratio. The structure of these analogues was identified by NMR, MS, IR.The antitumor activities of these derivetives were evaluated with Topoisomerase I inhibitory assay on the basis of molecular target and MTT assay in vitro. The results indicate that all novel CPT analogues possessed a certain extent antitumor activities, including the forming of CPT-DNA-TopoI complex and cell-growth inhibition in vitro. Analogue 11, 21 and 22 showed better Topo I inhibitory activity and lower cytotoxicity. These compounds kept the stability of active lactone, decreaced the toxicity, and increased the biologic assimilation.Compound 11, 21 and 22 exhibited good antitumot activitis on HCT-8 xenografted in vivo. Especially, the value of tumor inhibition rate(TIR) was 62.6% on compound 11 group, however, the chosen dose was 1.3 mg/kg, sixth of that of contrast Topotecan. Then TIR of compound 21 and 22 was 51.3% and 50.0%, respectively.Analogue I1 exhibited better antitumor activity in vivo and in vitro and more excellent Topo I inhibitory activity than other analogures, and retained stability in blood, which had promising perspective.