Camptothecin N-Acetyl Dipeptides And Glycine Esters Derivatives:Synthesis And Preliminary Evaluation Of Antitumor Activity

Camptothecin is natural alkaloids isolated from the Chinese tree Camptotheca acuminata and attracted widespread attention due to its strong anti-tumor activity and unique mechanism of Topoisomerase I inhibition. The essential E-ring lactone structure undergoes a rapid, reversible hydrolysis to severely toxic water-soluble carboxylate form at physiological pH.To protect E-ring lactone structure and decrease the toxicity, the esterification at20(s)-OH were introduced in the present study and a series of camptothecin N-acetyl dipeptides and glycine ester derivatives were synthesized. In addition, two N-Acetyl-amino ester derivatives of10-methoxycamptothecin were also synthesized at C-20position. The structures were identified through NMR and mass spectrometry.In vitro anti-cancer screening were tested on human ovarian cancer cell lines (2774), human prostate cancer cell lines (DU145) human pancreatic cancer cell line (MPC2). Compared with camptothecin, most derivatives showed lower cytotoxicity. For human ovarian cancer cell lines (2774), compounds13showed stronger activity than camptothecin, Compounds4,8,12,14displayed similiar activity as camptothecin; Except compounds14,16, and17, other derivatives showed lower activity against human prostate cancer cell line DU145, and Compound9,14showed similar anti-tumor activity comparing with camptothecin. For human ovarian carcinoma cell line2774, compounds12,13,14have slightly lower activity,,and compound17doesstronger activity than camptothecin..