A Study On The Synthesis And Antitumor Activity Of Camptothecin Analogues

Camptothecin(CPT), a pentacyclic alkaloid isolated from Chinese tree Camptotheca acuminata by ME Wall and MC Wani in 1966. It exhibits antitumor activity to many solid tumors such as gastric carcinoma, lung cancer, hepatoma, rectal carcinoma, colonic carcinoma and ovarian carcinoma and so on. CPT acts by binding to the cleavable complex of topoisomerase I - DNA, leading to an accumulation of triplex complex. The cleavable complex is steadied and the road blocker is formed. So the replication fork can't carry through. The replication of DNA is inhibited to cause cell death. We synthesized a series of derivatives of camptothecin according to the research on the structure activity relation (SAR) of camptothecin. Their cytotoxicities of the compounds were tested by MTT assay. The in vivo antitumor activities of these derivatives of CPT were evaluated against mouse liver tumor H₂₂ and Lewis lung cancer in mouse. Most of derivatives of CPT showed comparative or better cytotoxicities comparing with topotecan and camptothecin. But the in vivo antitumor activities of these derivatives of CPT were worse comparing with topotecan and paclitaxol. However the toxicities of the compounds were much lower.A series of 5-substituted and 7-substituted CPT were synthesized starting from CPT or 7-hydroxymethyl-CPT. New heptacyclic lactone of CPT and many 20-O-esters of CPT or the derivatives of CPT were synthesized starting from CPT , substituted propionic acid and substituted acetic acid.Twenty two new compounds were synthesized in this paper have not been reported. The structures of these compounds were confirmed by IR, NMR, MS and HRMS.