Inhibition of acetylcholinesterase by the anticancer prodrug CPT-11

摘要: CPT-11 (irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) is an anticancer prodrug that has been approved for the treatment of colon cancer. It a member camptothecin class drugs and activation to active metabolite SN-38, mediated by carboxylesterases (CE). SN-38 potent topoisomerase I poison highly effective at killing human tumor cells, with IC50 values in low nM range. However, upon high dose administration cancer patients, cholinergic syndrome observed, can be rapidly ameliorated atropine. This suggests direct interaction drug or its metabolites acetylcholinesterase (AChE). Kinetic studies indicated was primarily responsible AChE inhibition 4-piperidinopiperidine moiety, major determinant loss enzyme activity. Structural analogs however, did not inhibit AChE, including benzyl piperazine derivate CPT-11. These results suggest novel could synthesized do alternatively, inhibitors designed based around scaffold.