The inhibition of acetylcholinesterase by irinotecan and related camptothecins: key structural properties and experimental variables.

喜树碱 乙酰胆碱酯酶 化学 立体化学 拓扑异构酶 酶抑制剂 阿切 伊立替康 生物化学 内科学 医学 癌症 结直肠癌
作者
Helen M. Dodds,Jane R. Hanrahan,Laurent P. Rivory
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期刊:PubMed 卷期号:16 (4-5): 239-46 被引量:5
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Irinotecan (CPT-11), a water-soluble and semi-synthetic topoisomerase I poison of the camptothecin family, has activity against both adult and paediatric malignancies. Recently, we demonstrated that CPT-11 (lactone) is also a potent inhibitor of human acetylcholinesterase (AChE) at clinically relevant concentrations. Attachment of heterocyclic and branched amino groups onto the camptothecin back-bone continues to be a strategy for the synthesis of water-soluble analogues, but this may lead to undesirable inhibition of AChE. In this study, we screened a range of camptothecin analogues, degradation products and metabolites for their ability to inhibit AChE. Those compounds possessing N-substitutions at C-10 were all found to inhibit AChE in a similar kinetic manner to CPT-11, but with a broad range of potencies. It is recognized that the charge-state is important for ligands that bind to the peripheral anionic site and we postulated that the protonated distal piperidine of CPT-11 would be important. To address this question, an N-methyl piperidinium iodide analogue was synthesized and tested. This derivative inhibited electric eel AChE with an inhibition constant (Ki) of 1 nM. Kinetic and deacylation experiments demonstrated that it acted relatively less as an inhibitor of deacylation than CPT-11. Overall, our experiments reveal that nitrogenous substitutions at the permissive C-10 of the camptothecin backbone may lead to AchE inhibition, particularly if they involve a quaternary nitrogen.

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