The inhibition of acetylcholinesterase by irinotecan and related camptothecins: key structural properties and experimental variables.
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.
Dodds
H M
HM
Department of Pharmacology, University of Sydney, New South Wales, Australia.
Hanrahan
J
J
Rivory
L R
LR
D000110:Acetylcholinesterase / Q000378:metabolism*; D000465:Algorithms; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D002166:Camptothecin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D002853:Chromatography, Liquid; D003640:Dealkylation; D004593:Electrophorus; D000077146:Irinotecan; D007700:Kinetics; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D000972:Antineoplastic Agents, Phytogenic; D002800:Cholinesterase Inhibitors; D008024:Ligands; D000077146:Irinotecan; D000110:Acetylcholinesterase; D002166:Camptothecin