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A large number of cycloSal-nucleotide triesters 1-49 have been studied concerning their ability to inhibit cholinesterases of different origins as well as to inhibit HIV replication in cell culture. It was shown that none of the triesters showed inhibitory effects against human acetylcholinesterase (AChE; isolated enzyme) as well as against AChE from beef erythrocytes and calf serum. In contrast, inhibition of butyrylcholinesterase (BChE) has been observed for some triesters in human and mouse serum. cycloSal pronucleotides showed strong competitive inhibition with respect to the substrate acetylcholine chloride (K(i)/K(m): approximately 2 x 10(-5)) and acted by time-dependent irreversible inhibition of the human serum BChE. Detailed studies demonstrated that the inhibitory effect against BChE is dependent on the nucleoside analogue, the substitution pattern of the cycloSal-moiety, and particularly on the stereochemistry at the phosphorus atom. Structural requirements to avoid the inhibition of BChE by cycloSal-nucleotide triesters have been elucidated in the reported study.

Original publication

DOI

10.1021/jm031032a

Type

Journal article

Journal

Journal of medicinal chemistry

Publication Date

05/2004

Volume

47

Pages

2839 - 2852

Addresses

Institute of Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany. chris.meier@chemie.uni-hamburg.de

Keywords

Serum, Animals, Cattle, Humans, Mice, Acetylcholinesterase, Butyrylcholinesterase, Nucleotides, Cholinesterase Inhibitors, Prodrugs, Anti-HIV Agents, Species Specificity, Structure-Activity Relationship, Stereoisomerism, Organophosphates