Interaction of cycloSal-pronucleotides with cholinesterases from different origins. A structure-activity relationship.
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.
Meier
Chris
C
Institute of Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany. chris.meier@chemie.uni-hamburg.de
Ducho
Christian
C
Görbig
Ulf
U
Esnouf
Robert
R
Balzarini
Jan
J
D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002091:Butyrylcholinesterase / Q000378:metabolism*; D002417:Cattle; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D009711:Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010755:Organophosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D044967:Serum; D013045:Species Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D002800:Cholinesterase Inhibitors; D009711:Nucleotides; D010755:Organophosphates; D011355:Prodrugs; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase