Azetidine Based Transition State Analogue Inhibitors of N-Ribosyl Hydrolases and Phosphorylases

Title
Azetidine Based Transition State Analogue Inhibitors of N-Ribosyl Hydrolases and Phosphorylases
Publication Date
2008
Author(s)
Evans, Gary B
Furneaux, Richard H
Greatrex, Ben
( author )
OrcID: https://orcid.org/0000-0002-0356-4966
Email: bgreatre@une.edu.au
UNE Id une-id:bgreatre
Murkin, Andrew S
Schramm, Vern L
Tyler, Peter C
Type of document
Journal Article
Language
en
Entity Type
Publication
Publisher
American Chemical Society
Place of publication
United States of America
DOI
10.1021/jm701265n
UNE publication id
une:8312
Abstract
N-Ribosyl phosphorylases and hydrolases catalyze nucleophilic displacement reactions by migration of the cationic ribooxacarbenium carbon from the fixed purine to phosphate and water nucleophiles, respectively. As the lysis reaction progresses along the reaction coordinate, the distance between the purine and carbocation increases and the distance between carbocation and nucleophile decreases. Immucillin-H and DADMe-immucillin-H have been shown previously to be potent inhibitors of purine nucleoside phosphorylases and lie more toward the reactant and products side of this reaction coordinate, respectively. Both these enzyme inhibitors, which are currently in human clinical trials for different indications, are chiral and expensive to manufacture. We now report the synthesis of azetidine analogues of the DADMe-immucillins, which, despite their lack of stereochemical complexity, remain potent inhibitors (equilibrium dissociation constants as low as 229 pM) of purine nucleoside phosphorylase (PNP), methylthioadenosine phosphorylase (MTAP), and methylthioadenosine nucleosidase (MTAN), with potential utility as drug candidates.
Link
Citation
Journal of Medicinal Chemistry, 51(4), p. 948-956
ISSN
1520-4804
0022-2623
Start page
948
End page
956

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