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Title: Azetidine Based Transition State Analogue Inhibitors of N-Ribosyl Hydrolases and Phosphorylases
Contributor(s): Evans, Gary B (author); Furneaux, Richard H (author); Greatrex, Ben  (author)orcid ; Murkin, Andrew S (author); Schramm, Vern L (author); Tyler, Peter C (author)
Publication Date: 2008
DOI: 10.1021/jm701265n
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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.
Publication Type: Journal Article
Source of Publication: Journal of Medicinal Chemistry, 51(4), p. 948-956
Publisher: American Chemical Society
Place of Publication: United States of America
ISSN: 1520-4804
Field of Research (FOR): 030503 Organic Chemical Synthesis
060107 Enzymes
030401 Biologically Active Molecules
Socio-Economic Outcome Codes: 970106 Expanding Knowledge in the Biological Sciences
970103 Expanding Knowledge in the Chemical Sciences
920102 Cancer and Related Disorders
Peer Reviewed: Yes
HERDC Category Description: C1 Refereed Article in a Scholarly Journal
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School of Rural Medicine

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