Azetidine based transition state analogue inhibitors of N-ribosyl hydrolases and phosphorylases

Gary B. Evans, Richard H. Furneaux, Ben Greatrex, Andrew S. Murkin, Vern L. Schramm, Peter C. Tyler

Research output: Contribution to journalArticle

64 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)948-956
Number of pages9
JournalJournal of Medicinal Chemistry
Volume51
Issue number4
DOIs
StatePublished - Feb 28 2008

Fingerprint

Purine-Nucleoside Phosphorylase
Phosphorylases
Nucleophiles
Hydrolases
Enzyme Inhibitors
Carbon
Phosphates
Clinical Trials
Water
Pharmaceutical Preparations
purine
azetidine
5'-methylthioadenosine phosphorylase
DADMe-immucillin H
forodesine

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Azetidine based transition state analogue inhibitors of N-ribosyl hydrolases and phosphorylases. / Evans, Gary B.; Furneaux, Richard H.; Greatrex, Ben; Murkin, Andrew S.; Schramm, Vern L.; Tyler, Peter C.

In: Journal of Medicinal Chemistry, Vol. 51, No. 4, 28.02.2008, p. 948-956.

Research output: Contribution to journalArticle

Evans, Gary B. ; Furneaux, Richard H. ; Greatrex, Ben ; Murkin, Andrew S. ; Schramm, Vern L. ; Tyler, Peter C. / Azetidine based transition state analogue inhibitors of N-ribosyl hydrolases and phosphorylases. In: Journal of Medicinal Chemistry. 2008 ; Vol. 51, No. 4. pp. 948-956.
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