Synthesis of Second-Generation Transition State Analogues of Human Purine Nucleoside Phosphorylase

Gary B. Evans, Richard H. Furneaux, Andrzej Lewandowicz, Vern L. Schramm, Peter C. Tyler

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

Purine nucleoside phosphorylases (PNPs) catalyze nucleophilic displacement reactions by migration of the cationic ribooxacarbenium carbon between the fixed purine and phosphate nucleophiles. As the phosphorolysis reaction progresses along the reaction coordinate, the distance between the purine and carbocation increases and the distance between carbocation and phosphate anion decreases. Immucillin-H and Immucillin-G have been shown previously to be potent inhibitors of PNP. We now report the synthesis of a second generation of stable transition state analogues, DADMe-Immucillins 2, 3, and 4, with increased distance between ribooxacarbenium and purine mimics by incorporation of a methylene bridge between these groups. These compounds are potent inhibitors with equilibrium dissociation constants as low as 7 pM against human PNP. Stable chemical analogues of enzymatic transition states are necessarily imperfect since they lack the partial bond character of the transition state. The immucillins and DADMe-Immucillins represent approaches from the product and reaction side of the transition state.

Original languageEnglish (US)
Pages (from-to)5271-5276
Number of pages6
JournalJournal of Medicinal Chemistry
Volume46
Issue number24
DOIs
StatePublished - Nov 20 2003

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Purine-Nucleoside Phosphorylase
Phosphates
Nucleophiles
Anions
Carbon
purine

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Synthesis of Second-Generation Transition State Analogues of Human Purine Nucleoside Phosphorylase. / Evans, Gary B.; Furneaux, Richard H.; Lewandowicz, Andrzej; Schramm, Vern L.; Tyler, Peter C.

In: Journal of Medicinal Chemistry, Vol. 46, No. 24, 20.11.2003, p. 5271-5276.

Research output: Contribution to journalArticle

Evans, Gary B. ; Furneaux, Richard H. ; Lewandowicz, Andrzej ; Schramm, Vern L. ; Tyler, Peter C. / Synthesis of Second-Generation Transition State Analogues of Human Purine Nucleoside Phosphorylase. In: Journal of Medicinal Chemistry. 2003 ; Vol. 46, No. 24. pp. 5271-5276.
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