Second generation transition state analogue inhibitors of human 5′-methylthioadenosine phosphorylase

Gary B. Evans, Richard H. Furneaux, Dirk H. Lenz, Gavin F. Painter, Vern L. Schramm, Vipender Singh, Peter C. Tyler

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

The polyamine biosynthetic pathway is a therapeutic target for proliferative diseases because cellular proliferation requires elevated levels of polyamines. A byproduct of the synthesis of spermidine and spermine is 5′-methylthioadenosine (MTA). In humans MTA is processed by 5′-methylthioadenosine phosphorylase (MTAP) so that significant amounts of MTA do not accumulate. Products of the MTAP reaction (adenine and 5-methylthio-α-D-ribose-1-phosphate) are recycled to S-adenosylmethionine, the precursor for polyamine synthesis. Potent inhibitors of MTAP might allow the build-up of sufficient levels of MTA to generate feedback inhibition of polyamine biosynthesis and/or reduce S-adenosylmethionine levels. We recently reported the design and synthesis of a family of potent transition state analogue inhibitors of MTAP. We now report the synthesis of a second generation of stable transition state analogues with increased distance between the ribooxocarbenium ion and purine mimics. These compounds are potent inhibitors with equilibrium dissociation constants as low as 10 pM. The first and second generation inhibitors represent synthetic approaches to mimic early and late features of a dissociative transition state.

Original languageEnglish (US)
Pages (from-to)4679-4689
Number of pages11
JournalJournal of Medicinal Chemistry
Volume48
Issue number14
DOIs
StatePublished - Jul 14 2005

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Polyamines
S-Adenosylmethionine
Spermidine
Ribose
Spermine
Biosynthesis
Biosynthetic Pathways
Adenine
Byproducts
Cell Proliferation
Ions
Feedback
5'-methylthioadenosine phosphorylase
Therapeutics

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Second generation transition state analogue inhibitors of human 5′-methylthioadenosine phosphorylase. / Evans, Gary B.; Furneaux, Richard H.; Lenz, Dirk H.; Painter, Gavin F.; Schramm, Vern L.; Singh, Vipender; Tyler, Peter C.

In: Journal of Medicinal Chemistry, Vol. 48, No. 14, 14.07.2005, p. 4679-4689.

Research output: Contribution to journalArticle

Evans, Gary B. ; Furneaux, Richard H. ; Lenz, Dirk H. ; Painter, Gavin F. ; Schramm, Vern L. ; Singh, Vipender ; Tyler, Peter C. / Second generation transition state analogue inhibitors of human 5′-methylthioadenosine phosphorylase. In: Journal of Medicinal Chemistry. 2005 ; Vol. 48, No. 14. pp. 4679-4689.
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