Syntheses and bio-activities of the l-enantiomers of two potent transition state analogue inhibitors of purine nucleoside phosphorylases

Keith Clinch, Gary B. Evans, George W.J. Fleet, Richard H. Furneaux, Stephen W. Johnson, Dirk H. Lenz, Simon P.H. Mee, Peter R. Rands, Vern L. Schramm, Erika A. Taylor Ringia, Peter C. Tyler

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

(1R)-1-(9-Deazahypoxanthin-9-yl)-1,4-dideoxy-1,4-imino-l-ribitol [(+)-5] and (3S,4S)-1-[(9-deazahypoxanthin-9-yl)methyl]-4-(hydroxymethyl)pyrrolidin-3-ol [(-)-6] are the l-enantiomers of immucillin-H (d-ImmH) and DADMe-immucillin-H (d-DADMe-ImmH), respectively, these d-isomers being high affinity transition state analogue inhibitors of purine nucleoside phosphorylases (PNPases) developed as potential pharmaceuticals against diseases involving irregular activation of T-cells. The C-nucleoside hydrochloride d-ImmH [(-)-5)·HCl], now "Fodosine™" is in phase II clinical trials as an anti-T-cell leukaemia agent, while d-DADMe-ImmH is a second generation inhibitor with extreme binding to the target enzyme and has entered the clinic for phase I testing as an anti-psoriasis drug. Since the enantiomers of some pharmaceuticals have revealed surprising biological activities, the l-nucleoside analogues (+)-5·HCl and (-)-6, respectively, of d-ImmH and d-DADMe-ImmH, were prepared and their PNPase binding properties were studied. For the synthesis of compound (-)-6 suitable enzyme-based routes to the enantiomerically pure starting material (3S,4S)-4-(hydroxymethyl)pyrrolidin-3-ol [(-)-16] and its enantiomer were developed. The l-enantiomers (+)-5·HCl and (-)-6 bind to the PNPases approximately 5- to 600-times less well than do the d-compounds, but nevertheless remain powerful inhibitors with nanomolar dissociation constants.

Original languageEnglish (US)
Pages (from-to)1131-1139
Number of pages9
JournalOrganic and Biomolecular Chemistry
Volume4
Issue number6
DOIs
StatePublished - Mar 20 2006

ASJC Scopus subject areas

  • Biochemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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    Clinch, K., Evans, G. B., Fleet, G. W. J., Furneaux, R. H., Johnson, S. W., Lenz, D. H., Mee, S. P. H., Rands, P. R., Schramm, V. L., Taylor Ringia, E. A., & Tyler, P. C. (2006). Syntheses and bio-activities of the l-enantiomers of two potent transition state analogue inhibitors of purine nucleoside phosphorylases. Organic and Biomolecular Chemistry, 4(6), 1131-1139. https://doi.org/10.1039/b517883e