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

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) x 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 x 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 [(-)-6] and its enantiomer were developed. The L-enantiomers (+)-5 x 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.

• Authors: 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
• Journal: Organic & biomolecular chemistry (Org Biomol Chem) Vol. 4 Issue 6 Pg. 1131-9 (Mar 21 2006) ISSN: 1477-0520 [Print] England
• PMID: 16525558 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Indicators and Reagents
• Purine Nucleosides
• Pyrimidinones
• Pyrrolidines
• forodesine
• Purine-Nucleoside Phosphorylase

Topics

• Enzyme Inhibitors (chemistry, pharmacology)
• Indicators and Reagents
• Kinetics
• Models, Molecular
• Molecular Conformation
• Purine Nucleosides (chemistry, pharmacology)
• Purine-Nucleoside Phosphorylase (antagonists & inhibitors)
• Pyrimidinones (chemistry, pharmacology)
• Pyrrolidines (chemistry, pharmacology)
• Stereoisomerism