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

Organic & Biomolecular Chemistry
Keith ClinchPeter C Tyler

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 ...Continue Reading

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Citations

Dec 25, 2007·Journal of the American Chemical Society·Agnes Rinaldo-MatthisVern L Schramm
Feb 26, 2010·Nucleosides, Nucleotides & Nucleic Acids·Bogdan Doboszewski
Dec 3, 2014·European Journal of Medicinal Chemistry·Gheorghe Roman
Mar 28, 2009·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Tadeusz RobakPawel Robak
Aug 12, 2015·Bioorganic & Medicinal Chemistry·Gary B EvansPeter C Tyler
Aug 19, 2007·Organic & Biomolecular Chemistry·Keith ClinchSarah J Wilcox
Oct 26, 2013·The Journal of Biological Chemistry·Yong ZhangVern L Schramm
Mar 6, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Andreas LuxenburgerChristian Peifer
Sep 20, 2008·Journal of Medicinal Chemistry·Jennifer M MasonBrian W Skelton
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Apr 10, 2019·Journal of Medicinal Chemistry·Thomas ChevietSuzanne Peyrottes
Feb 7, 2008·Journal of Medicinal Chemistry·Gary B EvansPeter C Tyler
Nov 30, 2021·Organic & Biomolecular Chemistry·Sian S Berry, Simon Jones

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