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)·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.