TY - JOUR
T1 - Syntheses and bio-activities of the l-enantiomers of two potent transition state analogue inhibitors of purine nucleoside phosphorylases
AU - Clinch, Keith
AU - Evans, Gary B.
AU - Fleet, George W.J.
AU - Furneaux, Richard H.
AU - Johnson, Stephen W.
AU - Lenz, Dirk H.
AU - Mee, Simon P.H.
AU - Rands, Peter R.
AU - Schramm, Vern L.
AU - Taylor Ringia, Erika A.
AU - Tyler, Peter C.
PY - 2006
Y1 - 2006
N2 - (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.
AB - (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.
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U2 - 10.1039/b517883e
DO - 10.1039/b517883e
M3 - Article
C2 - 16525558
AN - SCOPUS:33644884485
SN - 1477-0520
VL - 4
SP - 1131
EP - 1139
JO - Organic and Biomolecular Chemistry
JF - Organic and Biomolecular Chemistry
IS - 6
ER -