Syntheses and bio-activities of the L-enantiomers of two potent transition state analogue inhibitors of purine nucleoside phosphorylases.
(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.
Clinch
Keith
K
Carbohydrate Chemistry Team, Industrial Research Limited, P.O. Box 31310, Lower Hutt, New Zealand. k.clinch@irl.cri.nz
Evans
Gary B
GB
Fleet
George W J
GW
Furneaux
Richard H
RH
Johnson
Stephen W
SW
Lenz
Dirk H
DH
Mee
Simon P H
SP
Rands
Peter R
PR
Schramm
Vern L
VL
Taylor Ringia
Erika A
EA
Tyler
Peter C
PC
D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D007202:Indicators and Reagents; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D011684:Purine Nucleosides / Q000737:chemistry / Q000494:pharmacology; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism
D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D011684:Purine Nucleosides; D011744:Pyrimidinones; D011759:Pyrrolidines; C113101:forodesine; D011683:Purine-Nucleoside Phosphorylase