Synthesis and evaluation of multisubstrate analogue inhibitors of purine nucleoside phosphorylases.
1,1-Difluoro-2-(tetrahydro-3-furanyl)ethylphosphonic acids (+/-)-cis-4a and (+/-)-trans-4a possessing a (purine-9-yl)methyl functionality at the ring as well as their homologues (+/-)-cis-4b and (+/-)-trans-4b were synthesized and tested as 'multi-substrate analogue' inhibitors for purine nucleoside phosphorylases. Radical cyclization of allylic alpha,alpha-difluorophosphonates 8a,b was applied to construct the alpha,alpha-difluorophosphonate-functionalized oxacycles 9a,b. The IC50 values of the nucleotide analogues (+/-)-cis-4a and (+/-)-cis-4b were 88 and 38 nM, respectively, for human erythrocyte PNP-catalyzed phosphorylation of inosine in the presence of 100mM orthophosphate. The stereochemistry of the inhibitors was found to affect significantly the inhibitory potency. The transisomers (+/-)-trans-4a and (+/-)-trans-4b were ca. 4-fold less potent than the corresponding cis-isomers. At an intracellular concentration of orthophosphate (1 mM), (+/-)-cis-4b, the most potent compound of this series, was shown to have IC50 and Ki values of 8.7 and 3.5 nM, respectively.
Yokomatsu
T
T
School of Pharmacy, Tokyo University of Pharmacy & Life Science, Hachioji, Japan. yokomatu@ps.toyaku.ac.jp
Hayakawa
Y
Y
Kihara
T
T
Koyanagi
S
S
Soeda
S
S
Shimeno
H
H
Shibuya
S
S
D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004912:Erythrocytes / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008968:Molecular Conformation; D015394:Molecular Structure; D009711:Nucleotides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D009711:Nucleotides; D063065:Organophosphonates; D011683:Purine-Nucleoside Phosphorylase