RESUMEN
1,1-Difluoro-2-(tetrahydro-3-furanyl)ethylphosphonic acids cis-3 and trans-3 possessing a N9-purinylmethyl functionality at the ring were synthesized and tested as "multi-substrate analogue" inhibitors for purine nucleoside phosphorylases. Radical cyclization of allyic alpha,alpha-difluorophosphonate (E)-7 was applied to construct the alpha,alpha-difluorophosphonate-functionalized tetrahydrofuranyl moiety. The IC50 values of cis-3 and trans-3 for human erythrocyte PNP-catalyzed phosphorylation of inosine were determined to be 88 and 320 nM, respectively. The stereochemistry of the inhibitors was found to affect significantly the inhibitory potency.
Asunto(s)
Compuestos de Flúor/síntesis química , Furanos/síntesis química , Organofosfonatos/síntesis química , Purina-Nucleósido Fosforilasa/antagonistas & inhibidores , Purinas/síntesis química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Eritrocitos/enzimología , Compuestos de Flúor/farmacología , Furanos/farmacología , Bacilos Grampositivos Asporogénicos/enzimología , Humanos , Inosina/metabolismo , Estructura Molecular , Organofosfonatos/farmacología , Fosforilación , Purinas/farmacologíaRESUMEN
A series of 1,1-difluoro-5-(1H-9-purinyl)-2-pentenylphosphonic acids, (E)-2a,b and (Z)-2a,b, as well as the related methano analogues (+/-)-3a,b and (+/-)-4a,b were prepared for evaluation of their PNP inhibitory activities. The cyclopopane ring and the hypoxanthine residue were found to increase the profile of inhibitory activity. The IC50 and Ki values of difluoro¿(1R*,2S*)-2-[2-(6-oxo-6,9-dihydro-1H-9-purinyl)ethyl]cycl opropyl¿methylphosphonic acid (+/-)-3b toward PNP purified from Cellulomonas sp. were determined to be 70 nM and 8.8 nM, respectively.