CARBOCYCLIC ANALOGS OF THE POTENT CYTIDINE DEAMINASE INHIBITOR -(BETA-D-RIBOFURANOSYL)-1,2-DIHYDROPYRIMIDIN-2-ONE (ZEBULARINE)

Three carbocylic analogues of the potent cytidine deaminase inhibitor (CDA) zebularine [1-(beta-D-ribofuranosyl)-1,2-dihydropyrimidin-2- one -, 1a] were synthesized. The selected pseudosugar templates correspond , respectively, to the cyclopentenyl moiety of neplanocin A (compound 4), the cyclopentyl moiety of aristeromycin (compound 5), and a newly designed, rigid bicyclo[3.1,0]hexane moiety (compound 6). These three carba-nucleoside versions of zebularine were fashioned to overcome the inherent instability of the parent drug. Each target compound was app roached differently using either convergent or linear approaches. The immediate precursor to the cyclopentenyl analogue 4 was obtained by a Mitsunobu coupling of pseudosugar 7 with 2-hydroxypyrimidine. The cycl opentyl analogue 5 was linearly constructed from carbocyclic amine 17, and the final target 6 was similarly constructed from the carbobicycl ic amine 27. Of the three target compounds, only 5 showed a significan t level of inhibition against human CDA, but it was 16 times less pote nt than zebularine (K-i = 38 mu M vs K-i(apparent) = 2.3 mu M). Althou gh these carbocyclic analogues appeared to be more stable than zebular ine, replacement of the electronegative CO4' oxygen for the less elect ronegative carbon in 4-6 presumably reduces the capacity of the pyrimi din-2(1H)-one ring to form a covalent hydrate, a step considered cruci al for the compound to function as a transition-state inhibitor of the enzyme.