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Carbocyclic analogues of the potent cytidine deaminase inhibitor 1-(β- D-ribofuranosyl)-1,2-dihydropyrimidin-2-one (zebularine)

Title
Carbocyclic analogues of the potent cytidine deaminase inhibitor 1-(β- D-ribofuranosyl)-1,2-dihydropyrimidin-2-one (zebularine)
Authors
Jeong L.S.Buenger G.McCormack J.J.Cooney D.A.Hao Z.Marquez V.E.
Ewha Authors
정낙신
Issue Date
1998
Journal Title
Journal of Medicinal Chemistry
ISSN
0022-2623JCR Link
Citation
vol. 41, no. 14, pp. 2572 - 2578
Indexed
SCI; SCIE; SCOPUS scopus
Abstract
Three carbocylic analogues of the potent cytidine deaminase inhibitor (CDA) zebularine [1-(β-D-ribofuranosyl)-l,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 approached 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 cyclopentyl analogue 5 was linearly constructed from carbocyclic amine 17, and the final target 6 was similarly constructed from the carbobicyclic amine 27. Of the three target compounds, only 5 showed a significant level of inhibition against human CDA, but it was 16 times less potent than zebularine (K(i) = 38 μM vs K(i(apparent)) = 2.3 μM). Although these carbocyclic analogues appeared to be more stable than zebularine, replacement of the electronegative CO4' oxygen for the less electronegative carbon in 4-6 presumably reduces the capacity of the pyrimidin-2(1H)-one ring to form a covalent hydrate, a step considered crucial for the compound to function as a transition-state inhibitor of the enzyme.
DOI
10.1021/jm980111x
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약학대학 > 약학과 > Journal papers
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