Carbocyclic Analogues of the Potent Cytidine Deaminase Inhibitor 1-(β-d-Ribofuranosyl)-1,2-dihydropyrimidin-2-one (Zebularine)

• Published in: Journal of medicinal chemistry Vol. 41; no. 14; pp. 2572 - 2578
• Main Authors: Jeong, Lak Shin, Buenger, Greg, McCormack, John J, Cooney, David A, Hao, Zhang, Marquez, Victor E
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 02.07.1998; Amer Chemical Soc
• Subjects: Analytical, structural and metabolic biochemistry; Animals; aristeromycin; Biological and medical sciences; Chemistry, Medicinal; Cytidine - analogs & derivatives; cytidine deaminase; Cytidine Deaminase - antagonists & inhibitors; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Humans; Hydrolases; Life Sciences & Biomedicine; Mice; Pharmacology & Pharmacy; Pyrimidine Nucleosides - chemical synthesis; Pyrimidine Nucleosides - chemistry; Pyrimidine Nucleosides - pharmacology; Science & Technology; Structure-Activity Relationship; zebularine; THYMIDINE; NEPLANOCIN-A; PRODUCTS; CRYSTAL-STRUCTURE; BIOLOGICAL-ACTIVITY; URACIL NUCLEOSIDES; OLIGONUCLEOTIDES; Cyclitol; Enantioselectivity; Structure activity relation; Bicyclic compound; Chemical synthesis; Pyrimidine nucleoside; Monocyclic compound; Ethylenic compound
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980111x

Three carbocylic analogues of the potent cytidine deaminase inhibitor (CDA) zebularine [1-(β-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 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.