Syntheses of 4-[1-(2-deoxy-beta-D-ribofuranosyl)]-derivatives of 2-substituted-5-fluoroaniline: '' cytosine replacement '' analogs of deoxycytidine for evaluation as anticancer and antihuman immunodeficiency virus (anti-HIV)agents

A group of 4-[1-(2-deoxy-beta-D-ribofuranosyl)]-derivatives of 5-fluoroanil ine possessing a variety of aryl C-2 substituents (6a R = H, 6b R = F, 6c R = Me) were synthesized. Accordingly, a Heck-type coupling reaction of the 4-iodoaniline derivatives (13a-c) with the bis(tert-butyldimethylsilyl)glyc al (11) in the presence of Pd(OAc)(2) and Ph3As, followed by removal of the tert-butyldimethylsilyl protection groups using n-Bu4N+F-, yielded the cor responding 4-(beta-D-glycero-pentofuran-3-ulos-1-yl)aniline derivatives (14 a-c) having a C-3 C=O in the sugar ring. Reduction of the C-3 C=O compounds (14a-c) using NaB(OAc)(3)H afforded the target 4-[1-(2-deoxy-beta-D-ribofu ranosyl)]-derivatives of the respective 2-substituted-5-fluoroaniline (6a-c ). The deoxycytidine mimic, 3-fluoro-4-[1-(2-deoxy-beta-D-ribofuranosyl)]an iline (6a), in which the cytosine ring of deoxycytidine is replaced by a 4- (3-fluoroaniline) ring system, was inactive as an anticancer agent against a variety of tumor cell lines, and as an antihuman immunodeficiency virus ( HIV-1, HIV-2) agent. The failure of this unnatural deoxycytidine mimic (6a) to exhibit anticancer-antiviral activity may be due to its inability to un dergo phosphorylation by host cell- and virus-induced kinases.