Synthesis of 4,6-dideoxy-3-fluoro-2-keto-β-d-glucopyranosyl analogues of 5-fluorouracil, N6-benzoyl adenine, uracil, thymine, N4-benzoyl cytosine and evaluation of their antitumor activities

Abstract

The synthesis of the unsaturated 4,6-dideoxy-3-fluoro-2-keto-beta-d-glucopyranosyl nucleosides of 5-fluorouracil (6a), N(6)-benzoyl adenine (6b), uracil (6c), thymine (6d) and N(4)-benzoyl cytosine (6e), is described. Monoiodination of compounds 1a,b, followed by acetylation, catalytic hydrogenation and finally regioselective 2'-O-deacylation afforded the partially acetylated dideoxynucleoside analogues of 5-fluorouracil (5a) and N(6)-benzoyl adenine (5b), respectively. Direct oxidation of the free hydroxyl group at the 2'-position of 5a,b, with simultaneous elimination reaction of the beta-acetoxyl group, afforded the desired unsaturated 4,6-dideoxy-3-fluoro-2-keto-beta-D-glucopyranosyl derivatives 6a,b. Compounds 1c-e were used as starting materials for the synthesis of the dideoxy unsaturated carbonyl nucleosides of uracil (6c), thymine (6d) and N(4)-benzoyl cytosine (6e). Similarly a protection-selective deprotection sequence followed by oxidation of the free hydroxyl group at the 2'-position of the dideoxy benzoylated analogues 9c-e with simultaneous elimination reaction of the beta-benzoyl group, gave the desired nucleosides 6c-e. None of the compounds was inhibitory to a broad spectrum of DNA and RNA viruses at subtoxic concentrations. The 5-fluorouracil derivative 6a was more cytostatic (50% inhibitory concentration ranging between 0.2 and 12 microM) than the other compounds.

Synthesis of Novel Thiopurine Pyranonucleosides: Evaluation of Their Bioactivity

“…[12,13] In recent years, pyranosyl nucleosides are viewed as important modifications of natural nucleosides, offering promising avenues in the development of novel bioactive agents with promising therapeutic potential. [14][15][16][17][18][19][20][21][22][23][24] In our previous investigations, we demonstrated that base-modified pyranonucleosides rank among the most potent glycogen phosphorylase (GP) [25,26] and thymidylate synthase (TS) [27] inhibitors, and were endowed with a pronounced cytostatic and antiviral action. [28] As a continuation of this research and based on the pharmacological properties of thiopurine analogues, we now report the synthesis and biology of new thiopurine pyranonucleosides via glycosylation of mercaptopurine and thioguanine pyranonucleosides bearing D-glucose, D-galactose, D-xylose, D-mannose, and D-lyxose as sugar moiety.…”

Synthesis of Novel 2-(Substituted amino)alkylthiopyrimidin-4(3H)-ones as Potential Antimicrobial Agents

“…Several pyrimidine derivatives exhibit diverse pharmacological activities as antiviral [1,2,3,4,5,6,7,8,9], anti-inflammatory [10,11,12], and antimalarial agents [13,14,15]. Many pyrimidines have been demonstrated to possess anticancer [16,17,18,19,20,21], antituberculosis [22] and anti-allergic [23] activities. Moreover, several pyrimidine derivatives have been reported as antithyroid [24] and antimicrobial agents [25,26,27,28,29,30], as well as human thymidine and uridine phosphorylase inhibitors [31,32,33].…”

Organic Reactions in “Green Surfactant”: An Avenue to Bisuracil Derivative

“…The uracil scaffold and its derivatives are known to have a wide spectrum of bioactivities that have helped chemists and biologists to move forward with harmony. − The nucleophilic nature of the C-5 position of uracil and its derivatives is well-known, − and its reactivity is greatly influenced by the nature of substituents in the uracil skeleton. In fact, this is one of the strategies adopted for the synthesis of bioactive 5-substituted uracil derivatives .…”