Synthesis and biological evaluation of 2′,4′- and 3′,4′-bridged nucleoside analogues

Abstract

Most nucleosides in solution typically exist in equilibrium between two major sugar pucker forms, N-type and S-type, but bridged nucleosides can be locked into one of these conformations depending on their specific structure. While many groups have researched these bridged nucleosides for the purpose of determining their binding affinity for antisense applications, we opted to look into the potential for biological activity within these conformationally-locked structures. A small library of 2′,4′- and 3′,4′-bridged nucleoside analogues was synthesized, including a novel 3′,4′-carbocyclic bridged system. The synthesized compounds were tested for antibacterial, antitumor, and antiviral activities, leading to the identification of nucleosides possessing such biological activities. To the best of our knowledge, these biologically active compounds represent the first example of 2′,4′-bridged nucleosides to demonstrate such properties. The most potent compound, nucleoside 33, exhibited significant antiviral activity against pseudoviruses SF162 (IC50 = 7.0 μM) and HxB2 (IC50 = 2.4 μM). These findings render bridged nucleosides as credible leads for drug discovery in the anti-HIV area of research.

Insights into the N,N-diacylation reaction of 2-aminopyrimidines and deactivated anilines: an alternative N-monoacylation reaction

“…[11][12][13][14] By the addition of the appropriate benzoyl chloride to 2-amino-4-(3-pyridinyl)pyrimidine in refluxing pyridine, 6 a group of N-mono-and N,N-dibenzoyl derivatives has been prepared in low yield. The same mixture of N-monobenzoyland N,N-dibenzoyl-2-aminopyrimidines has been obtained (15% and 45%, respectively) by reaction of the 2-aminopyrimidine scaffold with benzoyl chloride in refluxing dichloromethane 15 and excess pyridine for 48 h. Peracylation of a 2,4-diaminopyrimidine-derivative has also been obtained with excess of benzoyl chloride in pyridine at room temperature for 18 hours, 16,17 while N,N-dibenzoyl-deoxycytidine has been formed as a by-product in the N-benzoylation of deoxycytidine 18 and 2-aminopyridines. 19 Finally, 2-N-pyrimidinyl acrylamide has been prepared under forcing conditions (NaH/THF) from acryloyl chloride in modest yield.…”

“…Previous reports related to this type of transformations have appeared in the literature, but they have been only briefly investigated. 6,[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] Activation methods have found the reagents to be resistant to amide formation of 2-aminopyrimidines with low or moderate yields. [11][12][13][14] By the addition of the appropriate benzoyl chloride to 2-amino-4-(3-pyridinyl)pyrimidine in refluxing pyridine, 6 a group of N-mono-and N,N-dibenzoyl derivatives has been prepared in low yield.…”

Antioxidant and Antitumor Activities of New Synthesized Aromatic C-Nucleoside Derivatives

“…Synthesis of carbohydrazones 3a-e and 4. Condensative cyclization of carbohydrazone 3a with acetic anhydride in the presence of anhydrous sodium acetate gave a cyclized product that according to physical and chemical studies, could not be reconciled with the structure of 10a, that but rather was compatible with that of [1,3,4]oxadiazolo-[2,3-a]isoindole 10b. The infrared spectrum of this compound showed the disappearance of the carboxylic acid hydroxyl group, sugar hydroxyl groups, and CONH absorption bands.…”

“…The carbohydrazide 1 was used as the precursor for the synthesis of a number of new aromatic C-nucleosides containing 1,3,4-oxadiazole 7, [1,3,4]oxadiazolo[2,3-a]isoindole 10b and pyrazole units 18. On the other hand, the thiosemicarbazone 20 was used as the key intermediate for synthesis of 1,3,4-oxadiazole and 1,2,4-triazole-3-thione derivatives 21 and 23.…”

“…A number of nucleoside analogues have been found to show a broad spectrum of biological effects such as antifungal [1,2], antibacterial [1][2][3], antitumor [3][4][5], antiviral [3,4,[6][7][8][9][10][11][12][13][14] anti-inflammatory [15] and analgesic [15] activities. Moreover, 2'-deoxy-2'-fluoro-2'-C-methyl nucleoside analogues have showed promising activity against HCV replication [16].…”