title: Synthesis of new 2'-deoxy-2'-fluoro-4'-azido nucleoside analogues as potent anti-HIV agents.
abstract: We prepared 1-(4'-azido-2'-deoxy-2'-fluoro-β-D-arabinofuranosyl)cytosine (10) and its hydrochloride salt (11) as potential antiviral agents based on the favorable antiviral profiles of 4'-substituted nucleosides. Compounds 10 and 11 were synthesized from 1,3,5-O-tribenzoyl-2-deoxy-2-fluoro-D-arabinofuranoside in multiple steps, and their structures were unequivocally established by IR, (1)H NMR, (13)C NMR, and (19)F NMR spectroscopy, HRMS, and X-ray crystallography. Compounds 10 and 11 exhibited potent anti-HIV-1 activity (EC(50): 0.3 and 0.13 nM, respectively) without significant cytotoxicity in concentrations up to 100 μM. Compound 11 exhibited extremely potent anti-HIV activity against NL4-3 (wild-type), NL4-3 (K101E), and RTMDR viral strains, with EC(50) values of 0.086, 0.15, and 0.11 nM, respectively. Due to the high potency of 11, it was also screened against an NIH Reagent Program NRTI-resistant virus panel containing eleven mutated viral strains and for cytotoxicity against six different human cell lines. The results of this screening indicated that 11 is a novel NRTI that could be developed as an anti-AIDS clinical trial candidate to overcome drug-resistance issues.
authors: Department of Chemistry, Zhengzhou University, Zhengzhou 450001, PR China.
authors: Qiang
authors: Q
authors: Wang
authors: Weidong
authors: W
authors: Hu
authors: Shuyang
authors: S
authors: Wang
authors: Zhenliang
authors: Z
authors: Pan
authors: Le
authors: L
authors: Tao
authors: Xiaohe
authors: X
authors: Guo
authors: Keduo
authors: K
authors: Qian
authors: Chin-Ho
authors: CH
authors: Chen
authors: Kuo-Hsiung
authors: KH
authors: Lee
authors: Junbiao
authors: J
authors: Chang
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D018360:Crystallography, X-Ray; D003561:Cytarabine / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013055:Spectrophotometry, Infrared
chemical_list: D019380:Anti-HIV Agents; D009705:Nucleosides; D003561:Cytarabine