Synthesis, antiviral activity, and mechanism of drug resistance of D- and L-2',3'-didehydro-2',3'-dideoxy-2'-fluorocarbocyclic nucleosides.
Synthesis, antiviral activity, and mechanism of drug resistance of D- and L-2',3'-didehydro-2',3'-dideoxy-2'-fluorocarbocyclic nucleosides.
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DOI：
10.1021/jm050096d
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发表时间：
2005-05
影响因子：
7.3
通讯作者：
Jianing Wang;Yunho Jin;K. Rapp;M. Bennett;R. Schinazi;C. K. Chu
中科院分区：
文献类型：
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作者：
Jianing Wang;Yunho Jin;K. Rapp;M. Bennett;R. Schinazi;C. K. Chu
碳环核苷类化合物由于其独特的生物活性和代谢稳定性而受到广泛关注。在核苷类似物中，在碳水化合物部分上的氟取代或引入2 '，3'-不饱和结构基序已被证明成功地产生有效的抗病毒剂。通过结合这些结构特征，D-和L-2 '，3'-双脱氧-2 '，3'-二氢-2 '-氟-碳环核苷（D-和L-2' F-C-d4 Ns）被合成为潜在的抗HIV药物。目标D-和L-碳环核苷都是从D-核糖立体特异性合成的。研究了所合成的化合物在活化的人外周血单个核细胞中抗HIV-1的构效关系，发现L-2 '，3'-二脱氧-2 '，3'-二脱氧-2 '-氟腺苷类似物（L-2 'F-C-d4 A）46显示出有效的抗HIV活性（EC 50 = 0.77 μ M），尽管它对拉米夫定抗性变体（HIV-1 M184 V）具有交叉抗性。建模研究表明，计算的相对结合能和活性/电阻数据之间有很好的相关性。模拟研究还表明，额外的氢键和有利的货车德瓦尔斯相互作用有助于L-2 'F-C-d4 A的抗病毒活性高于其D-对应物。与其它L-核苷一样，L-2 ′ F-C-d4 A的糖部分和Val 184的侧链的不利的空间位阻可以解释L-2 ′ F-C-d4 A与M184 V突变体的交叉抗性。Carbovir及其类似物L-2 ′ F-C-d4 G 25的抗病毒活性的显著差异可能是由于L-2 ′ F-C-d4 G-TP/HIV-RT复合物中Tyr 115的苯环发生畸变，从而导致弱的π-π相互作用。
Carbocyclic nucleosides have received much attention due to their interesting biological activity and metabolic stability. Among nucleoside analogues, a fluorine substitution on the carbohydrate moiety or introduction of a 2',3'-unsaturated structure motif has been proven to be successful in producing effective antiviral agents. By combining these structural features, both D- and L-2',3'-dideoxy-2',3'-didehydro-2'-fluoro-carbocyclic nucleosides (D- and L-2'F-C-d4Ns) were synthesized as potential anti-HIV agents. The target D- and L-carbocyclic nucleosides were both stereospecifically synthesized from D-ribose. The structure-activity relationships of synthesized compounds against HIV-1 in activated human peripheral blood mononuclear (PBM) cells were studied, from which we found that the L-2',3'-dideoxy-2'3'-didehydro-2'-fluoroadenosine analogue (L-2'F-C-d4A) 46 showed potent anti-HIV activity (EC50 = 0.77 microM), although it is cross-resistant to the lamivudine-resistant variant (HIV-1M184V). Modeling studies demonstrated a good correlation between calculated relative binding energies and activity/resistance data. The modeling study also indicated that an additional hydrogen bond and a favorable van der Waals interaction contribute to the higher antiviral activity of L-2'F-C-d4A in comparison to its D-counterpart. Also, like other L-nucleosides, the unfavorable steric hindrance of the sugar moiety of L-2'F-C-d4A and the side chain of Val184 could explain the cross-resistance of L-2'F-C-d4A with the M184V mutant. The significant difference of antiviral activity between carbovir and its analogue L-2'F-C-d4G 25 may be due to distortion of the phenyl ring of Tyr115 in the L-2'F-C-d4G-TP/HIV-RT complex, which resulted in a poor pi-pi interaction.