Stuyver Lieven J, Lostia Stefania, Adams Marjorie, Mathew Judy S, Pai Balakrishna S, Grier Jason, Tharnish Phillip M, Choi Yongseok, Chong Youhoon, Choo Hyunah, Chu Chung K, Otto Michael J, Schinazi Raymond F
Veterans Affairs Medical Center and Department of Pediatrics, Emory University School of Medicine, Decatur, Georgia 30033, USA.
Antimicrob Agents Chemother. 2002 Dec;46(12):3854-60. doi: 10.1128/AAC.46.12.3854-3860.2002.
The antiviral efficacies and cytotoxicities of 2',3'- and 4'-substituted 2',3'-didehydro-2',3'-dideoxycytidine analogs were evaluated. All compounds were tested (i) against a wild-type human immunodeficiency virus type 1 (HIV-1) isolate (strain xxBRU) and lamivudine-resistant HIV-1 isolates, (ii) for their abilities to inhibit hepatitis B virus (HBV) production in the inducible HepAD38 cell line, and (iii) for their abilities to inhibit bovine viral diarrhea virus (BVDV) production in acutely infected Madin-Darby bovine kidney cells. Some compounds demonstrated potent antiviral activities against the wild-type HIV-1 strain (range of 90% effective concentrations [EC(90)s], 0.14 to 5.2 micro M), but marked increases in EC(90)s were noted when the compounds were tested against the lamivudine-resistant HIV-1 strain (range of EC(90)s, 53 to >100 micro M). The beta-L-enantiomers of both classes of compounds were more potent than the corresponding beta-D-enantiomers. None of the compounds showed antiviral activity in the assay that determined their abilities to inhibit BVDV, while two compounds inhibited HBV production in HepAD38 cells (EC(90), 0.25 micro M). The compounds were essentially noncytotoxic in human peripheral blood mononuclear cells and HepG2 cells. No effect on mitochondrial DNA levels was observed after a 7-day incubation with the nucleoside analogs at 10 micro M. These studies demonstrate that (i) modification of the sugar ring of cytosine nucleoside analogs with a 4'-thia instead of an oxygen results in compounds with the ability to potently inhibit wild-type HIV-1 but with reduced potency against lamivudine-resistant virus and (ii) the antiviral activity of beta-D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine against wild-type HIV-1 (EC(90), 0.08 micro M) and lamivudine-resistant HIV-1 (EC(90) = 0.15 micro M) is markedly reduced by introduction of a 3'-fluorine in the sugar (EC(90)s of compound 2a, 37.5 and 494 micro M, respectively).
评估了2'，3'-和4'-取代的2'，3'-二脱氢-2'，3'-二脱氧胞苷类似物的抗病毒效力和细胞毒性。所有化合物都进行了以下测试：（i）针对野生型人类免疫缺陷病毒1型（HIV-1）分离株（xxBRU株）和对拉米夫定耐药的HIV-1分离株；（ii）测试它们在可诱导的HepAD38细胞系中抑制乙型肝炎病毒（HBV）产生的能力；（iii）测试它们在急性感染的Madin-Darby牛肾细胞中抑制牛病毒性腹泻病毒（BVDV）产生的能力。一些化合物对野生型HIV-1株表现出强效抗病毒活性（90%有效浓度[EC(90)s]范围为0.14至5.2微摩尔），但当测试这些化合物对拉米夫定耐药的HIV-1株时，EC(90)s显著增加（EC(90)s范围为53至>100微摩尔）。两类化合物的β-L-对映体比相应的β-D-对映体更具活性。在测定其抑制BVDV能力的试验中，没有一种化合物显示出抗病毒活性，而有两种化合物在HepAD38细胞中抑制了HBV的产生（EC(90)为0.25微摩尔）。这些化合物在人外周血单核细胞和HepG2细胞中基本无细胞毒性。在10微摩尔的核苷类似物中孵育7天后，未观察到对线粒体DNA水平的影响。这些研究表明：（i）用4'-硫取代而不是氧修饰胞嘧啶核苷类似物的糖环会产生能够有效抑制野生型HIV-1但对拉米夫定耐药病毒效力降低的化合物；（ii）通过在糖中引入3'-氟，β-D-2'，3'-二脱氢-2'，3'-二脱氧-5-氟胞苷对野生型HIV-1（EC(90)为0.08微摩尔）和拉米夫定耐药的HIV-1（EC(90)=0.15微摩尔）的抗病毒活性显著降低（化合物2a的EC(90)s分别为37.5和494微摩尔）。
