School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, United Kingdom.
Rega Institute for Medical Research - Laboratory of Virology and Chemotherapy, K.U. Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Bioorg Med Chem Lett. 2019 Dec 15;29(24):126721. doi: 10.1016/j.bmcl.2019.126721. Epub 2019 Oct 23.
Human Immunodeficiency Virus (HIV) damages the immune system and leads to the life-threatening acquired immunodeficiency syndrome (AIDS). Despite the advances in the field of antiretroviral treatment, HIV remains a major public health challenge. Nucleosides represent a prominent chemotherapeutic class for treating viruses, however their cellular uptake, kinase-mediated activation and catabolism are limiting factors. Herein, we report the synthesis and in vitro evaluation of stavudine (d4T) ProTides containing polyfluorinated aryl groups against two strains; HIV-1 (IIIB) and HIV-2 (ROD). ProTide 5d containing a meta-substituted pentafluorosulfanyl (3-SF) aryl group showed superior antiviral activity over the parent d4T and the nonfluorinated analogue 5a. ProTide 5d has low nanomolar antiviral activity; (IC = 30 nM, HIV-1) and (IC = 36 nM, HIV-2) which is over tenfold more potent than d4T. Interestingly, ProTide 5d showed a significantly high selectivity indices with SI = 1753 (HIV-1) and 1461 (HIV-2) which is more than twice that of the d4T. All ProTides were screened in wild type as well as thymidine kinase deficient (TK) cells. Enzymatic activation of ProTide 5d using carboxypeptidase Y enzyme and monitored using both P and F NMR is presented.
人类免疫缺陷病毒 (HIV) 会损害免疫系统，导致危及生命的获得性免疫缺陷综合征 (AIDS)。尽管在抗逆转录病毒治疗领域取得了进展，但 HIV 仍然是一个主要的公共卫生挑战。核苷类似物是治疗病毒的主要化疗药物类别之一，但它们的细胞摄取、激酶介导的激活和分解代谢是限制因素。在此，我们报告了含有多氟芳基的司他夫定 (d4T)ProTide 的合成和体外评估，针对两种株系；HIV-1 (IIIb) 和 HIV-2 (ROD)。含有间位取代的五氟磺酰基 (3-SF) 芳基的 ProTide 5d 对母体 d4T 和非氟化类似物 5a 表现出优越的抗病毒活性。ProTide 5d 具有低纳摩尔抗病毒活性；(IC = 30 nM，HIV-1) 和 (IC = 36 nM，HIV-2)，比 d4T 强十倍以上。有趣的是，ProTide 5d 表现出显著高的选择性指数，SI = 1753 (HIV-1) 和 1461 (HIV-2)，比 d4T 高两倍以上。所有 ProTides 均在野生型和胸苷激酶缺陷 (TK) 细胞中进行筛选。使用羧肽酶 Y 酶进行 ProTide 5d 的酶促激活，并使用 P 和 F NMR 进行监测。
