12-(2'-deoxythymidin-N3-yl)-nevirapine | 1449678-53-8

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 英文名称: 12-(2'-deoxythymidin-N3-yl)-nevirapine
• CAS: 1449678-53-8
• 化学式: C₂₅H₂₆N₆O₆
• 分子量: 506.518
• InChiKey: IYGQCZINZFFLJC-IPMKNSEASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.66
• 重原子数：
  37.0
• 可旋转键数：
  5.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  151.81
• 氢给体数：
  3.0
• 氢受体数：
  11.0

反应信息

• 作为产物：
  描述：

  11-环丙基-5,11-二氢-4-(羟基甲基)-6H-二吡啶并[3,2-b:2',3'-e][1,4]二氮杂卓-6-酮 在 吡啶 、 乙二胺四乙酸 作用下， 反应 364.0h， 生成 12-(2'-deoxythymidin-N3-yl)-nevirapine
  参考文献：
  名称：

  Effects of human sulfotransferases on the cytotoxicity of 12-hydroxynevirapine

  摘要：

  Nevirapine, a non-nucleoside reverse transcriptase inhibitor used for the treatment of AIDS, can cause serious skin rashes and hepatotoxicity. Previous studies have indicated that the benzylic sulfate 12-sulfoxynevirapine, the formation of which is catalyzed by human sulfotransferases (SULTs), may play a causative role in these toxicities. To characterize better the role of 12-sulfoxynevirapine in nevirapine-induced cytotoxicity, the ability of 12 expressed human SULT isoforms to conjugate 12-hydroxynevirapine was assessed. Of the 12 human SULTs, no detectable 12-sulfoxynevirapine was observed with SULT1A3, SULT1C2, SULT1C3, SULT2B1, SULT4A1, or SULT6B1. As determined by the V-max/K-m ratio, SULT2A1 had the highest overall 12-hydoxynevirapine sulfonation activity; lower activities were observed with SULT1A1, SULT1A2, SULT1B1, SULT1C4, and SULT1E1. Incubation of 12-sulfoxynevirapine with glutathione and cysteine led to adduct formation; lower yields were obtained with deoxynucleosides. 12-Hydroxynevirapine was more cytotoxic than nevirapine to TK6, TK6/SULT vector, and TK6/SULT2A1 cells. With nevirapine, there was no difference in cytotoxicity among the three cell lines, whereas with 12-hydroxynevirapine, TK6/SULT2A1 cells were more resistant than TK6 and TK6/SULT vector cells. Co-incubation of 12-hydroxynevirapine with the competitive SULT2A1 substrate dehydroepiandrosterone decreased the level of 12-sulfoxynevirapine and increased the cytotoxicity in TK6/SULT2A1 cells. These data demonstrate that although 12-sulfoxynevirapine reacts with nucleophiles to form adducts, sulfonation of 12-hydroxynevirapine decreases the cytotoxicity of 12-hydroxynevirapine in TK6 cells.

  DOI：

  10.1016/j.bcp.2018.07.016

文献信息

• 2'-Deoxythymidine Adducts from the Anti-HIV Drug Nevirapine
  作者：Alexandra Antunes、Benjamin Wolf、M. Oliveira、Frederick Beland、M. Marques

  DOI：10.3390/molecules18054955

  日期：——

  Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used against HIV-1. Currently, NVP is the most widely used anti-HIV drug in developing countries, both in combination therapy and to prevent mother-to-child transmission of HIV. Despite its efficacy against HIV, NVP produces a variety of toxic responses, including hepatotoxicity and skin rash. It is also associated with increased incidences of hepatoneoplasias in rodents. In addition, epidemiological data suggest that NNRTI use is a risk factor for non-AIDS-defining cancers in HIV-positive patients. Current evidence supports the involvement of metabolic activation to reactive electrophiles in NVP toxicity. NVP metabolism includes oxidation to 12-hydroxy-NVP; subsequent Phase II sulfonation produces an electrophilic metabolite, 12-sulfoxy-NVP, capable of reacting with DNA to yield covalent adducts. Since 2’-deoxythymidine (dT) adducts from several alkylating agents are regarded as having significant mutagenic/carcinogenic potential, we investigated the formation of NVP-dT adducts under biomimetic conditions. Toward this goal, we initially prepared and characterized synthetic NVP-dT adduct standards using a palladium-mediated Buchwald-Hartwig coupling strategy. The synthetic standards enabled the identification, by LC-ESI-MS, of 12-(2'-deoxythymidin-N3-yl)-nevirapine (N3-NVP-dT) in the enzymatic hydrolysate of salmon testis DNA reacted with 12-mesyloxy-NVP, a synthetic surrogate for 12-sulfoxy-NVP. N3-NVP-dT, a potentially cytotoxic and mutagenic DNA lesion, was also the only dT-specific adduct detected upon reaction of dT with 12-mesyloxy-NVP. Our data suggest that N3-NVP-dT may be formed in vivo and play a role in the hepatotoxicity and/or putative hepatocarcinogenicity of NVP.

  奈韦拉平 (NVP) 是一种用于对抗 HIV-1 的非核苷逆转录酶抑制剂 (NNRTI)。目前，NVP是发展中国家使用最广泛的抗艾滋病毒药物，用于联合治疗和预防艾滋病毒母婴传播。尽管 NVP 具有对抗 HIV 的功效，但它会产生多种毒性反应，包括肝毒性和皮疹。它还与啮齿动物肝肿瘤发病率增加有关。此外，流行病学数据表明，NNRTI 的使用是 HIV 阳性患者患非艾滋病定义癌症的危险因素。目前的证据支持反应性亲电子试剂的代谢激活与 NVP 毒性有关。 NVP代谢包括氧化为12-羟基-NVP；随后的第二阶段磺化产生亲电子代谢物 12-磺氧基-NVP，能够与 DNA 反应产生共价加合物。由于几种烷化剂的 2'-脱氧胸苷 (dT) 加合物被认为具有显着的致突变/致癌潜力，因此我们研究了仿生条件下 NVP-dT 加合物的形成。为了实现这一目标，我们最初使用钯介导的 Buchwald-Hartwig 偶联策略制备并表征了合成 NVP-dT 加合物标准品。合成标准品能够通过 LC-ESI-MS 鉴定与 12-甲磺酰氧基-反应的鲑鱼睾丸 DNA 的酶解产物中的 12-(2'-脱氧胸苷-N3-基)-奈韦拉平 (N3-NVP-dT)。 NVP，12-磺氧基-NVP 的合成替代品。 N3-NVP-dT 是一种潜在的细胞毒性和诱变 DNA 损伤，也是 dT 与 12-甲磺氧基-NVP 反应时检测到的唯一 dT 特异性加合物。我们的数据表明，N3-NVP-dT 可能在体内形成，并在 NVP 的肝毒性和/或假定的肝癌致癌性中发挥作用。