Cushman M, Golebiewski W M, Graham L, Turpin J A, Rice W G, Fliakas-Boltz V, Buckheit R W
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
J Med Chem. 1996 Aug 2;39(16):3217-27. doi: 10.1021/jm960082v.
Several novel alkenyldiarylmethane (ADAM) non-nucleoside HIV-1 reverse transcriptase inhibitors were synthesized. The most potent of these proved to be 3',3"-dibromo-4',4"-dimethoxy-5'5"-bis(methoxycarbonyl)-1,1-diphenyl-1-+ ++heptene (8) ADAM 8 inhibited the cytopathic effect of HIV-1 in CEM cell culture with an EC50 value of 7.1 microM and was active against an array of laboratory strains of HIV-1 in CEM-SS and MT-4 cells, but was inactive as an inhibitor of HIV-2. In common with the other known non-nucleoside reverse transcriptase inhibitors, ADAM 8 was an effective inhibitor of HIV-1 reverse transcriptase (IC50 1 microM) with poly(rC).oligo(dG), but not with poly(rA).oligo(dT), as the template/primer. ADAM 8 was inactive against HIV-1 reverse transcriptases containing non-nucleoside reverse transcriptase inhibitor resistance mutations at residues 101, 106, 108, 139, 181, 188, and 236, while it remained active against enzymes with mutations at residues 74, 98, 100, 103, and at 103/181. An AZT-resistant virus having four mutations in reverse transcriptase was more sensitive to inhibition by ADAM 8 than the wild-type HIV-1. In addition, ADAM 8 displayed synergistic activity with AZT, but lacked synergy with ddI. ADAM 8 or a structurally related analog may therefore be useful as an antiviral agent in combination with AZT or with other NNRTIs that are made ineffective by mutations at residues which do not confer resistance to ADAM 8.
合成了几种新型的烯基二芳基甲烷（ADAM）非核苷类HIV-1逆转录酶抑制剂。其中最有效的是3'，3"-二溴-4'，4"-二甲氧基-5'5"-双（甲氧基羰基）-1，1-二苯基-1-庚烯（8）。ADAM 8在CEM细胞培养中抑制HIV-1的细胞病变效应，EC50值为7.1微摩尔，并且在CEM-SS和MT-4细胞中对一系列HIV-1实验室菌株具有活性，但作为HIV-2的抑制剂无活性。与其他已知的非核苷类逆转录酶抑制剂一样，ADAM 8是以聚（rC）·寡聚（dG）为模板/引物时HIV-1逆转录酶的有效抑制剂（IC50为1微摩尔），但以聚（rA）·寡聚（dT）为模板/引物时则不是。ADAM 8对在第101、106、108、139、181、188和236位残基处含有非核苷类逆转录酶抑制剂抗性突变的HIV-1逆转录酶无活性，而对在第74、98、100、103位以及103/181位残基处有突变的酶仍有活性。一种在逆转录酶中有四个突变的AZT抗性病毒比野生型HIV-1对ADAM 8的抑制更敏感。此外，ADAM 8与AZT显示出协同活性，但与ddI没有协同作用。因此，ADAM 8或与其结构相关的类似物可作为抗病毒剂与AZT或与其他因在不赋予对ADAM 8抗性的残基处发生突变而失效的非核苷类逆转录酶抑制剂联合使用。
