抗艾滋病药物 82：新型抗 HIV 药物（S）-樟酰基-(+)-顺式金莲花内酯（DCK）衍生物的全合成。
Anti-AIDS agents 82: synthesis of seco-(3'R,4'R)-3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) derivatives as novel anti-HIV agents.
机构信息
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
出版信息
Bioorg Med Chem. 2010 Jun 15;18(12):4363-73. doi: 10.1016/j.bmc.2010.04.089. Epub 2010 Apr 29.
Abstract
Thirteen novel seco-DCK analogs (4-16) with several new skeletons were designed, synthesized and screened for in vitro anti-HIV-1 activity. Among them, three compounds (5, 13, and 16) showed moderate activity, and compound 9 exhibited the best activity with an EC(50) value of 0.058 microM and a therapeutic index (TI) of 1000. The activity of 9 was better than that of 4-methyl DCK (2, EC(50): 0.126 microM, TI: 301.2) in the same assay. Additionally, 9 also showed antiviral activity against a multi-RT inhibitor-resistant strain (RTMDR), which is insensitive to most DCK analogs. Compared with 2, compound 9 has a less complex structure, fewer hydrogen-bond acceptors, and a reduced log P value. Therefore, it is likely to exhibit better ADME, and appears to be a promising new lead for further development as an anti-HIV candidate.
摘要
设计、合成并筛选了 13 种新型的具有多个新骨架的 secodidehydrocytidine (DCK) 类似物（4-16），用于体外抗 HIV-1 活性的筛选。其中，有 3 种化合物（5、13 和 16）表现出中等活性，而化合物 9 表现出最佳的活性，EC50 值为 0.058 μM，治疗指数（TI）为 1000。在相同的测定中，化合物 9 的活性优于 4-甲基 DCK（2，EC50：0.126 μM，TI：301.2）。此外，化合物 9 对多 RT 抑制剂耐药株（RTMDR）也表现出抗病毒活性，而大多数 DCK 类似物对其不敏感。与 2 相比，化合物 9 的结构更简单，氢键供体更少，log P 值降低。因此，它可能具有更好的 ADME，有望成为进一步开发抗 HIV 候选药物的有前途的新先导化合物。
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