抗艾滋病药物 86. 2',3'-seco-3'-nor DCP 和 DCK 类似物的合成及抗 HIV 活性评价。
Anti-AIDS agents 86. Synthesis and anti-HIV evaluation of 2',3'-seco-3'-nor DCP and DCK analogues.
机构信息
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
出版信息
Eur J Med Chem. 2011 Oct;46(10):4924-36. doi: 10.1016/j.ejmech.2011.07.051. Epub 2011 Aug 4.
In a continuing study of novel anti-HIV agents with drug-like structures and properties, 30 1'-O-, 1'-S-, 4'-O- and 4'-substituted-2',3'-seco-3'-nor DCP and DCK analogues (8-37) were designed and synthesized. All newly synthesized seco-compounds were screened against HIV-1(NL4-3) and a multiple reverse transcriptase (RT) inhibitor-resistant (RTMDR) strain in the TZM-bl cell line, using seco-DCK (7) and 2-ethyl-DCP (4) as controls. Several compounds (14, 18, 19, 22-24, and 32) exhibited potent anti-HIV activity with EC(50) values ranging from 0.93 to 1.93 μM and therapeutic index (TI) values ranging from 20 to 39. 1'-O-Isopropoxy-2',3'-seco-3'-nor-DCP (12) showed the greatest potency among the newly synthesized compounds with EC(50) values of 0.47 and 0.88 μM, and TI of 96 and 51, respectively, against HIV-1(NL4-3) and RTMDR strains. The seco-compounds exhibited better chemical stability in acidic conditions compared with DCP and DCK compounds. Overall, the results suggested that seco-DCP analogues with simplified structures may be more favorable for development as novel anti-HIV candidates.
在一项针对具有类似药物结构和性质的新型抗 HIV 药物的持续研究中，设计并合成了 30 个 1'-O-、1'-S-、4'-O-和 4'-取代的 2'，3'-seco-3'-nor DCP 和 DCK 类似物（8-37）。所有新合成的 secocompounds 都在 TZM-bl 细胞系中针对 HIV-1（NL4-3）和多重逆转录酶（RT）抑制剂耐药（RTMDR）株进行了筛选，以 sec-DCK（7）和 2-乙基-DCP（4）作为对照。几种化合物（14、18、19、22-24 和 32）表现出很强的抗 HIV 活性，EC（50）值范围为 0.93 至 1.93 μM，治疗指数（TI）值范围为 20 至 39。在新合成的化合物中，1'-O-异丙氧基-2'，3'-seco-3'-nor-DCP（12）表现出最强的活性，对 HIV-1（NL4-3）和 RTMDR 株的 EC（50）值分别为 0.47 和 0.88 μM，TI 分别为 96 和 51。与 DCP 和 DCK 化合物相比，secocompounds 在酸性条件下表现出更好的化学稳定性。总的来说，结果表明，结构简化的 sec-DCP 类似物可能更适合开发为新型抗 HIV 候选药物。
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