Ring substituent effects on biological activity of vinyl sulfones as inhibitors of HIV-1
Ring substituent effects on biological activity of vinyl sulfones as inhibitors of HIV-1
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DOI：
10.1016/j.bmc.2006.10.017
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发表时间：
2007-01-15
影响因子：
3.5
通讯作者：
Gervay-Hague, Jacquelyn
中科院分区：
文献类型：
--
作者：
Meadows, D. Christopher;Sanchez, Tino;Gervay-Hague, Jacquelyn
在以前的研究中，我们制备了一个小的菊苣酸类似物库，具有有效的抗整合酶和抗病毒活性。研究还表明，活性化合物分为两组：抑制病毒复制早期阶段的化合物和抑制病毒复制后期阶段的化合物。在这项研究中，一系列的乙烯基偕二砜含有具有一系列的环取代基的化合物已被合成，以探讨结构上的抑制机制的影响。使用艾滋病毒药物敏感性试验鉴定了四种活性化合物。三个抑制剂具有要么没有取代基或吸电子取代基的芳环导致高水平的细胞毒性和抗病毒活性。电子效应对活性的潜在影响引起了我们的兴趣，我们探讨了活性化合物是否可以通过1，4-加成进行非特异性反应。为了研究这一假设，将化合物与谷胱甘肽一起孵育，并在LUMS分析后，鉴定了对应于单加成加合物和双加成加合物的分子离子峰。其次，我们合成了缺乏参与1，4-加成能力的类似物，并测试了它们的抗病毒活性和细胞毒性，发现化合物对这两种活性都无活性。总之，本文报道的研究表明，在芳环上缺乏给电子取代基的化合物是生物亲核试剂的混杂受体，而具有给电子取代基的化合物似乎抵抗加成或至少更具选择性且毒性显著降低。(c)2006爱思唯尔有限公司保留所有权利。
In a previous study, we prepared a small library of chicoric acid analogs that possessed both potent anti-integrase and antiviral activity. It was also shown that active compounds fell into one of two groups: those that inhibited an early stage in viral replication and those that inhibited at a later stage. In this study, a series of vinyl geminal disulfone-containing compounds possessing a range of ring substituents has been synthesized to probe the impact of structure on inhibitory mechanisms. Four active compounds were identified using HIV drug susceptibility assays. Three of the inhibitors possessing either no substituents or electron-withdrawing substituents on the aromatic rings led to high levels of cytotoxicity and antiviral activity. Intrigued by the potential implications of electronic effects on activity, we probed whether the active compounds could be nonspecifically reacting via 1,4-addition. To investigate this hypothesis, the compounds were incubated with glutathione and upon LUMS analysis, molecular ion peaks corresponding to both mono and double addition adducts were identified. Second, we synthesized analogs lacking the ability to participate in 1,4-addition and tested them for antiviral activity and cytotoxicity, and found the compounds inactive for both activities. Taken together, the studies reported herein suggest that compounds lacking electron-donating substituents on the aromatic ring are promiscuous acceptors of biological nucleophiles, whereas compounds possessing electron-donating substituents seem to resist addition or at least be more selective and significantly less toxic. (c) 2006 Elsevier Ltd. All rights reserved.