Synthesis and anti-HIV activity of cosalane analogues incorporating nitrogen in the linker chain.
Synthesis and anti-HIV activity of cosalane analogues incorporating nitrogen in the linker chain.
复制标题
在连接链中掺入氮的 cosalane 类似物的合成和抗 HIV 活性。
DOI：
10.1016/s0968-0896(99)00269-2
复制
发表时间：
2000
影响因子：
3.5
通讯作者：
Cushman,M
中科院分区：
文献类型：
--
作者：
Casimiro-Garcia,A;DeClercq,E;Pannecouque,C;Witvrouw,M;Stup,TL;Turpin,JA;BuckheitJr,RW;Cushman,M
将酰胺基或氨基部分引入 cosalane (1) 的烯基连接链中，得到了一系列新的类似物 3-8。这些新化合物被评估为细胞培养物中 HIV-1 和 HIV-2 细胞病变效应的抑制剂。 1 的连接链中的 1' 和 2' 碳被酰胺基取代通常是可以容忍的。连接链的长度和甾环C-3取代基的立体化学对抗病毒活性和效力有显着影响。将氨基部分掺入接头中完全消除了抗 HIV 活性。 HIV复制周期中有几个步骤已被提议作为治疗剂开发的目标（De Clercq, E. J. Med. Chem.1995, 38, 2491；De Clercq, E. Pure Appl. Chem.1998, 70, 567）。然而，目前批准的抗HIV药物仅针对病毒酶逆转录酶或蛋白酶（Carpenter, C. C. J.; Fischl, M. A.; Hammer, S. M.; Hirsch, M. S.; Jacobsen, D. M.; Katzenstein, D. A.; Montaner, J. S. G.; Richman, D. D.; Saag, M. S.; Schooley, R. T.; Thompson, M. A.；Vella，S.；Yeni，P.G.；Volberding，P.A.JAMA1998，280，78）。能够干扰病毒生命周期其他步骤的药物在艾滋病的抗逆转录病毒治疗中将非常有价值，因为它们将具有与目前临床使用的药物不同的耐药突变模式。此外，它们与其他治疗剂结合使用可以提供更有效的药物“鸡尾酒”，能够完全抑制病毒复制。因此，迫切需要发现具有新颖作用机制的临床上有用的抗HIV药物。
Introduction of an amido group or an amino moiety into the alkenyl linker chain of cosalane (1) provided a new series of analogues 3–8. The new compounds were evaluated as inhibitors of the cytopathic effect of HIV-1 and HIV-2 in cell culture. The replacement of the 1′ and 2′ carbons in the linker chain of 1 by an amido group was generally tolerated. The length of the linker chain and the stereochemistry of the substituent at C-3 of the steroidal ring had significant effects on the antiviral activity and potency. Incorporation of an amino moiety into the linker completely abolished the anti-HIV activity. There are several steps in the HIV replication cycle that have been proposed as targets for the development of therapeutic agents (De Clercq, E. J. Med. Chem.1995, 38, 2491; De Clercq, E. Pure Appl. Chem.1998, 70, 567). However, currently approved anti-HIV drugs are only directed against the viral enzymes reverse transcriptase or protease (Carpenter, C. C. J.; Fischl, M. A.; Hammer, S. M.; Hirsch, M. S.; Jacobsen, D. M.; Katzenstein, D. A.; Montaner, J. S. G.; Richman, D. D.; Saag, M. S.; Schooley, R. T.; Thompson, M. A.; Vella, S.; Yeni, P. G.; Volberding, P. A. JAMA1998, 280, 78). Drugs capable of interfering with other steps of the virus life cycle will be highly valuable in the antiretroviral therapy of AIDS, as they will have different patterns of resistance mutations than the drugs currently used clinically. In addition, their utilization in combination with other therapeutic agents could provide more potent drug ‘cocktails’ capable of completely suppressing virus replication. Consequently, there is an urgent need for the discovery of clinically useful anti-HIV agents possessing novel mechanisms of action.