Chemical library and structure-activity relationships of 11-demethyl-12-oxo calanolide A analogues as anti-HIV-1 agents
Chemical library and structure-activity relationships of 11-demethyl-12-oxo calanolide A analogues as anti-HIV-1 agents
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DOI：
10.1021/jm701405p
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发表时间：
2008-03-13
影响因子：
7.3
通讯作者：
Liu, Gang
中科院分区：
文献类型：
--
作者：
Ma, Tao;Liu, Li;Liu, Gang
（+）-Calanoprotein A（1）是一种天然产物，以前被发现是HIV-1逆转录酶的抑制剂。在我们对其模板的进一步研究中，外消旋的11-去甲基-12-氧代calanetrazine A（15）在C-11和C-12位置上比（+）-calanetrazine A少两个手性碳中心，在体外对HIV-1具有更好的抗HIV-1活性和治疗指数（EC（50）= 0.11 μ M，TI = 818）。然后根据其结构核心设计并合成了一个库，并引入了9个差异点。体外抗HIV-1活性评价结果表明，它们具有良好的构效关系。一种新的化合物（10-溴甲基-11-去甲基-12-氧代calanetrin A，123）被鉴定为具有比该类化合物高得多的抗HIV-1的抑制效力和治疗指数（EC（50）= 2.85 nM，TI > 10，526）。这一发现提供了一个非常重要的线索，即可以进行C-10位C环的修饰，以获得对HIV-1具有更好活性的候选药物。
(+)-Calanolide A (1) as a natural product was previously found as an inhibitor of HIV-1 reverse tratiscriptase. In our further investigation of its template, racemic 11-demethyl-12-oxo calanolide A (15), which had two fewer chiral carbon centers at the C-11 and C-12 positions than (+)-calanolide A, had a comparably inhibitory activity and better therapeutic index (EC(50) = 0.11 mu M, TI = 818) against HIV-1 in vitro. A library based on its structural core was then designed and synthesized with introduction of nine diversity points in this article. The evaluations of anti-HIV-1 activity in vitro concluded their structure-activity relationships (SARs). A novel compound (10-bromomethyl-11-demethyl-12-oxo calanolide A, 123) was identified to have much higher inhibitory potency and therapeutic index (EC(50) = 2.85 nM, TI > 10,526) than those of the class compound against HIV-1. This finding provided a very important clue that modifications of the C ring at the C-10 position may be conducted to obtain drug candidates with better activity against HIV-1.