Structural analogues of the calanolide anti-HIV agents. Modification of the trans-10,11-dimethyldihydropyran-12-ol ring (ring C).
Structural analogues of the calanolide anti-HIV agents. Modification of the trans-10,11-dimethyldihydropyran-12-ol ring (ring C).
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DOI：
10.1021/jm960355m
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发表时间：
1997-03
影响因子：
7.3
通讯作者：
D. Zembower;Shuyuan Liao;M. Flavin;Ze-Qi Xu;T. L. Stup;R. Buckheit;A. Khilevich;and Aye Aye Mar-and-Aye-Aye-Mar-2236776301;A. K. Sheinkman
中科院分区：
文献类型：
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作者：
D. Zembower;Shuyuan Liao;M. Flavin;Ze-Qi Xu;T. L. Stup;R. Buckheit;A. Khilevich;and Aye Aye Mar-and-Aye-Aye-Mar-2236776301;A. K. Sheinkman
(+)-Calanolide A 是人类免疫缺陷病毒 1 型 (HIV-1) 逆转录酶的有效抑制剂，它是从 Calophyllum lanigerum 提取物以及七种相关化合物中分离出来的。为了检查反式10,11-二甲基二氢吡喃-12-醇环（称为环C）的结构-活性关系，制备了一系列结构类似物并使用全细胞细胞病变测定（XTT）进行评估。去除 10-甲基会导致活性降低，只有一种差向异构体表现出抗 HIV 活性。用乙基链取代 10-甲基基团仍保持抗 HIV 活性，但相对于外消旋卡拉内酯 A，效力仅降低 4 倍。用异丙基部分取代 10-甲基基团完全消除了抗 HIV 活性。在 10- 或 11- 位添加额外的甲基保持了母体 Calanolide 系统的基本立体化学特征，同时去除了各自碳上的手性，但导致相对于 Calanolide A 的活性降低。在所有上述实施例中，在 10- 和 11- 烷基部分之间含有顺式关系的类似物完全缺乏活性。 12-羟基处于酮氧化态的合成中间体表现出抑制抗 HIV 活性，10,11-cis (6) 和 -trans (5) 系列的 EC50 值仅比 Calanolide A 低 5 倍。这些酮代表了卡拉内酯系列中第一个具有抗 HIV 活性但不含 12-羟基的衍生物。同样，酮衍生物6是第一个在10-和11-甲基之间具有顺式关系的calanolide系列化合物，被发现具有抗HIV活性。在CEM-SS细胞保护试验中显示出抗HIV活性的类似物被进一步证实为HIV-1逆转录酶的抑制剂。
(+)-Calanolide A is a potent inhibitor of reverse transcriptase from human immunodeficiency virus type 1 (HIV-1), which was isolated from an extract of Calophyllum lanigerum, along with seven related compounds. In order to examine the structure-activity relationships of the trans-10,11-dimethyldihydropyran-12-ol ring (designated ring C), a series of structural analogues were prepared and evaluated using a whole cell cytopathicity assay (XTT). Removal of the 10-methyl group resulted in decreased activity, with only one epimer exhibiting anti-HIV activity. Substituting the 10-methyl group with an ethyl chain maintained anti-HIV activity, with only a 4-fold reduction in potency relative to racemic calanolide A. Substitution of the 10-methyl group with an isopropyl moiety completely eliminated the anti-HIV activity. Addition of an extra methyl group at either the 10- or 11-position maintained the basic stereochemical features of the parent calanolide system while removing the chirality at the respective carbon, but resulted in decreased activity relative to calanolide A. In all the above examples, analogues containing a cis relationship between the 10- and 11-alkyl moieties were completely devoid of activity. Synthetic intermediates in which the 12-hydroxyl group was in the ketone oxidation state exhibited suppressing anti-HIV activity, with EC50 values only 5-fold less potent than that of calanolide A for both the 10,11-cis (6) and -trans (5) series. These ketones represent the first derivatives in the calanolide series to exhibit anti-HIV activity while not containing a 12-hydroxyl group. Likewise, ketone derivative 6 was the first example of a compound in the calanolide series having a cis relationship between the 10- and 11-methyl groups found to exhibit anti-HIV activity. Analogues which showed anti-HIV activity in the CEM-SS cytoprotection assay were further confirmed to be inhibitors of HIV-1 reverse transcriptase.