HIV INHIBITORY NATURAL-PRODUCTS .7. THE CALANOLIDES, A NOVEL HIV-INHIBITORY CLASS OF COUMARIN DERIVATIVES FROM THE TROPICAL RAIN-FOREST TREE, CALOPHYLLUM-LANIGERUM
HIV INHIBITORY NATURAL-PRODUCTS .7. THE CALANOLIDES, A NOVEL HIV-INHIBITORY CLASS OF COUMARIN DERIVATIVES FROM THE TROPICAL RAIN-FOREST TREE, CALOPHYLLUM-LANIGERUM
复制标题
DOI：
10.1021/jm00093a004
复制
发表时间：
1992-07-24
影响因子：
7.3
通讯作者：
BOYD, MR
中科院分区：
文献类型：
--
作者：
KASHMAN, Y;GUSTAFSON, KR;BOYD, MR
采用抗HIV生物活性测定引导的方法，分离得到8个新的香豆素类化合物(1-8)。通过广泛的波谱分析，特别是HMQC、HMBC和差示NOE核磁共振实验，确定了Calanolide A(1)、12-乙酰氧基Calanolide A(2)、12-甲氧基Calanolide A(3)、Calanolide B(4)、12-甲氧基Calanolide B(5)、Calanolide C(6)及其相关衍生物7和8的结构。用改进的Mosher方法建立了Calanolide A(1)和Calanolide B(4)的绝对立体化学模型。灯笼内酯A(1)和B(4)对HIV-1复制和细胞病变有完全保护作用(EC50值分别为0.1mU-M和0.4mU-M)，但对HIV-2无效。一些相关化合物也显示出抗HIV-1活性的证据。对纯化的细菌重组逆转录酶(RT)的研究表明，Calanoldes是HIV-1特异性RT抑制剂。此外，灯盏花内酯A不仅对耐AZT的HIV-1 G-9106株有抑制作用，而且对吡啶酮耐药的A17株也有抑制作用。这一点特别令人感兴趣，因为A17病毒对先前已知的HIV-1特异性非核苷类逆转录酶抑制剂(如TIBO；BI-RG-587；L693,593)具有高度耐药性，这些药物构成了一种结构多样但显然常见的药理学类别。灯盏花内酯在很大程度上偏离了已知的类别，因此为药物开发提供了一种新的抗HIV化学类型。
Eight new coumarin compounds (1-8) were isolated by anti-HIV bioassay-guided fractionation of an extract of Calophyllum lanigerum. The structures of calanolide A (1), 12-acetoxycalanolide A (2), 12-methyoxycalanolide A (3), calanolide B (4), 12-methoxycalanolide B (5), calanolide C (6) and related derivatives 7 and 8 were solved by extensive spectroscopic analyses, particularly HMQC, HMBC, and difference NOE NMR experiments. The absolute stereochemistry of calanolide A (1) and calanolide B (4) was established by a modified Mosher's method. Calanolides A (1) and B (4) were completely protective against HIV-1 replication and cytopathicity (EC50 values of 0.1-mu-M and 0.4-mu-M, respectively), but were inactive against HIV-2. Some of the related compounds also showed evidence of anti-HIV-1 activity. Studies with purified bacterial recombinant reverse transcriptases (RT) revealed that the calanolides are HIV-1 specific RT inhibitors. Moreover, calanolide A was active not only against the AZT-resistant G-9106 strain of HIV-1 but also against the pyridinone-resistant A17 strain. This was of particular interest since the A17 virus is highly resistant to previously known HIV-1 specific, non-nucleoside RT inhibitors (e.g., TIBO; BI-RG-587; L693,593) which comprise a structurally diverse but apparently common pharmacologic class. The calanolides represent a substantial departure from the known class and therefore provide a novel new anti-HIV chemotype for drug development.