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引用次数: 0
摘要
一种 12-酮型齐墩果酸衍生物(4)已被确认为一种强效的抗人类免疫缺陷病毒 1 型(HIV-1)化合物,可与多种类型的 HIV-1 中和抗体产生协同效应。在本研究中,我们利用一种常见的关键合成中间体,以 12-酮型齐墩果酸衍生物的化学结构为基础,对一种抗 HIV 化合物进行了后期衍生化。为了实施这一策略,我们设计了一种二酮型齐墩果酸衍生物(5)进行化学选择性转化,以他汀单元上的羧基和羟基以及齐墩果酸单元上的 3-羰基作为正交合成手柄。我们进行了四种化学选择性转化,最终确定吲哚型衍生物 (16) 为新型强效抗 HIV 化合物。此外,我们还进一步优化了他汀单元上的β-羟基,得到了 R-4-异丁基γ-氨基酸型衍生物 (6),该衍生物具有与 4 相似的强效抗 HIV 活性,但细胞毒性较低。
Late-Stage Derivatization of Oleanolic Acid-Based Anti-HIV-1 Compounds.
A 12-keto-type oleanolic acid derivative (4) has been identified as a potent anti-human immunodeficiency virus type-1 (HIV-1) compound that demonstrates synergistic effects with several types of HIV-1 neutralizing antibodies. In the present study, we used a common key synthetic intermediate to carry out the late-stage derivatization of an anti-HIV compound based on the chemical structure of a 12-keto-type oleanolic acid derivative. To execute this strategy, we designed a diketo-type oleanolic acid derivative (5) for chemoselective transformation, targeting the carboxy group and the hydroxyl group on the statine unit, as well as the 3-carbonyl group on the oleanolic acid unit, as orthogonal synthetic handles. We carried out four types of chemoselective transformations, leading to identification of the indole-type derivative (16) as a novel potent anti-HIV compound. In addition, further optimization of the β-hydroxyl group on the statine unit provided the R-4-isobutyl γ-amino acid-type derivative (6), which exhibited potent anti-HIV activity comparable to that of 4 but with reduced cytotoxicity.
期刊介绍:
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