Chemical modification of oleanene type triterpenes and their inhibitory activity against HIV-1 protease dimerization.
Chemical modification of oleanene type triterpenes and their inhibitory activity against HIV-1 protease dimerization.
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DOI：
10.1248/cpb.48.1681
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发表时间：
2000-11
影响因子：
1.7
通讯作者：
Chao-Mei Ma;N. Nakamura;M. Hattori
中科院分区：
文献类型：
--
作者：
Chao-Mei Ma;N. Nakamura;M. Hattori
合成了具有不同长度的3- o酸性酰基链的齐墩果酸衍生物，并评价了它们对HIV-1蛋白酶的抑制活性。酸性链的长度优化为6和8个碳。改变3-酯键为酰胺键或三萜的二聚化保留了它们对HIV-1蛋白酶的抑制活性。在齐墩果酸的C-28上引入一个额外的酸性链，可以明显提高抑制活性，尽管在C-28上只有一个酸性链的衍生物也显示出对HIV-1蛋白酶的有效活性。通过尺寸排斥层析直接证实其抑制机制是抑制酶多肽的二聚化。三萜衍生物的酯键在温和的碱性条件下对脂肪酶是稳定的。
Oleanolic acid derivatives with different lengths of 3-O-acidic acyl chains were synthesized and evaluated for their inhibitory activity against HIV-1 protease. The lengths of the acidic chains were optimized to 6 and 8 carbons. Changing a 3-ester bond to an amide bond or dimerization of the triterpenes retained their inhibitory activity against HIV-1 protease. Introduction of an additional acidic chain to C-28 of oleanolic acid increased the inhibitory activity appreciably, though a derivative with only one acidic chain linked at C-28 also showed potent activity against HIV-1 protease. The inhibitory mechanism was proved directly by size exclusion chromatography to be inhibition of dimerization of the enzyme polypeptides. The ester bonds of the triterpene derivatives were found to be stable to lipase under mild alkaline conditions.