Butitaxel analogues: Synthesis and structure-activity relationships
Butitaxel analogues: Synthesis and structure-activity relationships
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DOI：
10.1021/jm960505t
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发表时间：
1997-01-17
影响因子：
7.3
通讯作者：
Jayasinghe, LR
中科院分区：
文献类型：
--
作者：
Ali, SM;Hoemann, MZ;Jayasinghe, LR
丁紫杉醇(3)的N-酰基类似物8、9和12-26是以胺5和6为原料，通过肖顿-鲍曼酰化反应一步或两步合成的。合成了17个新的类似物，包括脂肪族氨基甲酸酯、脂环酰胺和杂芳酰胺。评估了它们在体外刺激微管形成的能力，它们对B16黑色素瘤细胞的细胞毒性，以及它们在水中的溶解性。在本研究中发现的最有效的类似物是N-去苯甲酰基-N-(2-噻吩酰基)丁紫杉醇(20)，它具有比紫杉醇更好的微管蛋白组装特性和对B16黑色素瘤细胞的细胞毒活性约2倍。化合物20的水溶性约为紫杉醇的25倍。
N-Acyl analogues 8, 9, and 12-26 of butitaxel (3) were prepared in one or two steps from amines 5 and 6 through Schotten-Baumann acylation. Seventeen novel analogues, consisting of aliphatic carbamates, alicyclic amides, and heteroaromatic amides, were synthesized. They were evaluated for their in vitro ability to stimulate the formation of microtubules, their cytotoxicity toward B16 melanoma cells, and their solubility in water. The most potent analogue found in this study was N-debenzoyl-N-(2-thenoyl)butitaxel (20), possessing ca. 2-fold better tubulin assembly properties and cytotoxic activity against B16 melanoma cells than paclitaxel. Compound 20 was ca. 25 times more water soluble than paclitaxel.