Ali S M, Hoemann M Z, Aubé J, Georg G I, Mitscher L A, Jayasinghe L R
Department of Medicinal Chemistry, University of Kansas, Lawrence 66045, USA.
J Med Chem. 1997 Jan 17;40(2):236-41. doi: 10.1021/jm960505t.
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.
通过肖滕-鲍曼酰化反应，以胺5和6为原料，经过一步或两步反应制备了布替他赛（3）的N-酰基类似物8、9和12 - 26。合成了17种新型类似物，包括脂肪族氨基甲酸酯、脂环族酰胺和杂芳族酰胺。对它们刺激微管形成的体外能力、对B16黑色素瘤细胞的细胞毒性以及在水中的溶解度进行了评估。本研究中发现的最有效的类似物是N-去苯甲酰基-N-（2-噻吩甲酰基）布替他赛（20），其微管蛋白组装特性和对B16黑色素瘤细胞的细胞毒性比紫杉醇约强2倍。化合物20的水溶性比紫杉醇约高25倍。
