Swindell C S, Krauss N E, Horwitz S B, Ringel I
Department of Chemistry, Bryn Mawr College, Pennsylvania 19010.
J Med Chem. 1991 Mar;34(3):1176-84. doi: 10.1021/jm00107a042.
Taxol, a potent inhibitor of cell replication, enhances the assembly of tubulin into stable microtubules and promotes the formation of microtubule bundles in cells. In addition to its unique mechanism of action, taxol exhibits unusual promise as an antitumor agent, but its application in cancer chemotherapy is hampered by its limited availability. In order to better define the structure-activity profile of taxol for the design of more accessible drugs and to provide insight into the chemical features of the taxol-microtubule interaction, taxol analogues 3-8, with deleted A-ring side chain substituents and both R and S C-2' configurations, were synthesized from baccatin III through esterification at the hindered 13-hydroxyl. Employing an improved hydroxyl protection strategy, lactate analogues 3 and 4 were prepared with reasonable efficiency owing to their simple side-chain structures, while N-benzoylisoserine analogues 7 and 8 were synthesized through esterification reactions whose rates were enhanced greatly by the participation of the amide functionality. Although less biologically active than taxol, analogues 5-7 were found to promote the polymerization of tubulin and to be cytotoxic; 5 and 6 were considerably more effective than 7, whereas 3, 4, and 8 were least active. Interestingly, tubulin polymerization was sensitive to the C-2' configuration only when the amide substituent was present in the side chain. This observation suggests that the 3'-amide substituent plays an important role in preorganizing the taxol side chain to bind to microtubules.
紫杉醇是一种有效的细胞复制抑制剂，可增强微管蛋白组装成稳定的微管，并促进细胞中微管束的形成。除了其独特的作用机制外，紫杉醇作为一种抗肿瘤药物还展现出非凡的前景，但其在癌症化疗中的应用因供应有限而受到阻碍。为了更好地确定紫杉醇的构效关系，以设计出更易获取的药物，并深入了解紫杉醇与微管相互作用的化学特征，从巴卡亭III出发，通过对受阻的13-羟基进行酯化反应，合成了A环侧链取代基缺失且具有R和S两种C-2'构型的紫杉醇类似物3 - 8。采用改进的羟基保护策略，由于乳酸类似物3和4的侧链结构简单，因此能以合理的效率制备得到；而N-苯甲酰异丝氨酸类似物7和8则通过酯化反应合成，酰胺官能团的参与极大地提高了反应速率。尽管类似物5 - 7的生物活性低于紫杉醇，但它们能促进微管蛋白的聚合且具有细胞毒性；5和6的效果明显优于7，而3、4和8的活性最低。有趣的是，只有当侧链中存在酰胺取代基时，微管蛋白聚合才对C-2'构型敏感。这一观察结果表明，3'-酰胺取代基在使紫杉醇侧链预组织以结合微管方面起着重要作用。
