Syntheses and structure-activity relationships of taxoids derived from 14 beta-hydroxy-10-deacetylbaccatin III
Syntheses and structure-activity relationships of taxoids derived from 14 beta-hydroxy-10-deacetylbaccatin III
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DOI：
10.1021/jm960563e
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发表时间：
1997-01-31
影响因子：
7.3
通讯作者：
Bernacki, RJ
中科院分区：
文献类型：
--
作者：
Ojima, I;Slater, JC;Bernacki, RJ
采用β-内酰胺合成子法，以14β-羟基-10-脱乙酰浆果赤霉素III为原料，合成了一系列新的紫杉烷类化合物。由此合成的大多数新紫杉烷对人卵巢(A121)、非小细胞肺癌(A549)、结肠(HT-29)和乳腺癌(MCF-7)癌细胞系具有优异的细胞毒性，并且其中一些紫杉烷表现出亚纳摩尔IC50值，比紫杉醇和多西紫杉醇好数倍至1个数量级。 3'-和3'-N-位置的修饰对活性产生显着影响。对于C-3'处的取代基，细胞毒性按以下顺序降低：2-呋喃基类似于2-甲基-1-丙烯基大于或等于2-甲基丙基>(E)-1-丙烯基大于或等于正丙基>苯基远大于2,2-二甲基丙基。对于 3'-N 取代基，活性按 t-BuOCO > Ph > 正己酰基的顺序降低。通过对 C-10 取代基的适当修饰，观察到对表达多药耐药性 (MDR) 表型的阿霉素耐药人乳腺癌细胞系 MCF7-R 的细胞毒性显着增加。观察到的 C-10 取代基对 MCF7-R 活性的显着影响可归因于这些新紫杉烷与导致 MDR 的 P-糖蛋白结合的有效抑制。
A series of new taxoids derived from 14 beta-hydroxy-10-deacetylbaccatin III was synthesized by means of the beta-lactam synthon method. Most of the new taxoids thus synthesized possess excellent cytotoxicity against human ovarian (A121), non-small-cell lung (A549), colon (HT-29), and breast (MCF-7) cancer cell Lines, and several of these taxoids show subnanomolar IC50 values which are severalfold to 1 order of magnitude better than those of paclitaxel and docetaxel. Modifications at the 3'- and 3'-N-positions exert marked effects on the activity. For the substituents at C-3', the cytotoxicity decreases in the order 2-furyl similar to 2-methyl-1-propenyl greater than or equal to 2-methylpropyl > (E)-1-propenyl greater than or equal to n-propyl > phenyl much greater than 2,2-dimethylpropyl. For the 3'-N substituents, the activity decreases in the order t-BuOCO > Ph > n-hexanoyl. A significant increase in the cytotoxicity against the doxorubicin-resistant human breast cancer cell line MCF7-R that expresses the multidrug resistance (MDR) phenotype is observed by the proper modification of the substituent at C-10. The observed remarkable effects of the substituents at C-10 on the activity against MCF7-R can be ascribed to the effective inhibition of the binding of these new taxoids to P-glycoprotein that is responsible for MDR.