THE EFFECT OF THE AROMATIC RINGS OF TAXOL ON BIOLOGICAL-ACTIVITY AND SOLUTION CONFORMATION - SYNTHESIS AND EVALUATION OF SATURATED TAXOL AND TAXOTERE ANALOGS
THE EFFECT OF THE AROMATIC RINGS OF TAXOL ON BIOLOGICAL-ACTIVITY AND SOLUTION CONFORMATION - SYNTHESIS AND EVALUATION OF SATURATED TAXOL AND TAXOTERE ANALOGS
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DOI：
10.1021/jm00046a018
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发表时间：
1994-09-30
影响因子：
7.3
通讯作者：
GEORG, GI
中科院分区：
文献类型：
--
作者：
BOGE, TC;HIMES, RH;GEORG, GI
详细介绍了紫杉醇和紫杉醇的新型环己基类似物的合成和生物活性评价。以巴卡菌素III为原料，经加氢反应制得2-(环己基羰基)-2-去苯甲酰巴卡菌素III(6)。6与N-t-BOC-3-[(叔丁基二甲基硅基)氧基]-4-苯基-2-氮杂二酮(7)偶联，去掉保护基后得到2-(环己基羰基)-2-脱苯甲酰紫杉醇(9)。以N-benzoyl-3-[(tert-butyldimethylsilyl)oxy]-4-cyclohexyl-2-azetidinone(12)和(三乙基硅基)巴卡菌素III为原料合成了3‘-环己基-3’-去苯基紫杉醇(14)。以紫杉醇为原料，通过氢化一步合成了紫杉醇类似物15，其中三个紫杉醇苯基全部被环己基取代。所有三个类似物(9、14和15)在微管组装实验中都显示出很强的活性，并且对B16黑色素瘤细胞的细胞毒性与紫杉醇相当。与紫杉醇和紫杉醇一样，9在氯仿中具有延伸的侧链，但在DMSO/水混合物中优先采用不同的构象，其中2-(环己基)、3‘-苯基和4-乙酰基聚集在一起。然而，这一行为似乎不会发生在3‘-环己基类似物14和15中，其中侧链构象保持延伸而不依赖于溶剂。这些结果表明，3‘苯环的芳香性显著稳定了簇状构象。
The synthesis and biological evaluation of novel cyclohexyl analogues of taxol and taxotere are detailed. 2-(Cyclohexylcarbonyl)-2-debenzoylbaccatin III (6) was prepared from baccatin III by hydrogenation. Subsequent coupling of 6 with N-t-BOC-3-[(tert-butyldimethylsilyl)oxy]- 4-phenyl-2-azetidinone (7), followed by removal of the protecting groups, afforded 2-(cyclohexylcarbonyl)-2-debenzoyltaxotere (9). In a similar synthetic sequence, 3'-cyclohexyl-3'-dephenyltaxol (14) was prepared from N-benzoyl-3-[(tert-butyldimethylsilyl)oxy]-4-cyclohexyl-2-azetidinone (12) and (triethylsilyl)baccatin III. The taxol analogue 15, in which all three taxol phenyl groups are substituted by a cyclohexyl moiety, was synthesized in one step from taxol via hydrogenation. All three analogues (9, 14, and 15) exhibited strong activity in the microtubule assembly assay and cytotoxicity comparable to taxol against B16 melanoma cells. It was also shown that 9, like taxol and taxotere, has an extended side chain in chloroform, but in DMSO/water mixtures preferentially adopts a different conformation in which the 2-(cyclohexylcarbonyl), 3'-phenyl, and 4-acetyl groups cluster. However, this behavior does not appear to occur for 3'-cyclohexyl analogues 14 and 15, in which the side chain conformation remains extended independent of solvent. These results suggest the aromaticity of the 3'phenyl ring significantly stabilizes the clustered conformation.