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首页> 外文期刊>Combinatorial Chemistry & High Throughput Screening >A Systematic SAR Study of C10 Modified Paclitaxel Analogues Using a Combinatorial Approach
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A Systematic SAR Study of C10 Modified Paclitaxel Analogues Using a Combinatorial Approach

机译：使用组合方法对C10修饰的紫杉醇类似物进行系统SAR研究

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A library with 63 paclitaxel analogues modified at the C10 position of paclitaxel has been prepared using parallel solution phase synthesis. Most of the C10 analogues were slightly less active than paclitaxel in the tubulin assembly assay and had reduced potency in the B16 melanoma and MCF-7 cell line cytotoxicity assays. These modifications at C10, however, did not lead to the total loss of activity, indicating that the C10 moiety of paclitaxel may not be directly involved in the drug-microtubule interactions, but could influence its binding affinity to P-glycoprotein. Approximately 50 percentof the analogues demonstrated better activity against the drug resistant cell line MCF7-ADR. However, the increase in activity was 10-fold at most. This result demonstrates that the cytotoxicity against this drug resistant cancer cell line is sensitive to structural changes at the C10 position of paclitaxel. It was also found that the presence of a nitrogen atom in the C10 substituent might play a role in the i nteraction of analogues with microtubules.
机译：使用平行溶液相合成方法制备了在紫杉醇C10位置修饰有63个紫杉醇类似物的文库。在微管蛋白组装试验中，大多数C10类似物的活性略低于紫杉醇，在B16黑色素瘤和MCF-7细胞系细胞毒性试验中，其效力降低。然而，在C10处的这些修饰并没有导致活性的完全丧失，这表明紫杉醇的C10部分可能不直接参与药物-微管相互作用，但可能影响其与P-糖蛋白的结合亲和力。大约50％的类似物表现出对耐药细胞系MCF7-ADR更好的活性。然而，活性的增加最多是10倍。该结果表明，针对这种抗药性癌细胞系的细胞毒性对紫杉醇C10位的结构变化敏感。还发现C 10取代基中氮原子的存在可能在类似物与微管的相互作用中起作用。

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