Comprehensive study of sansalvamide a derivatives and their structure-activity relationships against drug-resistant colon cancer cell lines
Comprehensive study of sansalvamide a derivatives and their structure-activity relationships against drug-resistant colon cancer cell lines
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DOI：
10.1021/jm070731a
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发表时间：
2008-02-14
影响因子：
7.3
通讯作者：
McAlpine, Shelli R.
中科院分区：
文献类型：
--
作者：
Otrubova, Katerina;Lushington, Gerald;McAlpine, Shelli R.
我们报道了62个化合物对两个耐药结肠癌细胞株的广泛的构效关系(SAR)。我们对两代化合物的综合评估使用了合成孔径雷达、核磁共振和分子建模来评估有效化合物的关键3D特征。在这里报道的七种最有效的化合物中，有五种是第二代化合物，强调我们有能力将第一代发现的有效特征结合起来，并利用它们的结构将效力设计到第二代中。这些类似物与目前的结肠癌药物在结构上没有同源性，细胞毒性水平与现有治疗其他癌症的药物相当，并显示出对耐药结肠癌细胞株的选择性高于非癌症细胞系。因此，我们已经确定丹沙尔瓦胺A是治疗多重耐药结肠癌的极佳先导药物。
We report an extensive structure-activity relationship (SAR) of 62 compounds active against two drug-resistant colon cancer cell lines. Our comprehensive evaluation of two generations of compounds utilizes SAR, NMR, and molecular modeling to evaluate the key 3D features of potent compounds. Of the seven most potent compounds reported here, five are second-generation, emphasizing our ability to incorporate potent features found in the first generation and utilize their structures to design potency into the second generation. These analogs share no structural homology to current colon cancer drugs, are cytotoxic at levels on par with existing drugs treating other cancers, and demonstrate selectivity for drug-resistant colon cancer cell lines over noncancerous cell lines. Thus, we have established sansalvamide A as an excellent lead for treating, multiple drug-resistant colon cancers.