High Anti-cancer Activity, Low Animal Toxicity, and Structure Activity Relationships of Curcumin Analogs
High Anti-cancer Activity, Low Animal Toxicity, and Structure Activity Relationships of Curcumin Analogs
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DOI：
10.2174/2352096513999200714103641
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发表时间：
2020-01-01
影响因子：
1
通讯作者：
Wang, Fei
中科院分区：
文献类型：
--
作者：
Song, Sen-Chuan;Mai, Yu-Liang;Wang, Fei
背景：抑制癌细胞生长和体内毒性低是抗癌药物开发的两个重要标准。姜黄素是开发新型抗癌药物类似物的有前途的候选药物。该研究小组设计了姜黄素的3，5-bis-(3，4，5-trimethoxybenzylidene)-1-methyl-piperidin-4-one类似物，在体内显著抑制了食道癌细胞的生长。本研究合成了81个姜黄素类似物，对其进行了体内外分析，并测定了它们的构效关系。方法：以姜黄素的母体结构为基础，设计合成81个3，5-bis(substitutedbenzylidene)-piperidin-4-one类似物。用四甲基偶氮唑盐比色法测定其对人癌细胞的抗癌活性，并用小鼠进行体内毒性试验。结果与讨论：在所设计的姜黄素类似物中，有61个化合物的体外抗癌活性高于母体化合物；23个化合物在低浓度(IC(50)值小于1mM)下抑制了人癌细胞的生长。对姜黄素类似物进行了小鼠急性毒性试验，筛选出13个化合物，在25.0 mg/kg剂量下无明显毒性。结论：设计了23个具有良好体外抗癌活性和低体内毒性的姜黄素类似物。合成孔径雷达分析表明，分子中具有抗癌活性所需的最佳官能团。本研究不仅为设计姜黄素类似物用于抗癌药物的开发提供了有用的策略，而且还揭示了一组可以进一步探索的姜黄素类似物。
Background: Inhibition of cancer cell growth and low in vivo toxicity are two important criteria for the development of anti-cancer drugs. Curcumin is a promising candidate for developing novel anti-cancer drug analogs. The research group designed the 3,5-bis-(3,4,5-trimethoxybenzylidene)-1-methyl-piperidin-4-one analog of curcumin that significantly inhibited the growth of esophageal cancer cells in vivo. In this study, 81 curcumin analogs were synthesized, analyzed both in vitro and in vivo, and their structure activity relationships (SARs) were determined.Methods: Based on the parent structure of curcumin, 81 analogs of 3,5-bis(substitutedbenzylidene)-piperidin-4-one compounds were designed and synthesized. Their anti-cancer activity in the human cancer cell lines was evaluated using the MTT assay, and in vivo toxicity was evaluated in mice. The SARs of selected compounds were analyzed.Results and Discussion: Among the designed curcumin analogs, 61 compounds exerted anti-cancer effects higher than the parent compound in vitro; 23 compounds inhibited cell growth in the human cancer cell line at low concentrations (IC(50 )values below 1 mu M). The acute toxicity of curcumin analogs was tested in mice; 13 compounds were selected, which did not show any obvious toxicity at doses as high as 25.0 mg/kg. The SARs of these shortlisted curcumin analogs were determined.Conclusion: Twenty-three curcumin analogs exhibiting promising in vitro anti-cancer activity and low in vivo toxicity were designed. SAR analysis indicated the optimal functional groups in the molecule required for anti-cancer activity. This study not only suggested a useful strategy to design curcumin analogs for the development of anti-cancer drugs, but also revealed a group of curcumin analogs which could be further explored.