(1E,4E)-1,5双(2,3-二甲氧基苯基)戊-1,4-二烯-3-酮类似物的合成及其体外抗胃癌活性的研究

Synthesis of (1E,4E)-1,5-bis(2,3-dimethoxyphenyl) penta-1,4-dien-3-one Analogs and Its Anti-gastric Cancer Activity In Vitro

目的寻找不对称单羰基姜黄素类似物高效经济的合成方法,并设计合成一系列B19[(1E,4E)-1,5双(2,3-二甲氧基苯基)戊-1,4-二烯-3-酮]类似物及初步探讨其体外抗胃癌活性。方法通过药物化学拼合原理,设计出一系列含2,3-二甲氧基苯基的不对称B19类似物,并得到用L-脯氨酸催化一步合成中间体(E)-2-(2,3-二甲氧基亚苄基)环戊酮的方法。目标产物经四甲基偶氮唑蓝(MTT)法筛选,并用集落克隆实验进一步验证其体外抗胃癌活性。结果合成得到10个结构全新的目标化合物,用LC-MS和1H-NMR表征其结构。其中6e对胃癌细胞SGC-7901和BGC-823的生长活性抑制最高,IC50分别为9. 80和13. 50μmol·L^(-1)。结论 L-脯氨酸可作为高效经济合成不对称单羰基姜黄素类似物的催化剂。活性化合物6e具有较好的体外抗胃癌活性,其毒性及对肿瘤细胞生长抑制机制有待进一步研究。

OBJECTIVE To explore the efficient and economical synthesis method of asymmetric monocarbonyl curcumin analogues (AMCACs),design and sgnthesize a series of B19(1E ,4E)-1,5-bis (2,3-dimethoxyphenyl)penta-1,4-dien-3-one analogs to investigate their anti-gastric cancer activities in vitro.METHODS A series of asymmetric B19 analogues containing 2,3-dimethoxyphenyl were designed via the combination principle of medicinal chemistry,and obtained a method for synthesizing intermediate (E)-2- (2,3-dimethoxybenzylidene)cyclopentanone by one step catalyzed by L-proline.The targeted compounds were screened by MTT assay,and colony cloning experiments were used to further verify its anti-gastric cancer activity in vitro.RESULTS Ten novel target compounds were synthesized,and the structures were confirmed by LC-MS and ^1 H-NMR spectral analysis.Among them,compound 6e had the highest inhibitory activity on the growth of gastric cancer cells SGC-7901 and BGC-823,whose IC50 were 9.80 and 13.50 μmol ·L^-1,respectively.CONCLUSION L-proline could be used as a catalyst to synthesize asymmetric monocarbonyl cureumin analogues efficiently and economically.Compound 6e could effectively inhibit the growth of gastric cancer cells in vitro,and its toxicity and inhibition mechanism of tumor cell growth need to be further studied.