3-取代苯基苯并吡喃酮类化合物的设计合成及抗肿瘤活性

Synthesis and antitumor activities of novel 3-(substituted phenyl) chromone derivatives

目的在7-甲氧基或7-羟基苯并吡喃酮的3位引入各种取代苯基,以发现抗肿瘤活性更强的异黄酮类化合物。方法以丹皮酚和甲酸乙酯为原料,经多步反应制得关键中间体3-碘-7-甲氧基苯并吡喃酮(5),再经Suzuki coupling反应制得目标化合物,通过1H-NMR、MS和IR方法确定目标化合物的结构,部分化合物还进行了13C-NMR测定。选择人结肠癌细胞株HCT116和人肝癌细胞株7721为试验瘤株,以姜黄素和大豆异黄酮为阳性对照测定目标化合物的体外抗肿瘤活性。结果设计合成的20个新目标化合物均有一定的体外抗肿瘤活性,其中化合物6,9,16和19的活性较好,与对照品姜黄素的IC50值相当,明显优于对照品大豆异黄酮的IC50值。结论引入不同的3-取代苯基可以改变异黄酮类化合物的抗肿瘤活性;在这类化合物的3位苯基上引入甲基、甲氧基或三氟甲基体积较小的基团似乎有利于其抗肿瘤活性。

Aim In order to find new isoflavones with more potent antitumor activities by the introduction of substituted phenyl groups at position 3 of chromone with a 7-methoxyl or hydroxyl group.Methods The key intermediate 3-iodo-7-methoxyl-4H-chromen-4-one（5） was prepared from 2-hydroxyl-4-methoxyl-acetophenone and ethyl formate.The target compounds were synthesized by Suzuki coupling reaction of 5 and substituted phenylboronic acids.All of the target compounds were confirmed by 1H-NMR,MS and IR spectra respectively,some of them were also confirmed by 13C-NMR spectra.The IC50 of antitumor activity of target compounds were determined by the standard method using two kinds of human tumor cell lines,colon cancer cell HCT116 and liver cancer cell 7721.Results Twenty new compounds were designed and synthesized.The results of preliminary antitumor test show that all the target compounds exhibit potent antitumor activities to a certain extent except that the solubility of 4 compounds is too low to be tested.The activities of four target compounds are nearly same with that of curcumin and much more potent than that of genistein in vitro.Conclusion The antitumor activities of isoflavone anlogues can be promoted by introduction of different substituted phenyl groups at position 3 of chromone.It seems that it is favorable to the antitumor activity of target compound by introduction of small groups such as methyl,methoxyl and trifluoromethyl on the phenyl ring at position 3 of chromone.