槲皮素-3-O-酰胺类衍生物的合成及其抗癌活性研究

Study on synthesis and biological activities of quercetin-3-O-amide derivatives

目的设计并合成槲皮素酰胺类衍生物,并对该系列化合物进行体外抗肿瘤活性研究。方法以廉价的芦丁为原料,经苄基选择性保护、Williamson成醚反应,再经Pd/C催化加氢脱苄基得到目标产物,采用DPPH法考察目标化合物的抗氧化活性,MTT法考察目标化合物对人食管鳞癌细胞EC109、人食管鳞癌细胞EC9706、人胃癌细胞SGC7901及小鼠黑色素瘤细胞B16-F10的增殖抑制作用。结果合成的15个槲皮素酰胺类衍生物结构均经~1H-NMR、^(13)C-NMR、ESI-MS确证。抗氧化活性结果显示大部分目标化合物的半数清除率(SC_(50))小于槲皮素或与槲皮素相当,这提示3-OH不是槲皮素抗氧化活性的必需基团。抗肿瘤实验结果显示,通过化学方法对槲皮素进行结构修饰后,其体外抗肿瘤活性显著增强。其中,化合物7-6对EC109细胞的抑制作用(IC_(50)=10.25μmol/L)明显优于母药槲皮素(IC_(50)=31.884μmol/L)和5-FU(IC_(50)=41.738μmol/L),是一个很有潜力的新型抗肿瘤候选化合物。结论 15个槲皮素-3-O-酰胺衍生物均为新化合物,其中化合物7-6具有较好的抗肿瘤活性,值得进一步研究。

Objective To design and synthesize quercetin amide derivatives and study the antitumor activity of these compounds in vitro. Methods The cheap rutin was used as the raw material, the benzyl group was selectively protected, the Williamson was converted into ether, and then the target product was obtained by the hydrogenation debenzylation of Pd/C catalyst. The antioxidant activity of the target compound was investigated by the DPPH method. The inhibitory effects of the target compounds on the proliferation of human esophageal squamous cell carcinoma cell EC109, human esophageal squamous cell carcinoma cell EC9706, human gastric cancer cell SGC7901, and mouse melanoma cells B16-F10 were investigated by MTT method. Results The structures of the 15 quercetin amide derivatives were confirmed by 1H-NMR, 13C-NMR, and ESI-MS. The antioxidant results showed that the SC50 of most target compounds was smaller than or equivalent to quercetin, which suggests that 3-OH is not an essential group for the antioxidant activity of quercetin. The results of anti-tumor experiments showed that after the structural modification of quercetin by chemical methods, its anti-tumor activity was significantly enhanced in vitro. Among them, the inhibitory effect of compound 7-6 on EC109(IC50 = 10.25 μmol/L) is significantly better than that of the parent drugs quercetin(IC50 = 31.884 μmol/L) and 5-FU(IC50 = 41.738 μmol/L). Potential new antitumor candidate compounds. Conclusion The 15 quercetin-3-O-amide derivatives are all new compounds. Among them, compounds 7-6 have good antitumor activity and deserve further study.