黄酮衍生物的合成与抗肿瘤活性评价

Synthesis and Anti-tumor in vitro Evaluation of Flavonoid Derivatives

目的合成一系列具有抗肿瘤活性的黄酮衍生物。方法通过Friedel-Crafts反应和改进后的Baker-Venkataraman重排反应合成三甲氧基黄酮2和4,再与水杨酸衍生物6a和6b通过酯化反应得到目标化合物7a、7b、8a、8b、9a、9b。采用MTT法检测目标化合物对人源性胃癌细胞MGC-803、鼠源性胃癌细胞MFC、肝癌细胞Hep G-2和乳腺癌细胞MCF-7的体外抗增殖活性。流式细胞仪检测化合物7b作用于MFC细胞24 h后的凋亡情况。结果目标化合物经1H NMR,ESI-MS确证。化合物7b对肿瘤细胞生长的抑制作用最强,优于其黄酮母体2和5-氟尿嘧啶,并对人正常肝细胞L-02的毒性较低。化合物7b对MFC细胞表现出显著的生长抑制作用,IC50为(13.73±2.04)μM。凋亡实验结果进一步证明化合物7b对MFC细胞凋亡的诱导呈浓度依赖性。结论化合物7b有望成为新型高效低毒抗肿瘤的候选药物,需进一步探究其抗肿瘤活性及其作用机制。

Objective To synthesize a series of flavonoid derivatives with anti-tumor activity. Methods Trimethoxy flavonoids 2 and 4 were prepared by a Friedel-Crafts reaction and an improved Baker-Venkatarama rearrangement reaction,followed by esterification with salicylic acid derivatives 6a and 6b to obtain target compounds 7a,7b,8a,8b,9a and 9b. MTT colorimetric assay was used to detect the anti-proliferative activity of target compounds on MGC-803 cells,MFC cells,HepG2 cells and MCF-7 cells. Flow cytometry investigated MFC cells apoptosis after treatment with compound 7b at different concentrations for 24 h. Results The target compound was confirmed by 1H NMR and ESI-MS which were in full accordance with their depicted structures. On the whole,compound 7b showed the most potent anti-proliferative activity than other compounds and 5-Fu. It also showed low toxicity on normal liver cells L-02. What’s more, compound 7b showed obvious inhibition against MFC cells with IC50 values of (13.73±2.04)μM. It induced apoptosis of MFC cells in a dose-dependent manner. Conclusion Compound 7b is expected to become a new type of highly effective,low-toxic anti-tumor candidate drug,and its anti-tumor activity and its mechanism still need further exploration.