黄酮乙酸类衍生物肿瘤血管破坏剂的设计、合成及其抗肿瘤活性的初步评价

Design,synthesis and activity evalution of flavonoid acetic acid analoges as vascular disrupting agent

目的设计、合成一系列黄酮乙酸类衍生物肿瘤血管破坏剂,并测定其体外抗肿瘤活性。方法以邻羟基苯乙酮为起始原料,通过氯甲基化、氰基取代、水解以及缩合等反应得到相应的目标化合物;以5,6-二甲基呫吨酮-4-乙酸(DMXAA)为阳性对照药,通过3种模型对目标化合物的抗肿瘤活性进行评价,包括采用Alpha LISA法检测目标化合物对RAW 264.7细胞的促TNF-α分泌作用、采用MTS法测定化合物的细胞毒作用,以及采用鸡胚绒毛尿囊膜模型测定化合物对鸡胚血管生成的影响。结果与结论合成的18个化合物均未见文献报道,其结果经1H-NMR、MS谱确证;活性评价结果表明有3个目标化合物在抗肿瘤测试中表现出较好的体外抗肿瘤活性。

As the first discovered flavonoid vascular disrupting agent,flavonoid acetic acid（ FAA） had show n significant antitumor activity in animal model. 5,6-Dimethylxanthenone-4-acetic acid（ DM XAA）,a FAA analogue w ith potent activity in vivo against tumor,has entered into phase Ⅲ clinical trials. But DM XAA didn＇t reach the expected results w hen it combined w ith paclitaxel against non-small cell lung cancer. How ever,analogues of FAA and DM XAA still have great potential to develop into anti-cancer drugs. A series of new flavonoid acetic acid analoges w ere designed and synthesized. Eighteen target compounds w ere synthesized and identified by M S and1H-NM R. These compounds w ere evaluated for the antitumor activity by three models：the concentration of TNF-α in the cell culture supernatant by an Alpha LISA method,test the inhibitory proliferation by a M TS method on RAW 264. 7 cells and the chicken embryo chorioallantoic membrane assay model w as adopted to evaluate the activation of the target compounds. Three of these compounds（ Ⅰ1,Ⅰ2,Ⅰ5） were found to have significant anti-cancer activity in vitro.