三取代靛红衍生物的合成及其对肿瘤细胞增殖、凋亡和细胞周期的影响

Synthesis of Tri-substituted Isatin Derivatives and Their Effects on Tumor Cell Proliferation,Apoptosis and Cell Cycle

为了研究三取代靛红衍生物的抗肿瘤作用及机制,合成了1,4,5–三取代靛红衍生物(化合物a)、1,5,6–三取代靛红衍生物(化合物b)、1,5,7–三取代靛红衍生物(化合物c),经过核磁共振方法对产物进行结构鉴定,确定了这3种化合物的结构.采用MTT法检测这3种化合物对肿瘤细胞的细胞毒作用,流式细胞仪测定了3种化合物对细胞凋亡和细胞周期的影响.MTT测试结果表明:与母核靛红比较,化合物a和化合物b的生物学活性未有提高,而化合物c的活性显著提高,这可能是在1,4,5位(化合物a)和1,5,6位(化合物b)引入3个4–甲氧基苯基取代基造成空间太挤,1,5,7位引入3个4–甲氧基苯基(化合物c)避免了空间拥挤的问题,从而使活性得到显著提高.进一步采用流式细胞仪检测研究化合物c的作用机制,结果显示其能显著诱导白血病K562细胞的凋亡,并产生G2/M期阻滞.

In order to study the effect of trisubstituted isatin derivatives on the antitumor activity,three compound derivatives 1,4,5-trisubstituted isatin(compound a),1,5,6-trisubstituted isatin(compound b),and 1,5,7-trisubstituted isatin(compound c)were synthesized for the first time.The cytotoxicity of the three compounds was determined by MTT assay.The mechanisms of cell apoptosis and cell cycle of the compounds were examined with flow cytometry.The structures of compounds a,b,and c were confirmed by NMR.MTT test showed that compound a and compound b did not increase the cytotoxicity compared with isatin,while compound c had higher activity.It is quite possible that three 4-methoxyphenyl substituents at positions 1,4 and 5(compound a),and 1,5,and 6(compound b)caused too much space,while three 4-methoxyphenyl groups(compound c)at 1,5,and 7 positions could avoid the problem of steric crowding and thus significantly increases the activity.The mechanism of compound c was detected by flow cytometry,which showed that compound c can significantly induce cell apoptosis and arrest G2/M phase in leukemia K562 cells.