1-苯基-1-苯并呋喃/噻吩甲烯基环烷烃衍生物的合成及抗肿瘤活性研究

Synthesis and antitumor activity evaluation of novel 1-phenyl-1 benzofuran/benzothiopheneyl methenecycloalkane derivatives

目的设计合成1-苯基-1-苯并呋喃/噻吩甲烯基环烷烃衍生物,测定其体外抗肿瘤活性。方法以甲氧基取代的2-羟基苯甲醛或苯乙酮(4a^4c)为起始原料,经缩合、Mcmurry偶联反应得到目标化合物2a^2c;以2-羟基-4-甲氧基苯甲醛或苯乙酮(6a^6b)为起始原料,经酯化、重排、水解、缩合、Mcmurry偶联反应得到目标化合物3a^3b;采用四氮唑盐(MTT)法测定对人白血病细胞活性。结果共合成5个衍生物,其结构均经核磁共振氢谱、碳谱和高分辨质谱确证;其中衍生物3a^3b的体外抗人白血病CEM细胞活性与先导物1相当,但低于考布他汀A-4(CA-4)。结论采用苯并噻吩环取代先导物的B环能保持化合物的体外抗肿瘤活性。

Objective To synthesize and evaluate antitumor activity of a series of novel 1- phenyl- 1- benzofuran /benzothiopheneyl methenecycloalkane derivatives. Methods Compounds 2a ~ 2c were synthesized via condensation,Mcmurry reaction,using substituted salicylaldehydes or 2-hydroxyacetophenone（ 4a ~ 4c） as starting materials; using salicylaldehyde（ 6a） or 2-hydroxyacetophenone（ 6b） as starting materials,after treated with dimethylthiocarbamoyl chloride,rearrangement,hydrolysis,condensation,Mcmurry reaction to yield 3a ~ 3b. The antitumor activity on human CEM cells was assessed by MTT method.Results The structures of 5 target compounds synthesized in this paper were confirmed by1H-NMR,13C-NMR and HRMS.Compounds 3a ~ 3b showed similar antitumor activity against human leukemia cells CEM to that of lead compound 1,but all target compounds were less effective than that of Combretastatin A- 4（ CA- 4）. Conclusion Replacement the B-ring of lead compound 1 with benzothiophene resulted in the retention of antitumor activity.