新型维甲酸类化合物的合成及生物活性研究  

Synthesis and Biological Evaluation of New Retinoid Derivatives

作　　者：徐之涵[1] 潘燊 黄焰根[1] 

机构地区：[1]东华大学化学化工与生物工程学院国家染整工程技术研究中心,上海201620

出　　处：《有机化学》2014年第7期1391-1398,共8页Chinese Journal of Organic Chemistry

基　　金：上海市教委科研创新项目(No.13ZZ047);教育部留学归国人员科研启动基金(No.教外司留[2011]1139号);中央高校基本科研业务费专项资金资助项目~~

摘　　要：以苯甲醚为起始原料,经Friedel-Crafts反应、溴化和亲核取代转化为硼酸中间体2.以羟基丙酮12为起始原料,经过Wittig反应、溴化、Arbuzov反应、Horner-Wadsworth-Emmons(HWE)反应后得到共轭烯烃溴代物3;化合物2分别与化合物3、4-溴-2-氟苯甲酸甲酯(4)和6-溴烟酸甲酯(5)经Suzuki偶联反应和水解反应,得到三个未见报道的维甲酸类似物1a^1c.同时,以溴苯为起始原料经Friedel-Crafts反应、硝化反应、三氟甲基化反应、硝基还原和亲核取代合成了含有三氟甲基的维甲酸类似物1d.化合物1a^1d的结构经过1H NMR,13C NMR,IR及HRMS的表征,并对四个化合物进行了HL-60细胞株分化活性能力的测试.结果表明化合物1a^1d都具有潜在的药物活性,其中含氟维甲酸类似物1b和1d拥有较商品化药物全反式维甲酸(ATRA)更低的IC50值.The key intermediate boronic acid 2 was synthesized via sequential reactions of Friedel-Crafts alkylation, bromi- nation and nucleophilic reaction by using anisole as starting material. Hydroxyacetone was converted to bromide compound 3 by the Wittig reaction, bromination, Arbuzov reaction and Horner-Wadsworth-Emmons （HWE） ＇reaction. Three novel retinoid derivatives ladle can be obtained via the Suzuki coupling reaction of the boronic acid 2 with bromide compound 3, methyl 4-bromo-2-fluorobenzoate （4） or methyl 6-bromonicotinate （5） and followed by hydrolysis of the corresponding esters. In addition, trifluoromethyl substituted retinoid derivative ld was synthesized via sequential reactions of Friedel-Craffs alkyla- tion, nitration, trifluoromethylation, reduction and nucleophilic reaction with bromobenzene as strarting material. The structures of four new retinoid derivatives1a-1d were confirmed by 1H NMR, 13C NMR, IR and HRMS analyses. Furthermore, the inducing differentiation abilities of molecules 1a-1d for HL-60 cells were tested, and the results revealed that these four retinoid derivatives are biological active. The IC50 values of fluorinated derivatives 1b and 1d are lower than that of commercial medicine all trans retinoid acid （ATRA）.

关 键 词：维甲酸类似物 合成 有机氟化合物 抗肿瘤 

分 类 号：TQ460.1[化学工程—制药化工]