Synthesis and Biological Evaluation of New Retinoid Derivatives

Zhihan Xu, Shen Pan, Yangen Huang
2014 Youji huaxue  
研究论文 新型维甲酸类化合物的合成及生物活性研究 徐之涵 潘 燊 黄焰根 * (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) 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 1 H NMR, 13 C 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,
more » ... 似物 1b 和 1d 拥有较商品化药物全反式维甲酸(ATRA)更低的 IC 50 值. Abstract The key intermediate boronic acid 2 was synthesized via sequential reactions of Friedel-Crafts alkylation, bromination 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 1a~1c 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 1d was synthesized via sequential reactions of Friedel-Crafts alkylation, nitration, trifluoromethylation, reduction and nucleophilic reaction with bromobenzene as strarting material. The structures of four new retinoid derivatives 1a~1d were confirmed by 1 H NMR, 13 C 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 IC 50 values of fluorinated derivatives 1b and 1d are lower than that of commercial medicine all trans retinoid acid (ATRA).
doi:10.6023/cjoc201401047 fatcat:on4if7iwhfdglnw5huckmtydfa