1/2,5-二取代吲唑-3-甲酰胺衍生物的合成及其抗肿瘤活性  

Synthesis and Antitumor Activities of 1/2,5-Disubstituted Indazole-3-carboxamide Derivatives

作　　者：奉强[1,2] 何华龙 高添桃 朱永霞 张强胜 刘志昊 何冰 张力丹 余洛汀[1] 

机构地区：[1]华西医院药物化学实验室肿瘤中心四川大学协同创新中心,四川成都610041 [2]成都师范学院化学与生命科学学院,四川成都611130

出　　处：《合成化学》2017年第9期721-729,768,共10页Chinese Journal of Synthetic Chemistry

基　　金：国家自然科学基金资助项目(81602398);中国博士后基金资助项目(2016T90861)

摘　　要：以吲唑-3-羧酸为原料,依次经溴代和酯化反应制得中间体5-溴吲唑-3-羧酸甲酯(2);2经N-烷基化并原位水解生成1/2-取代-5-溴吲唑-3-羧酸(3);3与吡啶酮甲胺类化合物经缩合反应制得酰胺(4);4与芳基频哪醇硼酸酯发生Suzuki偶联反应合成了14个新型二取代吲唑-3-甲酰吡啶酮甲胺衍生物(5a^5n),收率26%~32%,其结构经~1H NMR,^(13)C NMR和HR-MS(ESI-TOF)表征。通过NOE差谱确证了取代基在吲唑氮原子上的取代位置。采用MTT法研究了5a^5n对人B淋巴瘤细胞(Ramos)、人黑色素瘤细胞(CHL-1,WM-266-4)和乳腺癌细胞(BT-474)的体外抗肿瘤活性。结果表明:5a,5b,5m对Ramos细胞、5a,5b,5l对WM-266-4细胞、5a,5b,5d,5e,5h,5j,5m,5n对CHL-1细胞和5a,5b,5d,5h,5m对BT-474细胞具有较好的抑制活性(IC50<10.0μmol.L-1)。Fourteen novel disubsitituted indazole-3-carboxamide derivatives（5a - 5n） were synthesized from indazole-3-earboxylic acid via bromination, esterificafion, N-alkylafion, amidation and Suzukicoupling reactions in overall yields of 26% - 32%. These products were characterized by ＇H NMR, 13C NMR and HR-MS（ESI-TOF）. We also examined the ^1H-^1H NOE difference spectroscopy of 3a and 3b and confirmed the exact substitution position of Ron the N of indazole. The in vitro antitumor activities against human B lymphoma cells（ Ramos）, human melanoma cells（ CHL-1, WM-266-4） and breast cancer cells（BT-474） have been demonstrated by MTY assays. The results showed that 5a, 5b and Sm exhibited good inhibition against Ramos; 5a, 5b and 51 exhibited excellent inhibition against WM-266-4; 5a, 5b, 5d, 5e, 5h, 5j, 5m and 5n showed advanced inhibition against CHL-1 ; 5a,5b, 5d, 5h and 5m exhibited good inhibition against BT-474 with IC50 〈 10.0 μmol·^-1 , respectively.

关 键 词：吲唑-3-甲酸 1/2 5.二取代吲唑.3.甲酰胺衍生物j SUZUKI偶联反应 合成 抗肿瘤活性 

分 类 号：O626.21[理学—有机化学] O626.32[理学—化学]