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

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(IC5010.0μmol.L-1)。

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

Fourteen novel disubsitituted indazole-3-carboxamide derivatives (5a～5n) were synthesized from indazole-3-carboxylic acid via bromination, esterification, N-alkylation, amidation and Suzuki-coupling reactions in overall yields of 26％～32％.These products were characterized by 1 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 R on 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 MTT assays .The results showed that 5a, 5b and 5m exhibited good inhibition against Ramos;5a, 5b and 5l 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 <10.0μmol· L-1 , respectively .