新型吲唑拼接鬼臼毒素衍生物的合成及抗肿瘤活性研究  

Synthesis and Antitumor Activities of Novel Indazole Fused Podophyllotoxin

作　　者：杨俊 梁玉清 尹彩霞 梁光平 王丹丹 YANG Jun;LIANG Yu-qing;YIN Cai-xia;LIANG Guang-ping;WANG Dan-dan(Zunyi Medical and Pharmaceutical College,Guizhou Zunyi 563006;Tongren Polytechnic College,Guizhou Tongren 554300,China)

机构地区：[1]遵义医药高等专科学校,贵州遵义563006 [2]铜仁职业技术学院,贵州铜仁554300

出　　处：《广州化工》2022年第6期47-50,共4页GuangZhou Chemical Industry

基　　金：贵州省科技计划项目(黔科合基础[2020]1Y397号);遵义市科技计划课题(遵市科合社字[2019]210号)。

摘　　要：以鬼臼毒素为原料,与N-丁二酸单取代-5-溴吲唑在DMAP/DCC催化下反应得到目标化合物。采用MTT法评价其对A549细胞、A549/DDP细胞、MCF-7细胞的体外抗肿瘤活性,Autodock评价新型吲唑拼接鬼臼毒素衍生物与微管蛋白秋水仙碱作用位点的结合能力。结果表明新型吲唑拼接鬼臼毒素衍生物对MCF-7细胞[IC_(50)=(38.29±2.45)μM]、A549/DDP细胞[IC_(50)=(82.43±2.35)μM]具有一定的抑制活性,且对A549/DDP耐药细胞具有较好的选择性,RF值小于1,对与微管蛋白秋水仙碱作用位点的ASN-101氨基酸残基与形成氢键(d=2.3),结合能(affinity)为-11.2 kcal/mol,能够较好的结合。Novel indazole fused podophyllotoxin was synthesized by catalyzing podophyllotoxin and 4-(5-bromo-1H-indazol-1-yl)-4-oxobutanoic acid under DMAP/DCC.Its anti-tumor activity in vitro against human non-small cell lung cancer cells(A549),cisplatin-resistant human lung adenocarcinoma cells(A549/DDP)and human breast cancer cells(MCF-7)was evaluated using the MTT method.The binding ability of novel indazole fused podophyllotoxin in the colchicine site of tubulin was evaluated using molecular docking software Autodock.The result showed novel indazole fused podophyllotoxin presented good cytotoxicity to MCF-7[IC_(50)=(38.29±2.45)μM]cells,A549/DDP[IC_(50)=(82.43±2.35)μM].The resistant factor(RF value)was<1,showing a good selectivity to the resistant cell strain A549/DDP.It could form a hydrogen bond with amino acid residue ASN-101 of tubulin(d=2.3),with the affinity of-11.2 kcal/mol,suggesting a high binding ability.

关 键 词：鬼臼毒素 吲唑 体外抗肿瘤活性 

分 类 号：R914.5[医药卫生—药物化学]