基于HSP90抑制剂BIIB021的硝基还原酶前药的设计、合成及潜在抗肿瘤活性评价  

Design,synthesis,and biological assessment of prodrugs for nitroreductasebased HSP90 inhibitor BIIB021:exploring their potential as anticancer agents

作　　者：吴争荣[1] 谢亲建 金鹏 张天峰 韩佳茜 贺殿[1] Zhengrong Wu;Qinjian Xie;Peng Jing;Tianfeng Zhang;Jiaxi Han;Dian He(School of Pharmacy,Lanzhou University,Lanzhou 730000,Gansu,China;Gansu Provincial General Hospital of Armed Police Force,Lanzhou 730000,Gansu,China)

机构地区：[1]兰州大学药学院,甘肃兰州730000 [2]甘肃武警医院药剂科,甘肃兰州730000

出　　处：《Journal of Chinese Pharmaceutical Sciences》2024年第1期15-25,共11页中国药学（英文版）

基　　金：CAPF Self-Help Research,Innovation(Grant No.ZZKY20222046);CAPF High-level Science and Technology Talent Development and Nova in Science.

摘　　要：在BIIB021的基础上合成了一系列硝基还原酶(NTR)前药,作为潜在的抗癌剂,并在体外测试了其细胞毒性作用。结果表明:化合物1c和2c具有良好的抗肿瘤活性,IC50分别为0.72和1.12μM。此外,与阳性母体化合物BIIB021相比,这两种化合物对正常细胞WI-38的毒性也较低(IC50=495.51和570.27μM vs 261μM)。细胞周期测试分析表明:两种化合物都对HeLa细胞周期阻滞在G2/M期,同时G0/G1期的细胞数量减少,并诱导其凋亡。综上所述:化合物1c和2c具有潜在的抗肿瘤活性,有潜力作为先导化合物,用于进一步结构优化和体内验证研究。A series of prodrugs based on BIIB021,designed for nitroreductase(NTR),were synthesized and tested in vitro for their cytotoxic effects as potential anticancer agents.The results revealed that compounds 1c and 2c exhibited promising antitumor activity,with IC50 values of 0.72 and 1.12μM,respectively.Notably,both compounds demonstrated lower toxicity to normal WI-38 cells compared to the positive control BIIB021(IC50=495.51 and 570.27μM vs.261μM).Cell cycle analysis indicated that both compounds induced cell cycle arrest in the G2/M phase,accompanied by a concomitant decrease in the population of the G0/G1 phase in HeLa cells,ultimately leading to apoptosis.These preliminary findings suggested that compounds 1c and 2c held the potential to serve as promising lead compounds for further structural optimization and in vivo validation studies.

关 键 词：热休克蛋白90 BIIB021 硝基还原酶 硝基苯甲酰胺 

分 类 号：R916[医药卫生—药学]