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

doi:10.5246/jcps.2024.01.002

中国药学(英文版) ›› 2024, Vol. 33 ›› Issue (1): 15-25.DOI: 10.5246/jcps.2024.01.002

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

吴争荣¹^,^#, 谢亲建²^,^#, 金鹏¹, 张天峰², 韩佳茜¹, 贺殿¹^,^*()

^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

收稿日期:2023-10-12 修回日期:2023-11-14 接受日期:2023-11-23 出版日期:2024-01-31 发布日期:2024-01-31
通讯作者: 贺殿

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

Zhengrong Wu¹^,^#, Qinjian Xie²^,^#, Peng Jing¹, Tianfeng Zhang², Jiaxi Han¹, Dian He¹^,^*()

¹ School of Pharmacy, Lanzhou University, Lanzhou 730000, Gansu, China
² Gansu Provincial General Hospital of Armed Police Force, Lanzhou 730000, Gansu, China

Received:2023-10-12 Revised:2023-11-14 Accepted:2023-11-23 Online:2024-01-31 Published:2024-01-31
Contact: Dian He
About author:
^# Zhengrong Wu and Qingjian Xie contributed equally to this work.
Supported by:
CAPF Self-Help Research, Innovation (Grant No. ZZKY20222046), CAPF High-level Science and Technology Talent Development and Nova in Science.

摘要/Abstract

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1.12 μM。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570.27 μM vs 261 μM)。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。

关键词: 热休克蛋白90, BIIB021, 硝基还原酶, 硝基苯甲酰胺

Abstract:

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 1.12 μM, respectively. Notably, both compounds demonstrated lower toxicity to normal WI-38 cells compared to the positive control BIIB021 (IC₅₀= 495.51 and 570.27 μM vs. 261 μM). 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.

Key words: Heat shock protein 90, BIIB021, NTR, Nitro benzamides

Supporting:

吴争荣, 谢亲建, 金鹏, 张天峰, 韩佳茜, 贺殿. 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[J]. 中国药学(英文版), 2024, 33(1): 15-25.

Zhengrong Wu, Qinjian Xie, Peng Jing, Tianfeng Zhang, Jiaxi Han, Dian He. Design, synthesis, and biological assessment of prodrugs for nitroreductase-based HSP90 inhibitor BIIB021: exploring their potential as anticancer agents[J]. Journal of Chinese Pharmaceutical Sciences, 2024, 33(1): 15-25.

图/表 5

Scheme 1. General synthesis of the target compounds 1a–2i. Reagents and conditions: (a) DMSO, K2CO3; (b) SOCl2, C5H5N; (c) THF, C5H5N.

Table 1. Cytotoxicity of target compounds 1a–2i to different cells following 24 h of exposure.

Figure 1. Effects of compounds 1c and 2c on HeLa cell cycle progression (a) Control; (b) treated with 1.0 μmol/L BIIB021; (c) treated with 5.0 μmol/L BIIB021; (d) treated with 1.0 μmol/L 1c; (e) treated with 5.0 μmol/L 1c; (f) treated with 1.0 μmol/L 2c and (g) treated with 5.0 μmol/L 2c.

Figure 2. Apoptosis in HeLa cells treated with compounds 1c and 2c for 48 h, as detected using flow cytometry with the annexin V/PI apoptosis detection kit. (a) Control; (b) treated with 1.0 μmol/L BIIB021; (c) treated with 5.0 μmol/L BIIB021; (d) treated with 1.0 μmol/L 1c; (e) treated with 5.0 μmol/L 1c; (f) treated with 1.0 μmol/L 2c and (g) treated with 5.0 μmol/L 2c.

Figure 3. Molecular binding mode of compounds 1c and 2c to NTR 1DS7.

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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 nitroreductase-based HSP90 inhibitor BIIB021: exploring their potential as anticancer agents

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