2. Academic Validation
  3. Discovery of polymethoxyphenyl-pyridines bearing amino side chains as tubulin colchicine-binding site inhibitors

Discovery of polymethoxyphenyl-pyridines bearing amino side chains as tubulin colchicine-binding site inhibitors

  • Bioorg Med Chem. 2022 Nov 1:73:117007. doi: 10.1016/j.bmc.2022.117007.
XiaoYang Li 1,  HuanXian Wu 2,  Kai-Wen Feng 1,  JiaHuan Xu 1,  Shaoyu Wu 3,  Zhong-Zhen Zhou 4,  Xiao-Fang Li 5
Affiliations

Affiliations

  • 1 Innovation Program of Drug Research on Neurological and Metabolic Diseases, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 2 Innovation Program of Drug Research on Neurological and Metabolic Diseases, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Clinical Pharmacy Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
  • 3 Innovation Program of Drug Research on Neurological and Metabolic Diseases, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: wushaoyu@smu.edu.cn.
  • 4 Innovation Program of Drug Research on Neurological and Metabolic Diseases, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Pharmacy Department, Zhujiang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address: zhouzz@smu.edu.cn.
  • 5 Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address: 2applepie@163.com.
PMID: 36150341 DOI: 10.1016/j.bmc.2022.117007
Abstract

Nineteen TH03 analogues were designed and synthesized as tubulin colchicine-binding site inhibitors with potent antiproliferative activities. Among these compounds, 3,5-dimethoxyphenylpyridines 8j bearing a 4-methoxybenzyl aniline side-chain displayed the best antiproliferative activities against glioma (U87MG and U251). In addition, the trimethoxyphenylpyridine 8o bearing a 4-methyl-N-methyl aniline side-chain showed the best antiproliferative activities against colon carcinoma and lung Cancer with the lowest IC50 value (0.09 µM < IC50 < 0.86 µM). Compared with CA-4, Compounds 8j and 8o displayed lower cytotoxicities toward normal cells but higher antiproliferative activities against RKO (IC50 = 0.15 µM and 0.09 µM respectively), NCI-H1299 (IC50 = 0.73 µM and 0.14 µM respectively), and A549 cells (IC50 = 0.86 µM and 0.37 µM respectively). Further investigations revealed that 8o shows higher tubulin polymerization inhibitory activity (IC50 = 3.1 ± 0.5 µM) than colchicine (IC50 = 8.6 ± 0.2 µM), and induced cell cycle arrest at the G2/M phase and cellular Apoptosis through disrupting the microtubule network.

Keywords

Antiproliferative activities; Apoptosis; Cell cycle arrest; Polymethoxyphenylpyridines; Tubulin colchicine-binding site inhibitors.

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