Design, synthesis and biological evaluation of 9-aryl-5 H-pyrido[4,3- b]indole derivatives as potential tubulin polymerization inhibitors

Lingyu Shi; Shanbo Yang; Jing Chang; Yujing Zhang; Wenjing Liu; Jun Zeng; Jingsen Meng; Renshuai Zhang; Chao Wang; Dongming Xing

doi:10.3389/fchem.2022.1004835

Design, synthesis and biological evaluation of 9-aryl-5 H-pyrido[4,3- b]indole derivatives as potential tubulin polymerization inhibitors

Front Chem. 2022 Sep 15:10:1004835. doi: 10.3389/fchem.2022.1004835. eCollection 2022.

Authors

Lingyu Shi^{1

2}, Shanbo Yang^{1

2}, Jing Chang^{1

2}, Yujing Zhang³, Wenjing Liu^{1

2}, Jun Zeng^{1

2}, Jingsen Meng^{1

2}, Renshuai Zhang^{1

2}, Chao Wang^{1

2}, Dongming Xing^{1

2

4}

Affiliations

¹ Cancer Institute, The Affiliated Hospital of Qingdao University and School of Basic Medicine, Qingdao University, Qingdao, China.
² Qingdao Cancer Institute, Qingdao, China.
³ The Affiliated Cardiovascular Hospital of Qingdao University, Qingdao University, Qingdao, China.
⁴ School of Life Sciences, Tsinghua University, Beijing, China.

Abstract

A series of new 9-aryl-5H-pyrido[4,3-b]indole derivatives as tubulin polymerization inhibitors were designed, synthesized, and evaluated for antitumor activity. All newly prepared compounds were tested for their anti-proliferative activity in vitro against three different cancer cells (SGC-7901, HeLa, and MCF-7). Among the designed compounds, compound 7k displayed the strongest anti-proliferative activity against HeLa cells with IC₅₀ values of 8.7 ± 1.3 μM. In addition, 7k could inhibit the polymerization of tubulin and disrupt the microtubule network of cells. Further mechanism studies revealed that 7k arrested cell cycle at the G2/M phase and induced apoptosis in a dose-dependent manner. Molecular docking analysis confirmed that 7k may bind to colchicine binding sites on microtubules. Our study aims to provide a new strategy for the development of antitumor drugs targeting tubulin.

Keywords: antitumor activity; molecular docking; pyrido[4,3-b]indole; tubulin; tubulin polymerization inhibitors.