Design, synthesis and biological evaluation of novel diarylpyridine derivatives as tubulin polymerisation inhibitors

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

doi:10.1080/14756366.2022.2130284

Design, synthesis and biological evaluation of novel diarylpyridine derivatives as tubulin polymerisation inhibitors

J Enzyme Inhib Med Chem. 2022 Dec;37(1):2755-2764. doi: 10.1080/14756366.2022.2130284.

Authors

Shanbo Yang^{1

2}, Chao Wang^{1

2}, Lingyu Shi^{1

2}, Jing Chang^{1

2}, Yujing Zhang³, Jingsen Meng^{1

2}, Wenjing Liu^{1

2}, Jun Zeng^{1

2}, Renshuai Zhang^{1

2}, Yingchun Shao^{1

2}, Dongming Xing^{1

2

4}

Affiliations

¹ The Affiliated Hospital of Qingdao University, Cancer Institute, 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 set of novel diarylpyridines as anti-tubulin agents were designed, synthesised using a rigid pyridine as a linker to fix the cis-orientation of ring-A and ring-B. All of the target compounds were evaluated for their in vitro antiproliferative activities. Among them, 10t showed remarkable antiproliferative activities against three cancer cell lines (HeLa, MCF-7 and SGC-7901) in sub-micromolar concentrations. Consistent with its potent antiproliferative activity, 10t also displayed potent anti-tubulin activity. Cellular mechanism investigation elucidated 10t disrupted the cellular microtubule structure, arrested cell cycle at G2/M phase and induces apoptosis. Molecular modelling studies showed that 10t could bind to the colchicine binding site on microtubules. These results provide motivation and further guidance for the development of new CA-4 analogues.

Keywords: Diarylpyridine; antiproliferative activity; colchicine binding site inhibitor; tubulin.

MeSH terms

Antineoplastic Agents* / chemistry
Cell Line, Tumor
Cell Proliferation
Colchicine / metabolism
Colchicine / pharmacology
Dose-Response Relationship, Drug
Drug Design
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Pyridines / pharmacology
Structure-Activity Relationship
Tubulin / metabolism
Tubulin Modulators*

Substances

Antineoplastic Agents
Pyridines
Tubulin
Tubulin Modulators
Colchicine

Grants and funding

This work was supported by grants from the Natural Science Foundation of Shandong [ZR2021QH156], the Medical and Health Science and Technology Development Plan Project of Shandong [202113051140] and the Youth Innovation Team Talent Introduction Program of Shandong Province [20190164].