Design, synthesis and biological evaluation of 1-Aryl-5-(4-arylpiperazine-1-carbonyl)-1 H-tetrazols as novel microtubule destabilizers

Chao Wang; Yuelin Li; Zi Liu; Zeyu Wang; Zihan Liu; Shuai Man; Yujing Zhang; Kai Bao; Yingliang Wu; Qi Guan; Daiying Zuo; Weige Zhang

doi:10.1080/14756366.2020.1759582

Design, synthesis and biological evaluation of 1-Aryl-5-(4-arylpiperazine-1-carbonyl)-1 H-tetrazols as novel microtubule destabilizers

J Enzyme Inhib Med Chem. 2021 Dec;36(1):549-560. doi: 10.1080/14756366.2020.1759582.

Authors

Chao Wang¹, Yuelin Li¹, Zi Liu², Zeyu Wang³, Zihan Liu¹, Shuai Man², Yujing Zhang¹, Kai Bao³, Yingliang Wu², Qi Guan¹, Daiying Zuo², Weige Zhang¹

Affiliations

¹ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.
² Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
³ Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, China.

Abstract

A series of 1-aryl-5-(4-arylpiperazine-1-carbonyl)-1H-tetrazols as microtubule destabilizers were designed, synthesised and evaluated for anticancer activity. Based on bioisosterism, we introduced the tetrazole moiety containing the hydrogen-bond acceptors as B-ring of XRP44X analogues. The key intermediates ethyl 1-aryl-1H-tetrazole-5-carboxylates 10 can be simply and efficiently prepared via a microwave-assisted continuous operation process. Among the compounds synthesised, compound 6-31 showed noteworthy potency against SGC-7901, A549 and HeLa cell lines. In mechanism studies, compound 6-31 inhibited tubulin polymerisation and disorganised microtubule in SGC-7901 cells by binding to tubulin. Moreover, compound 6-31 arrested SGC-7901cells in G2/M phase. This study provided a new perspective for development of antitumor agents that target tubulin.

Keywords: Tetrazole; antiproliferative activity; microtubule destabilizer; microwave; molecular docking.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Cycle / drug effects
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Microtubules / drug effects*
Microtubules / metabolism
Microwaves
Models, Molecular
Molecular Structure
Polymerization / drug effects
Structure-Activity Relationship
Tetrazoles / chemical synthesis
Tetrazoles / chemistry
Tetrazoles / pharmacology*
Tubulin / metabolism
Tubulin Modulators / chemical synthesis
Tubulin Modulators / chemistry
Tubulin Modulators / pharmacology*
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Tetrazoles
Tubulin
Tubulin Modulators

Grants and funding

We gratefully acknowledge the National Natural Science Foundation of China [81673293 and 81602969], Project funded by China Postdoctoral Science Foundation [2018M641715], Liaoning Revitalisation Talents Programme [XLYC1802072] and Plan for Development of Young Scholars of Shenyang pharmaceutical university [ZQN2018002] for the generous financial support. This work was also supported by the Programme for Innovative Research Team of the Ministry of Education.