4,5-Diaryl-3H-1,2-dithiole-3-thiones and related compounds as combretastatin A-4/oltipraz hybrids: Synthesis, molecular modelling and evaluation as antiproliferative agents and inhibitors of tubulin

Zhiwei Wang; Huan Qi; Qirong Shen; Guodong Lu; Mingyang Li; Kai Bao; Yingliang Wu; Weige Zhang

doi:10.1016/j.ejmech.2016.06.055

4,5-Diaryl-3H-1,2-dithiole-3-thiones and related compounds as combretastatin A-4/oltipraz hybrids: Synthesis, molecular modelling and evaluation as antiproliferative agents and inhibitors of tubulin

Eur J Med Chem. 2016 Oct 21:122:520-529. doi: 10.1016/j.ejmech.2016.06.055. Epub 2016 Jul 1.

Authors

Zhiwei Wang¹, Huan Qi², Qirong Shen³, Guodong Lu³, Mingyang Li³, Kai Bao⁴, Yingliang Wu⁵, Weige Zhang⁶

Affiliations

¹ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China; Department of Pharmaceutical Chemistry, Jinzhou Medical University, No.40, Section 3, Songpo Road, Linghe District, Jinzhou, 121001, China.
² Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
³ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
⁴ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China; Gordon Center for Medical Imaging, Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02214, USA.
⁵ Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China. Electronic address: yingliang_1016@163.com.
⁶ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China. Electronic address: zhangweige2000@sina.com.

PMID: 27428395
DOI: 10.1016/j.ejmech.2016.06.055

Abstract

A new series of 4,5-diaryl-3H-1,2-dithiole-3-thiones and related compounds were designed and synthesised as combretastatin A-4/oltipraz hybrids. We evaluated the antiproliferative activities, inhibition of tubulin polymerization, and cell-cycle effects of these compounds. Several compounds in this series, such as 4d and 5c, displayed significant activity against SGC-7901, KB and HT-1080 cell lines, as determined using MTT assays. The most active compound, 4d, markedly inhibited tubulin polymerization, with an IC50 value of 4.44 μM being observed. In mechanistic studies, 4d caused cell arrest in G2/M phase, induced apoptotic cell death, and disrupted microtubule formation. Molecular docking studies revealed that 4d interacts and binds efficiently with the tubulin protein.

Keywords: Antiproliferative activity; Cell cycle arrest; Combretastatin A-4/oltipraz hybrids; Molecular modelling studies; Tubulin polymerization.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology
Bibenzyls / chemistry*
Cell Cycle / drug effects
Cell Proliferation / drug effects
Chemistry Techniques, Synthetic
Drug Screening Assays, Antitumor
Humans
KB Cells
Molecular Docking Simulation*
Protein Multimerization / drug effects
Protein Structure, Quaternary
Pyrazines / chemistry*
Structure-Activity Relationship
Thiones / chemical synthesis*
Thiones / chemistry
Thiones / metabolism
Thiones / pharmacology*
Thiophenes / chemical synthesis*
Thiophenes / chemistry
Thiophenes / metabolism
Thiophenes / pharmacology*
Tubulin / chemistry*
Tubulin Modulators / chemical synthesis
Tubulin Modulators / chemistry
Tubulin Modulators / metabolism
Tubulin Modulators / pharmacology

Substances

Antineoplastic Agents
Bibenzyls
Pyrazines
Thiones
Thiophenes
Tubulin
Tubulin Modulators
oltipraz
combretastatin
1,2-dithiol-3-thione