title: 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.
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.
authors.affiliation: 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.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Qi
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
authors.forename: Qirong
authors.initials: Q
authors.lastname: Shen
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
authors.forename: Guodong
authors.initials: G
authors.lastname: Lu
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
authors.forename: Mingyang
authors.initials: M
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Kai
authors.initials: K
authors.lastname: Bao
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China. Electronic address: yingliang_1016@163.com.
authors.forename: Yingliang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Weige
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001632:Bibenzyls / Q000737:chemistry*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007624:KB Cells; D062105:Molecular Docking Simulation; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D011719:Pyrazines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013871:Thiones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry*; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001632:Bibenzyls; D011719:Pyrazines; D013871:Thiones; D013876:Thiophenes; D014404:Tubulin; D050257:Tubulin Modulators; C026209:oltipraz; C040105:combretastatin; C049325:1,2-dithiol-3-thione
keywords: Antiproliferative activity; Cell cycle arrest; Combretastatin A-4/oltipraz hybrids; Molecular modelling studies; Tubulin polymerization