title: Synthesis and biological evaluation of novel 3,4-diaryl-1,2,5-selenadiazol analogues of combretastatin A-4.
abstract: A set of novel selenium-containing heterocyclic analogues of combretastatin A-4 (CA-4) have been designed and synthesised using a rigid 1,2,5-selenadiazole 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 anti-proliferative activities. Among these compounds, compounds 3a, 3i, 3n and 3q exhibited superior potency against different tumour cell lines with IC50 values at the nanomolar level. Moreover, compound 3n significantly induced cell cycle arrest in the G2/M phase, inhibited tubulin polymerisation into microtubules and caused microtubule destabilisation. A molecular modelling study of compound 3n was performed to elucidate its binding mode at the colchicine site in the tubulin dimer and to provide a basis for the further structure-guided design of novel CA-4 analogues.
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: Qi
authors.initials: Q
authors.lastname: Guan
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: Fushan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Xu
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: Jiang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
authors.forename: Chunjiang
authors.initials: C
authors.lastname: Liu
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; Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, 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: D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology*; D001632:Bibenzyls / Q000737:chemistry*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006571:Heterocyclic Compounds / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D012643:Selenium / Q000737:chemistry*; D013267:Stilbenes / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001632:Bibenzyls; D006571:Heterocyclic Compounds; D013267:Stilbenes; C040105:combretastatin; D012643:Selenium; C058728:fosbretabulin
keywords: 3,4-Diaryl-1,2,5-selenadiazol; Anti-proliferative activity; Combretastatin A-4; Molecular modelling; Synthesis; Tubulin