title: Design, Synthesis, and Evaluation of in Vitro and in Vivo Anticancer Activity of 4-Substituted Coumarins: A Novel Class of Potent Tubulin Polymerization Inhibitors.
abstract: In this paper, a series of novel 4-substituted coumarin derivatives were synthesized. Among these compounds 34, 39, 40, 43, 62, 65, and 67 exhibited significant antiproliferative activity toward a panel of tumor cell lines at subnanomolar IC50 values. Compound 65 showed potent antiproliferative ability (IC50 values of 7-47 nM) and retained full activity in multidrug resistant cancer cells. Compound 65 caused G2/M phase arrest and interacted with the colchicine-binding site in tubulin, as confirmed by immune-fluorescence staining, microtubule dynamics assays, and competition assays with N,N'-ethylene-bis(iodoacetamide). Compound 65 reduced the cell migration and disrupted capillary-like tube formation in HUVEC cells. Importantly, compound 65 significantly and dose-dependently reduced tumor growth in four xenografts models including paclitaxel sensitive and resistant ovarian tumors (A2780s and A2780/T), adrmicycin sensitive and resistant breast tumors (MCF-7 and MCF-7/ADR), suggesting that compound 65 is a promising novel antimitotic compound for the potential treatment of cancer.
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Bai
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China.
authors.forename: Taijin
authors.initials: T
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China.
authors.forename: Minghai
authors.initials: M
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China.
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Ultrasound, West China Hospital of Sichuan University , Chengdu, 610041, China.
authors.forename: Buyun
authors.initials: B
authors.lastname: Ma
authors.affiliation: Division of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University , Chengdu, 610041, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Lei
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Science, Guiyang, 550002, China.
authors.forename: Bixue
authors.initials: B
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, 610041, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D058105:Polymerization / Q000187:drug effects; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014945:Wound Healing / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D003374:Coumarins; D014404:Tubulin; D050257:Tubulin Modulators