title: Triethylated chromones with substituted naphthalenes as tubulin inhibitors.
abstract: Previously synthesized 2-(benzo[b]thiophene-3'-yl)-6,8,8-triethyldesmosdumotin B (1, TEDB-TB) and 2-(naphth-1'-yl)-6,8,8-triethyldesmosdumotin B (2) showed potent activity against multiple human tumor cell lines, including a multidrug-resistant (MDR) subline, by targeting spindle formation and/or the microtubule network. Consequently, ester analogues of hydroxylated naphthyl substituted TEBDs (3-5) were prepared and evaluated for their effects on tumor cell proliferation and on tubulin assembly. Among all new compounds, compound 6, a 4'-acetoxynaphthalen-1'-yl derivative, displayed the most potent antiproliferative activity (IC500.2-5.7μM). Selected analogues were confirmed to be tubulin assembly inhibitors in cell-free and cell-based assays using MDR tumor cells. The new analogues partially inhibited colchicine binding to tubulin, suggesting their binding mode would be different from that of colchicine. This observation was supported by computational docking model analyses. Thus, the newly synthesized triethylated chromones with esterified naphthalene groups have good potential for development as a new class of mitotic inhibitors that target tubulin.
authors.affiliation: School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan; Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, United States. Electronic address: kngoto@p.kanazawa-u.ac.jp.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Nakagawa-Goto
authors.affiliation: School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Yukako
authors.initials: Y
authors.lastname: Taniguchi
authors.affiliation: School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Yurie
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Oda
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, United States.
authors.forename: Emika
authors.initials: E
authors.lastname: Ohkoshi
authors.affiliation: Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702, United States.
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, United States; Chinese Medicine Research and Development Center, China Medical University and Hospital, 2 Yuh-Der Road, Taichung 40447, Taiwan.
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, United States. Electronic address: goto@med.unc.edu.
authors.forename: Masuo
authors.initials: M
authors.lastname: Goto
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D002867:Chromones; D009281:Naphthalenes; D014404:Tubulin
keywords: Mitotic inhibitors; Naphthalene; Triethylated chromones