2. Academic Validation
  3. Triethylated chromones with substituted naphthalenes as tubulin inhibitors

Triethylated chromones with substituted naphthalenes as tubulin inhibitors

  • Bioorg Med Chem. 2016 Nov 15;24(22):6048-6057. doi: 10.1016/j.bmc.2016.09.062.
Kyoko Nakagawa-Goto 1,  Yukako Taniguchi 2,  Yurie Watanabe 2,  Akifumi Oda 2,  Emika Ohkoshi 3,  Ernest Hamel 4,  Kuo-Hsiung Lee 5,  Masuo Goto 6
Affiliations

Affiliations

  • 1 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.
  • 2 School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
  • 3 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, United States.
  • 4 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.
  • 5 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.
  • 6 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.
PMID: 27707623 DOI: 10.1016/j.bmc.2016.09.062
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 (IC50 0.2-5.7μM). 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.

Keywords

Mitotic inhibitors; Naphthalene; Triethylated chromones.

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