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Antitumor Agents. 284. New Desmosdumotin B Analogues with Bicyclic B-Ring as Cytotoxic and Antitubulin Agents

  1. Author:
    Nakagawa-Goto, K.
    Wu, P. C.
    Lai, C. Y.
    Hamel, E.
    Zhu, H.
    Zhang, L. Y.
    Kozaka, T.
    Ohkoshi, E.
    Goto, M.
    Bastow, K. F.
    Lee, K. H.

  2. Author Address

    [Nakagawa-Goto, Kyoko; Wu, Pei-Chi; Lai, Chin-Yu; Kozaka, Takashi; Ohkoshi, Emika; Lee, Kuo-Hsiung] Univ N Carolina, Nat Prod Res Labs, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. [Hamel, Ernest] Natl Canc Inst Frederick, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. [Zhu, Hao; Zhang, Liying] Univ N Carolina, Lab Mol Modeling, Div Med Chem & Nat Prod, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. [Goto, Masuo] Univ N Carolina, Sch Med, Chapel Hill, NC 27599 USA. [Lee, Kuo-Hsiung] China Med Univ & Hosp, Chinese Med Res & Dev Ctr, Taichung, Taiwan.;Nakagawa-Goto, K, Univ N Carolina, Nat Prod Res Labs, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA.;goto@email.unc.edu Ken_Bastow@unc.edu khlee@unc.edu
    1. Year: 2011
    2. Date: Mar
  2. Journal: Journal of Medicinal Chemistry
    1. 54
    2. 5
    3. Pages: 1244-1255
  4. Type of Article: Article
  5. ISSN: 0022-2623
  1. Abstract:

    We previously reported that the biological activity of analogues of desmosdumotin B (1) was dramatically changed depending on the B-ring system. A naphthalene B-ring analogue 3 exerted potent in vitro activity against a diverse panel of human tumor cell lines with GI(50) values of 0.8-2.1 mu M. In contrast, 1 analogues with a phenyl B-ring showed unique selective activity against P-glycoprotein (P-gp) over-expressing multidrug resistant cell line. We have now prepared and evaluated, 1 analogues with bicyclic or tricyclic aromatic B-ring systems as in vitro inhibitors of human cancer cell line proliferation. Among all synthesized derivatives, 21 with a benzo[b]thiophenyl B-ring was highly active, with GI(50) values of 0.06-0.16 mu M, and this activity was not influenced by overexpression of P-gp. Furthermore, 21 inhibited tubulin assembly in vitro with an IC50 value of 2.0 mu M and colchicine binding by 7896 as well as cellular microtubule polymerization and spindle formation.

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External Sources

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  2. DOI: 10.1021/jm1011947
  3. View record in Web of Science®
  4. WOS: 000287833300012

Library Notes

  1. Fiscal Year: FY2010-2011
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