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

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† Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States
‡ Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland 21702, United States
§ Laboratory for Molecular Modeling, Division of Medicinal Chemistry and Natural Products, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
∥ Cell and Developmental Biology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, United States
⊥ Division of Medicinal Chemistry and Natural Products, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States
# Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan
*For K.N.-G.: phone, 919-843-5209; fax, 919-966-3893; e-mail, [email protected]. For K.F.B.: phone, 919-966-7633; fax, 919-966-3893; e-mail, [email protected]. For K.-H.L.: phone, 919-962-0066; fax, 919-966-3893; e-mail, [email protected]
Cite this: J. Med. Chem. 2011, 54, 5, 1244–1255
Publication Date (Web):February 1, 2011
https://doi.org/10.1021/jm1011947
Copyright © 2011 American Chemical Society
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    Abstract

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    We previously reported that the biological acti-vity 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 GI50 values of 0.8−2.1 μM. In contrast, 1 analogues with a phenyl B-ring showed unique selective activity against P-glycoprotein (P-gp) overexpressing 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 GI50 values of 0.06−0.16 μM, 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 μM and colchicine binding by 78% as well as cellular microtubule polymerization and spindle formation.

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    Elemental analysis data for compounds 5−36 and HPLC analysis results for 46−53. This material is available free of charge via the Internet at http://pubs.acs.org.

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