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Lamellarins as Inhibitors of P-Glycoprotein-Mediated Multidrug Resistance in a Human Colon Cancer Cell Line

Authors

  • Fabien Plisson,

    1. Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, 360 Carmody Road, St Lucia, Brisbane, 4072, Queensland (Australia), Fax: (+61) 7-334-62090
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  • Xiao-Cong Huang,

    1. Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, 360 Carmody Road, St Lucia, Brisbane, 4072, Queensland (Australia), Fax: (+61) 7-334-62090
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  • Dr. Hua Zhang,

    1. Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, 360 Carmody Road, St Lucia, Brisbane, 4072, Queensland (Australia), Fax: (+61) 7-334-62090
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  • Zeinab Khalil,

    1. Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, 360 Carmody Road, St Lucia, Brisbane, 4072, Queensland (Australia), Fax: (+61) 7-334-62090
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  • Prof. Robert J. Capon

    Corresponding author
    1. Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, 360 Carmody Road, St Lucia, Brisbane, 4072, Queensland (Australia), Fax: (+61) 7-334-62090
    • Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, 360 Carmody Road, St Lucia, Brisbane, 4072, Queensland (Australia), Fax: (+61) 7-334-62090

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Abstract

Chemical analysis of a Didemnum sp. (CMB-01656) collected during scientific Scuba operations off Wasp Island, New South Wales, yielded five new lamellarins A1 (), A2 (), A3 (), A4 () and A5 () and eight known lamellarins C (), E (), K (), M (), S (), T (), X () and χ (). Analysis of a second Didemnum sp. (CMB-02127) collected during scientific trawling operations along the Northern Rottnest Shelf, Western Australia, yielded the new lamellarin A6 () and two known lamellarins G () and Z (). Structures were assigned to on the basis of detailed spectroscopic analysis with comparison to literature data and authentic samples. Access to this unique library of natural lamellarins () provided a rare opportunity for structure–activity relationship (SAR) investigations, probing interactions between lamellarins and the ABC transporter efflux pump P-glycoprotein (P-gp) with a view to reversing multidrug resistance in a human colon cancer cell line (SW620 Ad300). These SAR studies, which were expanded to include the permethylated lamellarin derivative () and a series of lamellarin-inspired synthetic coumarins () and isoquinolines (), successfully revealed as a promising new non-cytotoxic P-gp inhibitor pharmacophore.

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