title: Lamellarins as inhibitors of P-glycoprotein-mediated multidrug resistance in a human colon cancer cell line.
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 (1), A2 (2), A3 (3), A4 (4) and A5 (5) and eight known lamellarins C (6), E (7), K (8), M (9), S (10), T (11), X (12) and χ (13). 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 (14) and two known lamellarins G (15) and Z (16). Structures were assigned to 1-16 on the basis of detailed spectroscopic analysis with comparison to literature data and authentic samples. Access to this unique library of natural lamellarins (1-16) 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 (17) and a series of lamellarin-inspired synthetic coumarins (19-24) and isoquinolines (25-26), successfully revealed 17 as a promising new non-cytotoxic P-gp inhibitor pharmacophore.
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, 360 Carmody Road, St Lucia, Brisbane, 4072, Queensland, Australia.
authors.forename: Fabien
authors.initials: F
authors.lastname: Plisson
authors.forename: Xiao-Cong
authors.initials: XC
authors.lastname: Huang
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Zeinab
authors.initials: Z
authors.lastname: Khalil
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Capon
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000470:Alkaloids / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001315:Australia; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy*; D003374:Coumarins / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014561:Urochordata / Q000737:chemistry*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000470:Alkaloids; D000970:Antineoplastic Agents; D003374:Coumarins; D006576:Heterocyclic Compounds, 4 or More Rings; D007546:Isoquinolines