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

• Published in: Chemistry, an Asian journal an Asian journal, 2012-07, Vol.7 (7), p.1616-1623
• Main Authors: Plisson, Fabien, Huang, Xiao‐Cong, Zhang, Hua, Khalil, Zeinab, Capon, Robert J.
• Format: Article
• Language: English
• Subjects: Alkaloids - chemistry; Alkaloids - isolation & purification; Alkaloids - pharmacology; Animals; Antineoplastic Agents - pharmacology; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Australia; Biotechnology; Cancer; Cell Line, Tumor; Chemical analysis; Chemistry; Colon; Colonic Neoplasms - drug therapy; Colorectal cancer; Coumarins - chemistry; Coumarins - isolation & purification; Coumarins - pharmacology; Drug resistance; Drug Resistance, Multiple - drug effects; Drug Resistance, Neoplasm - drug effects; Efflux; Glycoproteins; Heterocyclic Compounds, 4 or More Rings - chemistry; Heterocyclic Compounds, 4 or More Rings - isolation & purification; Heterocyclic Compounds, 4 or More Rings - pharmacology; Humans; inhibitor; Isoquinolines - chemistry; Isoquinolines - isolation & purification; Isoquinolines - pharmacology; Lamellar structure; lamellarin; multidrug resistance; Multidrug resistant organisms; Organic chemistry; p-glycoprotein; Structure-Activity Relationship; Trawling; Urochordata - chemistry
• ISSN: 1861-4728; 1861-471X
• DOI: 10.1002/asia.201101049

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, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 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, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 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, 20, 21, 22, 23, 24) and isoquinolines (25, 26), successfully revealed 17 as a promising new non‐cytotoxic P‐gp inhibitor pharmacophore. New promise in fighting MDR: This study reports a selection of new (1–5, 14) and known (6–13, 15–16) lamellarins from two southern Australian Didemnum sp. All structures were assigned by detailed spectroscopic analysis. This unique library of marine alkaloids, supported by semi‐synthetic (17) and synthetic analogues (19–26), was used to probe interactions with the ABC transporter efflux pump P‐glycoprotein (P‐gp), leading to the discovery an optimized P‐gp inhibitor capable of reversing multidrug resistance (MDR) in a human cancer cell line.