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.

Nature curing cancer – review on structural modification studies with natural active compounds having anti-tumor efficiency

“…Some are found with anticancer activity while others can reverse back multidrug resistance in cancer cells. Lamellarins inhibit the P -glycoprotein whose mechanism includes transporting anticancer agents out of cancer cells and thus making them multidrug resistance [52]. SAR studies concluded many positive and negative factors responsible for anti-tumor activity of lamellarins.…”

Other Anticancer Drugs Targeting DNA and DNA-Associated Enzymes

“…119 Several members of the family, especially lamellarin I, reverse multidrug resistance (MDR) by direct inhibition of the P-gp-mediated efflux. 120,121 This pharmacological profile opens the possibility of their use as antitumor agents in resistant cells as well as their use as modulators of the MDR phenotype in combination with other antitumor compounds. Structure-activity relationship studies in the lamellarins 122 showed little tolerance toward changes in the substitution pattern in the natural products and underscored the importance of the methoxy and hydroxyl groups.…”

Rotational Energy Barrier around the C1–C11 Single Bond in Lamellarins: A Study by Variable-Temperature NMR

“…in 1985. [2][3][4][5][6][7][8][9][10][11][12][13][14][15] These lamellarins exhibit a number of interesting biological activities such as potent cytotoxicity against cancer cell lines, 8,9,11,12,[14][15][16][17][18][19][20][21] multi-drug resistance (MDR) reversal activity, 15,16 anti-HIV activity, 11,18,22 topoisomerase I inhibitory activity, 23,24 inhibition of mitochondrial function, [25][26][27][28] and protein kinases inhibitory activity. 29 Lamellarins possess a unique 14-phenyl-6H- [1]benzopyrano- According to X-ray crystallographic analyses of several lamellarins, the aryl group attached to C1 is This paper is dedicated to Professor Dr. Victor Snieckus on the occasion of his 77 th birthday.…”