Chalcogenopyrylium dyes as inhibitors/modulators of P-glycoprotein in multidrug-resistant cells

A series of chalcogenopyrylium compounds were evaluated as inhibitors/modulators of P-glycoprotein in lipid-activated protein, inside-out membrane vesicles, and in human MDCKIIMDR1 cells. A series of chalcogenopyrylium dyes were evaluated as modulators/inhibitors of P-glycoprotein (Pgp). Their abili...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2008-11, Vol.16 (22), p.9745-9756
Main Authors: Sawada, Geri A., Raub, Thomas J., William Higgins, J., Brennan, Nancy K., Moore, Teiah M., Tombline, Gregory, Detty, Michael R.
Format: Article
Language:English
Subjects:
Adenosine Triphosphatases - metabolism
Animals
Antineoplastic agents
ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors
ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism
Biological and medical sciences
Biological Transport
Calcium Channel Blockers - chemical synthesis
Calcium Channel Blockers - chemistry
Calcium Channel Blockers - pharmacology
Cell Membrane Permeability - drug effects
Cell Polarity
Cells, Cultured
Chalcogenopyrylium dyes
Chalcogens - chemistry
Dogs
Drug Resistance, Multiple
Fluoresceins - chemistry
Fluoresceins - metabolism
Fluorescent Dyes - chemistry
Fluorescent Dyes - metabolism
Fluorescent Dyes - pharmacology
General aspects
Humans
Inhibitors
Inhibitory Concentration 50
Medical sciences
Multidrug resistance
P-glycoprotein
Pharmacology. Drug treatments
Transporters
Verapamil - chemical synthesis
Verapamil - chemistry
Verapamil - pharmacology
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Summary:A series of chalcogenopyrylium compounds were evaluated as inhibitors/modulators of P-glycoprotein in lipid-activated protein, inside-out membrane vesicles, and in human MDCKIIMDR1 cells. A series of chalcogenopyrylium dyes were evaluated as modulators/inhibitors of P-glycoprotein (Pgp). Their ability to inhibit verapamil ( VER)-dependent ATPase activity (IC 50 values) in lipid-activated, mouse Cys-less mdr3 Pgp was determined. Their ability to promote calcein-AM ( CAM) uptake in MDCKII-MDR1 cells and their capacity to be transported by Pgp in monolayers of MDCKII-MDR1 cells were also evaluated. The chalcogenopyrylium dyes promoted CAM uptake with values of EC 50 between 5 × 10 −6 and 3.5 × 10 −5 M and 7 of the 9 dyes examined in transport studies were substrates for Pgp with efflux ratios ( P BA/AB) between 14 and 390. Binding of three compounds ( 1-S, 3-S, and 4-S) to Pgp was also assessed by fluorescence. These three thiopyrylium dyes showed increased fluorescence upon binding to Pgp, giving apparent binding constants, K app, on the order of 10 −7 to 10 −6 M. Compound 8-Te was particularly intriguing since it appeared to influence Pgp at low micromolar concentrations as evidenced by its influence on VER-stimulated ATPase activity (IC 50 of 1.2 × 10 −6 M), CAM uptake (EC 50 of 5.4 × 10 −6 M), as well as [ 3H]-vinblastine transport by Pgp in cells (IC 50 of 4.3 × 10 −6 M) and within inside-out membrane vesicles (IC 50 of 9.6 × 10 −6 M). Yet, Pgp did not influence the distribution of 8-Te in MDCKII-MDR1 monolayers suggesting that 8-Te may bind to an allosteric site.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2008.09.065