title: Chalcogenopyrylium compounds as modulators of the ATP-binding cassette transporters P-glycoprotein (P-gp/ABCB1) and multidrug resistance protein 1 (MRP1/ABCC1).
abstract: Twenty-seven chalcogenopyrylium derivatives varying in the heteroatom of the pyrylium core and substituents at the 2-, 4-, and 6-positions were examined for their effect on human MRP1-mediated uptake of tritiated estradiol glucuronide into inside-out membrane vesicles, their affinity for and ability to stimulate the ATPase activity of purified human P-glycoprotein (P-gp)-His(10), and their ability to promote uptake of calcein AM and vinblastine in multidrug-resistant cells. Differences in their effects on MRP1 and P-gp activity were noted, and a second set of thiopyrylium compounds with systematic substituent changes was examined to refine these differences further. Derivatives with tert-butyl substituents in the 2- and 6-positions had the lowest inhibitory activity toward both transporters. Derivatives with thioamide functionality in the 4-position were more active against MRP1 than derivatives with amide functionality. Conversely, derivatives with amide functionality in the 4-position were more active in P-gp than derivatives with thioamide functionality.
authors.affiliation: Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260-3000, United States.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Ebert
authors.forename: Bryan
authors.initials: B
authors.lastname: Wetzel
authors.forename: Robert L
authors.initials: RL
authors.lastname: Myette
authors.forename: Gwenaëlle
authors.initials: G
authors.lastname: Conseil
authors.forename: Susan P C
authors.initials: SP
authors.lastname: Cole
authors.forename: Geri A
authors.initials: GA
authors.lastname: Sawada
authors.forename: Tip W
authors.initials: TW
authors.lastname: Loo
authors.forename: M Claire
authors.initials: MC
authors.lastname: Bartlett
authors.forename: David M
authors.initials: DM
authors.lastname: Clarke
authors.forename: Michael R
authors.initials: MR
authors.lastname: Detty
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D018011:Chalcogens; D004285:Dogs; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018011:Chalcogens; D006575:Heterocyclic Compounds, 3-Ring; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C421109:multidrug resistance-associated protein 1