Chalcogenopyrylium Compounds as Modulators of the ATP-Binding Cassette Transporters P-Glycoprotein (P-gp/ABCB1) and Multidrug Resistance Protein 1 (MRP1/ABCC1)
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- 作者：Sean P. Ebert ; Bryan Wetzel ; Robert L. Myette ; Gwena毛lle Conseil ; Susan P. C. Cole ; Geri A. Sawada ; Tip W. Loo ; M. Claire Bartlett ; David M. Clarke ; Michael R. Detty
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：May 24, 2012
- 年：2012
- 卷：55
- 期：10
- 页码：4683-4699
- 全文大小：641K
- 年卷期：v.55,no.10(May 24, 2012)
- ISSN：1520-4804
文摘
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)-His10, 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.