Novel Chalcogenopyrylium Dyes as Modulators of ATP-Binding Cassette Transporters: P-glycoprotein and Multidrug Resistance-associated Protein 1
Ebert, Sean Philip
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The Detty group has made recent advances in the area of P-glycoprotein (P-gp) inhibition. After receiving promising results regarding the effect of amide/thioamide chalcogenorhodamine dyes on P-gp activity, a library of chalcogenopyrylium amide/thioamide dyes was synthesized to probe their effect on P-gp inhibition and transport. The thiopyrylium compounds underwent studies by the University of Toronto and Eli Lilly for stimulation, inhibition, and transport. Furthermore, this very set of dyes was also tested by Queens University for activity regarding Multidrug Resistance-associated Protein 1 (MRP1). The synthesis of this particular set of dyes and their results are described throughout. The synthesis of the thiopyrylium dyes involved varying substituents at the 2-, 4-, and 6-positions. These compounds were examined for their ability to stimulate the ATPase activity of and their affinity for purified human P-glycoprotein (P-gp)-His 10 , and to promote uptake of Calcein-AM and the efflux of vinblastine in multidrug-resistant, P-gp-overexpressing MDCKII-MDR1 cells. Furthermore, they were examined for their effect on human MRP1-mediated uptake of tritiated estradiol glucuronide ([ 3 H]E 2 17βG) into inside-out membrane vesicles. After analysis, derivatives with thioamide functionality in the 4-position were more active against MRP1 than derivatives with amide functionality in the 4-position. Conversely, amides were more active against P-gp than thioamides. Although determined to be micromolar modulators of both transporters, the potential exists for use of these compounds as photosensitizers for the treatment of MRP1- and P-gp-expressing cells by photodynamic therapy (PDT). Through inactivation of either efflux pump by PDT, a dual cancer treatment regimen involving both PDT and conventional chemotherapy may be on the horizon.