The design and synthesis of chalcogenopyrylium dyes as inhibitors/modulators of P-gp in multidrug resistant cells
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The onset of multidrug resistance (MDR) in cancer patients is a major barrier to the completion of a therapeutic regimen. There are three significant forms of MDR that cells can undergo; the most damaging is the increase of efflux pumps along the plasma membranes. P-glycoprotein (P-gp) was one of the first efflux pumps to be associated with MDR. Pgp can transport a wide range of substrates including anthracyclines, vinca alkaloids, taxanes, epipodophylotoxins, cancer agents such as mitomycin C, dactinomycin, trimetrexate, and even some HIV protease inhibitors such as ritonavir, indinavir, and saquinavir. The identification of a common pharmacophore has become an extremely difficult process due to the protein's ability to identify a large diversity of chemical structures as a substrate. It has been shown that P-gp does not fit the model of a “lock and key” type mechanism specifically, but could bind and eject small molecules by means of a conformational change. If this is indeed the case, than a library of compounds that have free rotation, as well as large structural diversity, could be developed to test for their ability to bind and inhibit/modulate P-gp. Due to the fact that tetramethylrosamine (TMR) derivatives act as excellent substrates for P-gp, a collection of chalcogenopyrylium dyes was synthesized. Unlike the rhodamine derivatives, where structural diversity can only be added at 9-position on the xanthylium core, chalcogenopyrylium dyes can add structural diversity at the 2-, 4-, and 6-position of the pyrylium core. Variation of the heteroatom was also performed on the compounds. The biological properties of the dyes were tested by their ability to stimulate or inhibit ATPase activity in human P-gp-His 10 , mouse MDR1 cys-less Pgp, and multidrug resistance protein 1 (MRP1). Transport assays of these compounds were also performed.