Biological Assessment of Thioamide and Amide-Containing Chalcogenorhodamine Dyes as Photosensitizers for PDT of Cancer, ECP, and GVHD & Synthesis and Evaluation of Oligothiophene-Containing Chalcogenorhodamine Dyes for Biological and Photochemical Applications
MetadataShow full item record
The synthesis of chalcogenorhodamine dyes having biological applications as photosensitizers for photodynamic therapy (PDT) of cancer, extracorporeal photopheresis (ECP) of malignant T-cells, and graft-versus-host disease (GVHD) due to their interactions with P-glycoprotein (P-gp), mitochondrial localization, and their strong absorption have been described by the Detty group. A library of selenorhodamine compounds were tested in vitro as P-gp interactive photosensitizers for PDT.Rhodamine dyes localize in mitochondria due to their cationic nature. ImageStream cytometry was used to confirm the co-localization of rhodamines with the mitochondrial specific probe, MitoTracker Green. Additionally, flow cytometry experiments in the absence and presence of verapamil (VER), a known inhibitor of P-gp, indicated that these compounds are substrates. Thiophene amide-containing dyes exhibited a greater ratio of uptake in the presence of VER, suggesting that they are transported more rapidly compared to thiophene thioamidecontaining dyes, thus supporting the “amide/thioamide switch.” Dose response curves were generated in order to determine LD50 values, EC50 values, and therapeutic ratios. Selenorhodamines were effective photosensitizers at lower doses, were less dark toxic, and therefore had higher therapeutic ratios compared to HPPH, Photofrin, and the structurally related compounds of AA1. Additionally, the thioamides showed enhanced cell death in combination with the clinically approved anticancer drug, doxorubicin. Alternatively, amides displayed a high potential for selectivity in ECP and were effective for the prevention of GVHD. Since amides stimulate P-gp activity, they are extruded from P-gp-expressing lymphocytes. Thus, resting lymphocytes, which are essential for mounting a normal immune response, are spared while malignant T cells are photodepleted.Approximately 10 years ago, a thiophene carboxylate dye was synthesized that contained a fraction of a dimeric byproduct (~95:5), presumably formed via self-condensation of the lithiated intermediate. This dye mixture bound tightly to P-gp and was classified as a noncompetitive inhibitor. However, removal of the impurity and subsequent reevaluation showed weaker binding, and the dye was classified as a substrate. These results suggested that the inhibition originally observed was solely due to the presence of the dimeric species. Dimer dyes as potential potent inhibitors of P-gp became of interest, but attempts at synthesizing these dyes were unsuccessful. With the lack of success, it was hypothesized that increasing the length of the thiophene linker may more easily afford a new class of novel dyes which would mimic dimer dyes. As a result, a series of oligothiophene-containing amide and thioamide dyes containing thieno[3,2-b]thiophene, 2,2’-bithiophene, and 2,2':5',2''-terthiophene were synthesized.Additionally, rhodamine dyes bearing carboxylic, hydroxamic, or phosphonic acid functionalities have been previously shown to function as metal-free alternative photosensitizes for solar cells and solar hydrogen production by the Detty, Watson, and McCamant groups. To date, rhodamines bearing phenyl and thienyl moieties located at the 9-position of the xanthylium core have been examined. However, thieno[3,2-b]thiophene, 2,2’-bithiophene, and 2,2’:5’,2”-terthiophene derivatives have yet to be investigated. Employing oligothiophenes as π-bridges in other organic D-π-A sensitizers has resulted in red shifted absorption and increased e, with subsequent increases in Jsc that led to improved overall PCEs. It was hypothesized that increasing the length of the thiophene bridge may also improve the photochemical performance of rhodamines, which have efficiencies of less than 1%. As a result of this, a series of oligothiophene-containing selenorhodamines were synthesized and preliminary photochemical data is described.