Synthesis, photophysical properties, and biological activity of tetramethylrosamine analogs
Holt, Jason James
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The synthesis of the 2,7-bis(dimethylamino)chalcogenoxanthone starting materials was significantly improved via optimization of a directed orthometalation, and the utilization of an intramolecular Vilsmeier-Hack reaction for cyclization with ∼5-fold increase in yield over the previously used LDA cyclization method. This new procedure also allowed for the first time the synthesis of the 2,7-bis(dimethylamino)telluriumxanthone ( 4-Te ), and the related tellurium dyes. We have synthesized julolidyl- TMR analogs ( 52-S, Se, Te ) with increased wavelengths of absorption and strong absorption >600 nm target range. We have also synthesized free amino xanthones ( 57-S, 64, and 65 ), and their phenyl dyes ( 68, 69 ). With this work we have expanded the ability to vary the xanthylium core scaffold, including the ability to create unsymmetric cores, and a variety of different scaffold combinations can now be accessed. The TMR analog libraries examined have shown that small changes in structure can have a significant effect on the phototoxicity in both chemosensitive (AUXB1) and drug-resistant cells (CR1R12) and that phototoxicity is not simply a function of uptake or quantum yield for the generation of singlet oxygen. Substituent effects extend to an analogs ability to stimulate ATPase activity as well, however, we have also discovered that select compounds that do not stimulate ATPase activity very well, never the less bind very well to Pgp without promoting ATP hydrolysis. In fact we have shown that verapamil stimulated ATPase activity can be competitively inhibited. We have also shown that ATPase activity and therefore Pgp efflux can be irreversibly destroyed via photosensitization.