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Enzymatic Synthesis
of New Cationic Photosensitizers
Bartlett, Jeremy1
and Indig, Guilherme1
University of Wisconsin1
Abstract-
Extensively conjugated cationic molecules with appropriate structural
features naturally accumulate into the mitochondria of living cells,
a phenomenon typically more prominent in tumor than in normal cells.
Since a variety of tumor cells also retain pertinent cationic structures
for longer periods of time as compared to normal cells, mitochondrial
targeting has been proposed as a selective therapeutic strategy of relevance
for both chemotherapy and photochemotherapy of neoplastic diseases.
However, the structural parameters that control the preferential uptake
and retention of a variety of cationic dyes by tumor tumors, as compared
to normal tissues, are not well understood. To explore how molecular
structure affects cellular uptake, subcellular distribution, and ultimately
mitochondrial accumulation, we have developed a new dye series specifically
tailored for this purpose. Through the horseradish peroxidase (HRP)-catalyzed
sequential N-demethylation of Crystal violet (CV+) we have synthesized
a series of dyes displaying monotonic variations in molecular structure
and lipophilic/hydrophilic character. CV+ was selected as the precursor
of this new series because it is known to act at the mitochondrial level
and to promote the photoinactivation of tumor cells with good selectivity.
Because the HRP-catalyzed oxidative N-demethylation requires hydrogen
peroxide to occur, if the reaction is permitted to go to its completion,
the level of demethylation can be easily controlled by the initial concentration
of H2O2. Therefore, the experimental conditions can be tailored to maximize
the yield of each product of interest, which facilitates their subsequent
isolation. These new dyes have been characterized by the measurement
of their partition coefficients, electronic and fluorescence spectroscopy,
mass spectrometry, and NMR. The synthetic strategy described in this
report was found to be highly appropriate for the production of a new
dye series for our subsequent investigations on the structural determinants
of specific mitochondrial accumulation. Supported in part by PharmaLux,
LLC.
Keywords: triarylmethanes,
mitochondria, dyes, photosensitizers
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