Abstract:Arylphosphonium salts (APS) are cytotoxic
lipophilic cations that can cross cell membranes. They interact with
DNA, both nuclear and mitochondrial, and can block the replication fork.
They are antibacterial and antifungal by unknown mechanism(s). APS have
shown activity against cancer cells in studies by more than one
researcher. These salts are preferentially taken up by malignant cells
and by mitochondria in normal cells. They have been used as carrier
molecules to deliver DNA-alkylating agents into mitochondria. Some APS
are inherently fluorescent. They can also be conjugated with a
flurophore to enhance fluorescence and cell imaging. We have synthesized
compounds and observed these effects in our laboratories. We will
synthesize and purify by HPLC a small targeted library of new examples
of these compounds for anti-cancer screening by collaborators here and
at other institutions. Three-step high-yield protocols developed in our
laboratories using readily available reagents, microwave-assisted and/or
solvent-free synthesis will be employed. Anti-cancer compounds will be
tested in cell-imaging and cell toxicity studies, in flourescence
assays, and DNA replication-blocking experiments to gain insight into
the mechanism(s) of their anti-cancer activity and general toxicity. In
vitro results will be calibrated to anti-cancer screening data to search
for a relationship that can prove predictive of activity for new
compounds in the anti-cancer screens. The QSAR variables cLogP,
molecular refractivity, polarizability, and polar surface area will be
calculated and tested for correlations with activity. Relative
fluorescence due to selective uptake by normal vs. malignant cells will
be explored as a basis for development of a diagnostic tool. Active
compounds discovered in screening will be considered for preclinical
trials. Analogues of active compounds will be syntesized and screened.
Four students can work in this project with stipend, supplies and
equipment support during the year of funding. Others may participate
while taking independent study for course credit. Success at any level
in any of the research areas will provide opportunities for four to six
students per year to continue past the first year of the project. This
will be supported by future grants and/or students taking independent
study for credit.
