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). Some are active against cancer
cells in culture and in vivo. 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 of these compounds are inherently fluorescent. They can also be
conjugated with a flurophore to enhance fluorescence and cell imaging. We
have synthesized some of these compounds and observed these effects in our
laboratories. We will synthesize and purify by HPLC a library of new
examples of these compounds for anti-cancer screening by collaborators
here and at other institutions. Three to five step high-yield protocols
developed in our laboratories using readily available reagents,
microwave-assisted and/or solvent-free synthesis will be employed.
Compounds will be tested in cell-imaging and cell toxicity studies, in
fluorescence assays, and DNA replication-blocking experiments to gain
insight into the mechanism(s) of their anti-cancer activity and general
toxicity. Leads discovered in screening will be modified to increase
potency to sub-micromolar activity. They will be tested for binding to
both ds and G4 DNA by CD and ITC experiments. Up to four students can be
involved directly in this project during the first year. Success at any
level in any of the research areas will provide opportunities for an
undetermined number of students past the first year of the project.