Investigator: John Williams Jr., Rhode Island College

Scientific Theme: Cancer

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). 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 more students to continue this work in subsequent years.

Human Health Relevance: Cancer therapy, early cancer diagnosis, breast cancer, cell-imaging, cell targeting, medicinal chemistry, computational medicinal chemistry, dsDNA toxicity, G4 DNA toxicity, selective drug uptake, blocking of DNA amplification, fluroescence labeling, mechanisms of antiproliferation agents, correlations for and predictors of anti-cancer activity, green chemistry, microwave assisted synthesis, computational screening, in vitro screening.