This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Arylphosphonium salts (APS) are cytotoxic. They exhibit structure-activity relationships (SARs) as antibiotics, in DNA binding, enzyme inhibition and in lethality to malignant cells. These lipophilic cations easily pass across cell membranes. They preferentially accumulate in the mitochondria of malignant cells in response to the larger charge gradient relative to normal cell mitochondria. This property has been exploited to deliver DNA alkylating agents into mitochondria of malignant cells. APS exhibit SARs for in vitro and in vivo inhibition of acetylcholinesterase. They are competitive inhibitors of bovine serum amine oxidase, protein kinase C and HIV integrase, among others. APS have been shown to modulate DNA toxicity in a collaborative project underway, for which preliminary results have been published. DNA binding is also evidenced by melting curve shifts, electrophoresis mobility and in silico binding studies done in our laboratories. We will do collaborative experiments to explore the specific mechanisms for toxicity of APS. We will synthesize APS bound to fluorescent molecules, polymers containing covalently bound antibiotic APS, APS for new DNA binding and toxicity experiments, and novel APS ionic liquids. AutoDock and HyperChem will be used to calculate APS-DNA interactions. The fluorescent-labeled compounds will be used to observe localization and dispersion of APS into cells using fluorescent microscopy. Polymeric APS will be tested for antibacterial activity and incorporated into plastics suitable for the fabrication of medical tubing, bagging and containers. New monomer APS will be screened in a continuation of DNA-replication toxicity studies and in melting and electrophoresis experiments.