Arylphosphonium salts interact with DNA to modulate cytotoxicity.
Arylphosphonium salts (APS) are compounds that have both lipophilic and cationic character, allowing them facile transport through plasma membranes or cell walls to accumulate in the cytoplasm or mitochondria of cells. APS molecules preferentially accumulate in tumor cells and are therefore under investigation as tumor imaging agents and mitochondrial targeting molecules. We have generated a systematic set of APS to study their ability to associate with DNA. The chemical structure of the APS determines the extent of its interaction with DNA and therefore its ability to aggregate the DNA. Also, APS compounds blocked DNA amplification in vitro at concentrations below the aggregation threshold, corroborating the structure/interaction relationship. Furthermore, the extent of APS:DNA interaction strongly correlates with bacterial toxicity, implying that APS molecules may deter cellular metabolic DNA pathways. Finally, DNA repair deficient and DNA bypass polymerase deficient bacterial strains were screened for sensitivity to APS. Interestingly, no single pathway for the repair or tolerance of these compounds was solely responsible for APS mediated toxicity. Taken together, these findings suggest that APS compounds may be capable of targeting and regulating unchecked cell growth and therefore show potential applications as a chemotherapeutic agent.
Bergeron
Krystal L
KL
Department of Physical Sciences, Rhode Island College, 600 Mt. Pleasant Ave, Providence, RI 02908-1991, United States.
Murphy
Eileen L
EL
Majofodun
Olulade
O
Muñoz
Luis D
LD
Williams
John C
JC
Almeida
Karen H
KH
D000890:Anti-Infective Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002412:Cations / Q000494:pharmacology; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004269:DNA, Bacterial / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D005784:Gene Amplification / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D008954:Models, Biological; D008968:Molecular Conformation; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012492:Salts / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000890:Anti-Infective Agents; D002412:Cations; D004269:DNA, Bacterial; D009943:Organophosphorus Compounds; D012492:Salts; D004247:DNA