title: Synthesis and Evaluation of Tetraarylethylene-based Mono-, Bis-, and Tris(pyridinium) Derivatives for Image-Guided Mitochondria-Specific Targeting and Cytotoxicity of Metastatic Melanoma Cells.
abstract: Metastatic melanoma is the most aggressive and lethal form of skin cancer. Emerging evidence suggests that differences in melanoma metabolism relative to nonmalignant cells represent potential targets for improved therapy for melanoma. Specifically, melanoma cells exhibit increased mitochondrial electron transport chain (ETC) activity and concomitant hyperpolarized mitochondrial membrane potential relative to nonmalignant cells. We have synthesized several new fluorescent lipophilic vinylpyridinium cations built from tetraarylethylene scaffolds that target mitochondria via attraction to the hyperpolarized mitochondrial membrane potential. Mitochondria-specific accumulation in melanoma cells relative to normal human fibroblasts was demonstrated using confocal fluorescence microscopy and resulted in the disruption of oxidative metabolism leading to melanoma specific cell death in vitro. Thus, the pyridinium tetraarylethylene platform represents a promising new mitochondrial-targeted delivery vehicle with potential imaging and therapeutic properties.
authors.affiliation: Departments of Radiology and Radiation Oncology, Free Radical and Radiation Biology Program and ‡Department of Chemistry, The University of Iowa , Iowa City, Iowa 52242, United States.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Reedy
authors.affiliation: Departments of Radiology and Radiation Oncology, Free Radical and Radiation Biology Program and ‡Department of Chemistry, The University of Iowa , Iowa City, Iowa 52242, United States.
authors.forename: Devin K
authors.initials: DK
authors.lastname: Hedlund
authors.affiliation: Departments of Radiology and Radiation Oncology, Free Radical and Radiation Biology Program and ‡Department of Chemistry, The University of Iowa , Iowa City, Iowa 52242, United States.
authors.forename: Moustafa T
authors.initials: MT
authors.lastname: Gabr
authors.affiliation: Departments of Radiology and Radiation Oncology, Free Radical and Radiation Biology Program and ‡Department of Chemistry, The University of Iowa , Iowa City, Iowa 52242, United States.
authors.forename: Grant M
authors.initials: GM
authors.lastname: Henning
authors.affiliation: Departments of Radiology and Radiation Oncology, Free Radical and Radiation Biology Program and ‡Department of Chemistry, The University of Iowa , Iowa City, Iowa 52242, United States.
authors.forename: F Christopher
authors.initials: FC
authors.lastname: Pigge
authors.affiliation: Departments of Radiology and Radiation Oncology, Free Radical and Radiation Biology Program and ‡Department of Chemistry, The University of Iowa , Iowa City, Iowa 52242, United States.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Schultz
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011726:Pyridinium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011726:Pyridinium Compounds; D000255:Adenosine Triphosphate