Synthesis and Evaluation of Tetraarylethylene-based Mono-, Bis-, and Tris(pyridinium) Derivatives for Image-Guided Mitochondria-Specific Targeting and Cytotoxicity of Metastatic Melanoma Cells

Jessica L Reedy; Devin K Hedlund; Moustafa T Gabr; Grant M Henning; F Christopher Pigge; Michael K Schultz

doi:10.1021/acs.bioconjchem.6b00394

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Synthesis and Evaluation of Tetraarylethylene-based Mono-, Bis-, and Tris(pyridinium) Derivatives for Image-Guided Mitochondria-Specific Targeting and Cytotoxicity of Metastatic Melanoma Cells

Journal article

Peer reviewed

Synthesis and Evaluation of Tetraarylethylene-based Mono-, Bis-, and Tris(pyridinium) Derivatives for Image-Guided Mitochondria-Specific Targeting and Cytotoxicity of Metastatic Melanoma Cells

Jessica L Reedy, Devin K Hedlund, Moustafa T Gabr, Grant M Henning, F Christopher Pigge and Michael K Schultz

Bioconjugate chemistry, Vol.27(10), pp.2424-2430

10/19/2016

DOI: 10.1021/acs.bioconjchem.6b00394

PMCID: PMC5278540

PMID: 27643916

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https://www.ncbi.nlm.nih.gov/pmc/articles/5278540View

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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.

Cell Survival - drug effects

Melanoma - diagnostic imaging

Chemistry Techniques, Synthetic

Drug Screening Assays, Antitumor - methods

Antineoplastic Agents - chemical synthesis

Humans

Mitochondria - metabolism

Melanoma - pathology

Mitochondria - drug effects

Antineoplastic Agents - chemistry

Membrane Potential, Mitochondrial - drug effects

Pyridinium Compounds - chemical synthesis

Microscopy, Confocal

Pyridinium Compounds - pharmacology

Adenosine Triphosphate - metabolism

Fibroblasts - drug effects

Melanoma - drug therapy

Cell Line, Tumor

Antineoplastic Agents - pharmacology

Pyridinium Compounds - chemistry

Microscopy, Fluorescence

Details

Title: Subtitle: Synthesis and Evaluation of Tetraarylethylene-based Mono-, Bis-, and Tris(pyridinium) Derivatives for Image-Guided Mitochondria-Specific Targeting and Cytotoxicity of Metastatic Melanoma Cells
Creators: Jessica L Reedy - 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
Devin K Hedlund - 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
Moustafa T Gabr - 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
Grant M Henning - 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
F Christopher Pigge - 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
Michael K Schultz - 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
Resource Type: Journal article
Publication Details: Bioconjugate chemistry, Vol.27(10), pp.2424-2430
DOI: 10.1021/acs.bioconjchem.6b00394
PMID: 27643916
PMCID: PMC5278540
NLM abbreviation: Bioconjug Chem
ISSN: 1043-1802
eISSN: 1520-4812
Publisher: United States
Grant note: T35 HL007485 / NHLBI NIH HHS S10 RR025439 / NCRR NIH HHS P30 CA086862 / NCI NIH HHS K25 CA172218 / NCI NIH HHS P50 CA097274 / NCI NIH HHS P50 CA174521 / NCI NIH HHS
Language: English
Date published: 10/19/2016
Academic Unit: Radiology; Stead Family Department of Pediatrics; Radiation Oncology; Urology; Chemistry
Record Identifier: 9983985710802771

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