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Synthesis of fluorinated triphenylphosphonium analogs that improve cancer cell selectivity and in vivo detection
Robert F Keyes1, Donna McAllister2, Michael B Dwinell3
1Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53122, USA; Program in Chemical Biology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53122, USA.
Abstract:
Triphenylphosphonium (TPP+) compounds like mito-metformin (MMe) target cancer cells by exploiting their hyperpolarized mitochondrial membrane potential. Here, we present a protocol for synthesizing TPP+ analogs with selectivity for mammalian cancer cells, reduced toxicity, and quantifiability using fluorine-19 nuclear magnetic resonance (19F-NMR). We describe steps for treating mammalian cells with mitochondria-targeted compounds, treating and preparing mouse tissue with these compounds, and 19F-NMR detection of MMe analogs in cells and tissue. TPP+-conjugated metformin analogs include para-methoxy (pMeO-MMe) and para-trifluoromethyl MMe (pCF3-MMe) and meta-trifluoromethyl MMe (mCF3-MMe).
Insights
This study introduces a new method for synthesizing triphenylphosphonium (TPP+) compounds that selectively target cancer cells. These novel mitochondria-targeted metformin (MMe) analogs offer reduced toxicity and are quantifiable using fluorine-19 nuclear magnetic resonance (19F-NMR).
Area of Science:
- Biochemistry
- Organic Chemistry
- Cancer Biology
Background:
- Triphenylphosphonium (TPP+) compounds, including mito-metformin (MMe), are utilized to target cancer cells.
- These compounds leverage the hyperpolarized mitochondrial membrane potential characteristic of cancer cells.
Purpose of the Study:
- To develop a protocol for synthesizing TPP+ analogs with enhanced selectivity for mammalian cancer cells.
- To reduce the toxicity of these mitochondria-targeted compounds.
- To enable quantification of these compounds in biological samples using fluorine-19 nuclear magnetic resonance (19F-NMR).
Main Methods:
- Synthesis of TPP+-conjugated metformin analogs, including para-methoxy (pMeO-MMe), para-trifluoromethyl MMe (pCF3-MMe), and meta-trifluoromethyl MMe (mCF3-MMe).
- Treatment of mammalian cells and mouse tissues with the synthesized mitochondria-targeted compounds.
- Detection and quantification of MMe analogs in cells and tissues using 19F-NMR.
Main Results:
- Successful synthesis of novel TPP+-conjugated metformin analogs.
- Demonstration of selective targeting of mammalian cancer cells.
- Quantification of MMe analogs in both cell cultures and mouse tissue samples via 19F-NMR.
Conclusions:
- The presented protocol facilitates the synthesis of TPP+ analogs with improved cancer cell selectivity and reduced toxicity.
- Fluorine-19 NMR provides a viable method for quantifying these novel mitochondria-targeted compounds in biological systems.
- These findings pave the way for developing new diagnostic and therapeutic agents for cancer treatment.
