Pyridinium and indole orientation determines the mitochondrial uncoupling and anti-cancer efficiency of F16

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Cancer Biology

Background:

• F16 is a preclinical anticancer agent targeting mitochondria.
• Developing targeted therapies with distinct properties is crucial for cancer treatment.

Purpose of the Study:

• To synthesize and characterize two fluorescent isomers of F16 (o-F16 and m-F16).
• To investigate their photophysical properties, mitochondrial uncoupling activity, and cytotoxicity.
• To evaluate their potential for mitochondria-specific imaging in cancer therapy.

Main Methods:

• Synthesis of o-F16 and m-F16 by modifying the linking orientation of pyridinium and indole units.
• Assessment of photophysical properties, including fluorescence emission.
• Measurement of mitochondrial respiration efficiency and proton dissociation capability.
• Evaluation of cytotoxicity against cancer cells.

Main Results:

• o-F16 and m-F16 exhibited entirely different photophysical properties, uncoupling activities, and cytotoxicity.
• o-F16 acted as a potent mitochondrial uncoupler, reducing respiration efficiency.
• m-F16 showed minimal uncoupling activity due to poor proton dissociation.
• Both isomers allowed specific mitochondria imaging (o-F16 in green, m-F16 in red channels).

Conclusions:

• Modification of linking orientation in F16 isomers significantly alters their biological and photophysical functions.
• o-F16 and m-F16 serve as valuable tools for mitochondria imaging and studying mitochondrial function.
• This study provides a foundation for designing novel mitochondria-targeted anticancer drugs and uncouplers.