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

Abstract

F16 is a mitochondria-targeted, broad-spectrum anticancer agent in the pre-clinic cancer therapy. Here we developed two fluorescent isomers of F16 (o-F16 and m-F16) with entirely different photophysical properties, uncoupling activity, and cytotoxicity by merely modifying the linking orientation of pyridinium and indole units. Individually, o-F16 acted as a strong uncoupler to reduce the mitochondrial respiration efficiency, while m-F16 could hardly uncouple the mitochondrial respiration due to its poor proton dissociation capability. Owing to their intrinsic fluorescence, o-F16 and m-F16 could specifically image mitochondria in the green and red channel, respectively. This work could provide useful information for the development of uncouplers and design of mitochondrial-targeted drugs.

• Authors: Juan Xu, Huan He, Lian-Jiao Zhou, Yu-Zhu Liu, Dong-Wei Li, Feng-Lei Jiang, Yi Liu
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 154 Pg. 305-313 (Jun 25 2018) ISSN: 1768-3254 [Electronic] France
• PMID: 29843101 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Fluorescent Dyes
• Indoles
• Pyridinium Compounds
• 4-(2-(indol-3-yl)vinyl)-1-methylpyridinium

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Fluorescent Dyes (chemical synthesis, chemistry, pharmacology)
• Humans
• Indoles (chemical synthesis, chemistry, pharmacology)
• Membrane Potential, Mitochondrial (drug effects)
• Mitochondria, Liver (drug effects)
• Molecular Dynamics Simulation
• Molecular Structure
• Pyridinium Compounds (chemical synthesis, chemistry, pharmacology)
• Rats
• Rats, Wistar
• Structure-Activity Relationship