Modulating Cytotoxicity with Lego-like Chemistry: Upgrading Mitochondriotropic Antioxidants with Prototypical Cationic Carrier Bricks

• Type: Article in International Scientific Journal
• Date: 2023

Authors

Benfeito, S (Author) Other; Fernandes, C (Author) Other; Chavarria, D (Author) Other; Barreiro, S (Author) Other; Cagide, F (Author) Other; Sequeira, L (Author) Other; Teixeira, J (Author) Other; Silva, R (Author) Other; Remiao, F (Author) Other; Oliveira, PJ (Author) Other; Uriarte, E (Author) Other; Fernanda Borges (Author) FCUP

Journal

Title: Journal of Medicinal Chemistry

Vol. 66

Pages: 1835-1851

ISSN: 0022-2623

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 0 Citations

Scopus - 1 Citation

Other information

Authenticus ID: P-00Z-WFT

DOI: 10.1021/acs.jmedchem.2c01630

Abstract (EN): Although the lipophilic triphenylphosphonium (TPP+) cation is widely used to target antioxidants to mitochondria, TPP+- based derivatives have shown cytotoxicity in several biological in vitro models. We confirmed that Mito.TPP is cytotoxic to both human neuronal (SH-SY5Y) and hepatic (HepG2) cells, decreasing intra-cellular adenosine triphosphate (ATP) levels, leading to mitochondrial membrane depolarization and reduced mitochondrial mass after 24 h. We surpassed this concern using nitrogen-derived cationic carriers (Mito.PICO, Mito.ISOQ, and Mito.IMIDZ). As opposed to Mito.TPP, these novel compounds were not cytotoxic to SH-SY5Y and HepG2 cells up to 50 mu M and after 24 h of incubation. All of the cationic derivatives accumulated inside the mitochondrial matrix and acted as neuroprotective agents against iron(III), hydrogen peroxide, and tert-butyl hydroperoxide insults. The overall data showed that nitrogen-based cationic carriers can modulate the biological performance of mitochondria-directed antioxidants and are an alternative to the TPP cation.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 17