Alkyl vs. aryl modifications: a comparative study on modular modifications of triphenylphosphonium mitochondrial vectors

• Type: Article in International Scientific Journal
• Date: 2021

Authors

Ong, HC (Author) Other; Coimbra, JTS (Author) Other; Kwek, G (Author) Other; Ramos, MJ (Author) FCUP; Xing, BA (Author) Other; Pedro A Fernandes (Author) FCUP; Garcia, F (Author) Other

Journal

The Journal is awaiting validation by the Administrative Services.

Title: RSC CHEMICAL BIOLOGY

Vol. 2

Pages: 1643-1650

ISSN: 2633-0679

Indexing

ISI Web of Knowledge - 7 Citations

Scopus - 7 Citations

Other information

Authenticus ID: P-00V-DE4

DOI: 10.1039/d1cb00099c

Abstract (EN): Triphenylphosphonium (TPP+) moieties are commonly conjugated to drug molecules to confer mitochondrial selectivity due to their positive charge and high lipophilicity. Although optimisation of lipophilicity can be achieved by modifying the length of the alkyl linkers between the TPP+ moiety and the drug molecule, it is not always possible. While methylation of the TPP+ moiety is a viable alternative to increase lipophilicity and mitochondrial accumulation, there are no studies comparing these two separate modular approaches. Thus, we have systematically designed, synthesised and tested a range of TPP+ molecules with varying alkyl chain lengths and degree of aryl methylation to compare the two modular methodologies for modulating lipophilicity. The ability of aryl/alkyl modified TPP+ to deliver cargo to the mitochondria was also evaluated by confocal imaging with a TPP+-conjugated fluorescein-based fluorophore. Furthermore, we have employed molecular dynamics simulations to understand the translocation of these molecules through biological membrane model systems. These results provide further insights into the thermodynamics of this process and the effect of alkyl and aryl modular modifications.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 8