Fluorescent 3-hydroxy-4-pyridinone hexadentate iron chelators: intracellular distribution and the relevance to antimycobacterial properties

• Type: Article in International Scientific Journal
• Date: 2010

Authors

Nunes, A (Author) Other; Podinovskaia, M (Author) Other; Leite, A (Author) Other; Paula Gameiro (Author) FCUP; Zhou, T (Author) Other; Ma, YM (Author) Other; Kong, XL (Author) Other; Schaible, UE (Author) Other; Hider, RC (Author) Other; Maria Rangel (Author) ICBAS

Journal

Title: Journal of Biological Inorganic Chemistry

Vol. 15 No. 6

Pages: 861-877

ISSN: 0949-8257

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 39 Citations

ISI Web of Science

Scopus - 38 Citations

Scientific classification

FOS: Engineering and technology > Chemical engineering

CORDIS: Physical sciences > Chemistry > Biochemistry > Cytochemistry ; Physical sciences > Chemistry > Molecular chemistry

Other information

Authenticus ID: P-003-4CY

DOI: 10.1007/s00775-010-0650-1

Abstract (EN): We report the synthesis and characterization of a fluorescent iron chelator (4), shown to be effective in inhibiting the growth of Mycobacterium avium in macrophages, together with the synthesis and characterization of two unsuccessful analogues selected to facilitate identification of the molecular properties responsible for the antimicrobial activity. Partition of the chelators in liposomes was investigated and the compounds were assessed with respect to uptake by macrophages, responsiveness to iron overload/iron deprivation and intracellular distribution by flow cytometry and confocal microscopy. The synthesis of the hexadentate chelators is based on a tetrahedral structure to which three bidentate 3-hydroxy-4-pyridinone chelating units are linked via amide bonds. The structure is synthetically versatile, allowing further addition of functional groups such as fluorophores. Here, we analyse the non-functionalized hexadentate unit (3) and the corresponding rhodamine B (4) and fluorescein (5) labelled chelators. The iron(III) stability constant was determined for 3 and the values log beta = 34.4 and pFe(3+) = 29.8 indicate an affinity for iron of the same order of magnitude as that of mycobacteria siderophores. Fluorescence properties in the presence of liposomes show that 4 strongly interacts with the lipid phase, whereas 5 does not. Such different behaviour may explain their distinct intracellular localization as revealed by confocal microscopy. The flow cytometry and confocal microscopy studies indicate that 4 is readily engulfed by macrophages and targeted to cytosol and vesicles of the endolysosomal continuum, whereas 5 is differentially distributed and only partially colocalizes with 4 after prolonged incubation. Differential distribution of the compounds is likely to account for their different efficacy against mycobacteria.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 17