Design, synthesis, physicochemical properties, and evaluation of novel iron chelators with fluorescent sensors.
The synthesis of a range of novel 3-hydroxypyridin-4-ones and 3-hydroxypyran-4-ones linked with different coumarin substituents is described. These compounds have been developed in order to provide a series of molecular probes for the quantification of intracellular labile iron pools. An evaluation of the effect of iron(III) on fluorescence intensity was undertaken. Chelation of iron(III) causes quenching of fluorescence. The relationship between iron(III) concentration and the extent of fluorescence quenching indicates that the metal is chelated in a complex with a metal-to-ligand stoichiometry of 1:3. The fluorescence of hydroxypyridinone compounds was found to be more efficiently quenched by iron(III) than were the hydroxypyranones. The metal-to-ligand stoichiometry at which maximum quenching is observed was found to depend on the site at which coumarin is attached. The efficiency of fluorescence quenching by iron(III) is markedly influenced by solvent polarity and pH. The permeability of two representative fluorescent chelators across human erythrocyte ghost membranes was investigated. The rate of permeability for a series of probes was found to be related to the corresponding ClogP values.
Ma
Yongmin
Y
Departments of Pharmacy, King's College London, Franklin-Wilkins Building, Stamford Street, London SE1 9NN, UK.
Luo
Wei
W
Quinn
Peter J
PJ
Liu
Zudong
Z
Hider
Robert C
RC
D002463:Cell Membrane Permeability / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004910:Erythrocyte Membrane / Q000378:metabolism; D005456:Fluorescent Dyes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D003374:Coumarins; D005456:Fluorescent Dyes; D007502:Iron Chelating Agents; D011714:Pyrans; D011728:Pyridones