Design and synthesis of fluorinated iron chelators for metabolic study and brain uptake
- Resource Type
- Authors
- Yu-Lin Chen; Yongmin Ma; Xiaole Kong; Robert C. Hider; Dingyong Liu; Sourav Roy
- Source
- Journal of medicinal chemistry. 55(5)
- Subject
- Pyridones
Guinea Pigs
Substituent
Glucuronidation
chemistry.chemical_element
In Vitro Techniques
Ring (chemistry)
Iron Chelating Agents
Permeability
chemistry.chemical_compound
Structure-Activity Relationship
Glucuronides
Cytochrome P-450 Enzyme System
Coordination Complexes
Drug Discovery
Pyridine
Organic chemistry
Animals
Deferiprone
Ferrous Compounds
Brain
Fluorine
Hydrogen-Ion Concentration
Combinatorial chemistry
MOPS
Partition coefficient
chemistry
Blood-Brain Barrier
Functional group
Microsomes, Liver
Molecular Medicine
Oxidation-Reduction
- Language
- ISSN
- 1520-4804
A range of fluorinated 3-hydroxypyridin-4-ones has been synthesized where fluorine or fluorinated substituent was attached at 2- or 5- position of the pyridine ring in order to improve chemical and biological properties of 3-hydroxypyridin-4-ones. The synthetic route is different from conventional counterparts where a functional group is introduced to a preformed 3-hydroxypyridin-4-one ring. Herein, we introduce a novel method which starts with a fluorine containing precursor and the two hydroxyl groups at 3- and 4- positions of the pyridine ring are introduced at a later stage. The pK(a) values of the free ligands and the affinity constants of their iron complexes demonstrate that the presence of fluorine dramatically alters the values. The distribution coefficient values of the free ligands and corresponding iron(III) complexes between 1-octanol and MOPS buffer (pH 7.4) are also influenced. Glucuronidation and oxidation studies of selected fluorinated 3-hydroxypyridin-4-ones demonstrate that some such fluorinated compounds have clear advantage over deferiprone in that they are metabolized more slowly. Blood-brain barrier permeability studies indicated that although lipophilicity influences the permeability it is not the only factor. Two of the selected seven fluorinated 3-hydroxypyridin-4-ones have improved brain distribution when compared with deferiprone.