Design and Synthesis of Fluorinated Iron Chelators for Metabolic Study and Brain Uptake

TY - JOUR

T1 - Design and Synthesis of Fluorinated Iron Chelators for Metabolic Study and Brain Uptake

AU - Ma, Yongmin

AU - Roy, Sourav

AU - Kong, Xiaole

AU - Chen, Yulin

AU - Liu, Dingyong

AU - Hider, Robert C.

PY - 2012/3/8

Y1 - 2012/3/8

N2 - 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.

AB - 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.

U2 - 10.1021/jm201475u

DO - 10.1021/jm201475u

M3 - Article

VL - 55

SP - 2185

EP - 2195

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 5

ER -