| Summary: | Lanthanides are of interest in the treatment of bone density disorders because they are found
to accumulate preferentially in bone (in vivo), have a stimulatory effect on bone formation,
and exhibit an inhibitory effect on bone degradation (in vitro), altering the homeostasis of the
bone cycle. In an effort to develop an orally active lanthanide drug, a series of 3-hydroxy-4-
pyridinone ligands were synthesized and eight of these ligands (H1 = 3-hydroxy-2-methyl-1-
(2-hydroxyethyl)-4-pyridinone, H2 = 3-hydroxy-2-methyl-1-(3-hydroxypropyl)-4-pyridinone,
H3 = 3-hydroxy-2-methyl-1-(4-hydroxybutyl)-4-pyridinone, H4 = 3-hydroxy-2-
methyl-1-(2-hydroxypropyl)-4-pyridinone, H5 = 3-hydroxy-2-methyl-1-(1-hydroxy-3-
methylbutan-2-yl)-4-pyridinone, H6 = 3-hydroxy-2-methyl-1-(1-hydroxybutan-2-yl)-4-
pyridinone, H8 = 1-carboxymethyl-3-hydroxy-2-methyl-4-pyridinone, H9 = 1-carboxyethyl-
3-hydroxy-2-methyl-4-pyridinone) were coordinated to ³⁺(Ln = La, Eu, Gd, Lu) forming
stable tris-ligand complexes (LnL₃, L = 1-, 2-, 3-, 4-, 5-, 6-, 8- and 9-). The dissociation (pKan)
and metal ligand stability constants (log βn) of the 3-hydroxy-4-pyridinones with La³⁺ and
Gd³⁺ were determined by potentiometric titrations, which demonstrated that the 3-hydroxy-4-
pyridinones form stable tris-ligand complexes with the lanthanide ions. One phosphinate-
EDTA derivative (H₅XT = bis[[bis(carboxymethyl)amino]methyl]phosphinate) was also
synthesized and coordinated to Ln³⁺ (Ln = La, Eu, Lu), forming the potassium salt of
[Ln(XT)]²-. Lastly, the naturally occurring curcuminoids found in turmeric were separated
into the three naturally occurring components (HCurc = (1E,6E)-1-(4-hydroxy-3-
methoxyphenyl)-7-(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione, HDMC = (1E,6E)-1,7-
bis(4-hydroxy-3-methoxy-phenyl)hepta-1,6-diene-3,5-dione, HBDMC = (1E,6E)-1,7-bis(4-
hydroxy-phenyl)hepta-1,6-diene-3,5-dione); HCurc was then coordinated to Ln³⁺ (Ln = Eu,
Gd, Yb, Lu), forming Ln(Curc)₃ complexes. The free ligands and metal complexes were
studied for their in vitro efficacy. Cytotoxicity assays were carried out in MG-63 cells; with
the exception of the curcuminoids, all the ligands and metal complexes tested were observed
to be non-toxic to this cell line. Further studies to investigate the toxicity, cellular uptake and iii
apparent permeability (Papp) of the lanthanide ions were conducted in Caco-2 cells and it was observed that [La(XT)]²- had the greatest cell uptake. Investigation into the binding affinities of free lanthanide ions (Ln = La, Gd and Lu), metal complexes and free 3-hydroxy-4-pyridinones with the bone mineral (HAP) indicate a strong binding affinity of the lanthanide ions for HAP, as well as a moderate to strong interaction of the free ligand with the bone mineral depending on the functional group.
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