title: In vitro studies of lanthanide complexes for the treatment of osteoporosis.
abstract: Lanthanide ions, Ln(III), 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, H7 = 1-carboxymethyl-3-hydroxy-2-methyl-4-pyridinone, H8 = 1-carboxyethyl-3-hydroxy-2-methyl-4-pyridinone) were coordinated to Ln(3+) (Ln = La, Eu, Gd, Lu) forming stable tris-ligand complexes (LnL(3), L = 1(-), 2(-), 3(-), 4(-), 5(-), 6(-), 7(-) and 8(-)). The dissociation (pK(an)) and metal ligand stability constants (log β(n)) of the 3-hydroxy-4-pyridinones with La(3+) and Gd(3+) 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 (H(5)XT = bis[[bis(carboxymethyl)amino]methyl]phosphinate) was also synthesized and coordinated to Ln(3+) (Ln = La, Eu, Lu), forming the potassium salt of [Ln(XT)](2-). Cytotoxicity assays were carried out in MG-63 cells; all the ligands and metal complexes tested were observed to be non-toxic to this cell line. Studies to investigate the toxicity, cellular uptake and apparent permeability (P(app)) of the lanthanide ions were conducted in Caco-2 cells where it was observed that [La(XT)](2-) had the greatest cell uptake. Binding affinities of free lanthanide ions (Ln = La, Gd and Lu), metal complexes and free 3-hydroxy-4-pyridinones with the bone mineral hydroxyapatite (HAP) are high, as well as moderate to strong for the free ligand with the bone mineral depending on the functional group.
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, Canada V6T 1Z1.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Mawani
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Cawthray
authors.forename: Stanley
authors.initials: S
authors.lastname: Chang
authors.forename: Kristina
authors.initials: K
authors.lastname: Sachs-Barrable
authors.forename: David M
authors.initials: DM
authors.lastname: Weekes
authors.forename: Kishor M
authors.initials: KM
authors.lastname: Wasan
authors.forename: Chris
authors.initials: C
authors.lastname: Orvig
mesh_terms: D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006882:Hydroxyapatites / Q000737:chemistry / Q000378:metabolism; D028581:Lanthanoid Series Elements / Q000737:chemistry*; D008024:Ligands; D010024:Osteoporosis / Q000188:drug therapy; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D056831:Coordination Complexes; D006882:Hydroxyapatites; D028581:Lanthanoid Series Elements; D008024:Ligands; D011728:Pyridones; C020366:3-hydroxy-4-pyridone