title: Dipicolinate Complexes of Gallium(III) and Lanthanum(III).
abstract: Three dipicolinic acid amine-derived compounds functionalized with a carboxylate (H3dpaa), phosphonate (H4dppa), and bisphosphonate (H7dpbpa), as well as their nonfunctionalized analogue (H2dpa), were successfully synthesized and characterized. The 1:1 lanthanum(III) complexes of H2dpa, H3dpaa, and H4dppa, the 1:2 lanthanum(III) complex of H2dpa, and the 1:1 gallium(III) complex of H3dpaa were characterized, including via X-ray crystallography for [La4(dppa)4(H2O)2] and [Ga(dpaa)(H2O)]. H2dpa, H3dpaa, and H4dppa were evaluated for their thermodynamic stability with lanthanum(III) via potentiometric and either UV-vis spectrophotometric (H3dpaa) or NMR spectrometric (H2dpa and H4dppa) titrations, which showed that the carboxylate (H3dpaa) and phosphonate (H4dppa) containing ligands enhanced the lanthanum(III) complex stability by 3-4 orders of magnitude relative to the unfunctionalized ligand (comparing log βMLand pM values) at physiological pH. In addition, potentiometric titrations with H3dpaa and gallium(III) were performed, which gave significantly (8 orders of magnitude) higher thermodynamic stability constants than with lanthanum(III). This was predicted to be a consequence of better size matching between the dipicolinate cavity and gallium(III), which was also evident in the aforementioned crystal structures. Because of a potential link between lanthanum(III) and osteoporosis, the ligands were tested for their bone-directing properties via a hydroxyapatite (HAP) binding assay, which showed that either a phosphonate or bisphosphonate moiety was necessary in order to elicit a chemical binding interaction with HAP. The oral activity of the ligands and their metal complexes was also assessed by experimentally measuring log Po/wvalues using the shake-flask method, and these were compared to a currently prescribed osteoporosis drug (alendronate). Because of the potential therapeutic applications of the radionuclides67/68Ga, radiolabeling studies were performed with67Ga and H3dpaa. Quantitative radiolabeling was achieved at pH 6.5 in 10 min at room temperature with concentrations as low as 10-5M, and human serum stability studies were undertaken.
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia , 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
authors.forename: David M
authors.initials: DM
authors.lastname: Weekes
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia , 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
authors.forename: Caterina F
authors.initials: CF
authors.lastname: Ramogida
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia , 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
authors.forename: Maria de Guadalupe
authors.initials: MG
authors.lastname: Jaraquemada-Peláez
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia , 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
authors.forename: Brian O
authors.initials: BO
authors.lastname: Patrick
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia , 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
authors.forename: Chirag
authors.initials: C
authors.lastname: Apte
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia , 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
authors.forename: Thomas I
authors.initials: TI
authors.lastname: Kostelnik
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia , 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Cawthray
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia , 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
authors.forename: Lisa
authors.initials: L
authors.lastname: Murphy
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia , 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
authors.forename: Chris
authors.identifier: http://orcid.org/0000-0002-2830-5493
authors.initials: C
authors.lastname: Orvig
mesh_terms: D001842:Bone and Bones / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry*; D018360:Crystallography, X-Ray; D005708:Gallium / Q000737:chemistry*; D007811:Lanthanum / Q000737:chemistry*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010848:Picolinic Acids / Q000737:chemistry* / Q000494:pharmacology; D049268:Positron-Emission Tomography; D013816:Thermodynamics
chemical_list: D056831:Coordination Complexes; D008024:Ligands; D010848:Picolinic Acids; D007811:Lanthanum; D005708:Gallium; C004860:dipicolinic acid