Lanthanum complexes as therapeutic agents for the treatment of bone resorption disorders
department or school: Science, Faculty of
department or school: Chemistry, Department of
data provider: DSpace
degree campus: UBCV
creator: Weekes, David Michael
issued: 2016-07-28T02:00:43
issued: 2016
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Lanthanum naturally targets and binds skeletal tissue in living systems, wherein it has the potential to treat bone resorption disorders by invoking a biological response that counteracts an imbalanced bone remodeling cycle. Because lanthanum is very poorly absorbed, the key to realizing this potential is through rational chelator design, and in this regard, a number of lanthanum complexes have been designed, synthesized, and tested in an effort to develop an orally-active drug. Previously, past group members Dr. Cheri Barta and Dr. Yasmin Mawani had identified tris-(1,2-dimetyl-3-oxypyridin-4-one) lanthanum(III) (La(dpp)₃) and bis-[[bis(carboxymethyl)amino] methyl]phosphinate lanthanum(III) (La(XT)) as lead drug candidates, and – after tailoring the synthetic procedures to access large quantities of each – these compounds were tested for their thermodynamic and kinetic interactions with synthetic hydroxyapatite (HAP) by isothermal titration calorimetry (ITC) and solution depletion studies, respectively. The systems were also tested for the first time in vivo (healthy Sprague Dawley rats) by measuring lanthanum biodistribution from single-dose intravenous (IV), acute IV, and short-term IV and oral administration of either compound. Overall, it was found that La(XT) was a more viable candidate than La(dpp)₃, primarily due to higher thermodynamic stability which led to better oral uptake. Four new compounds (H₂dpa, H₃cedpa, H₄pedpa, and H₇alenpa) and three of their lanthanum complexes (all but H₇alenpa) were also synthesized, and tested for ligand binding kinetics with HAP (solution depletion studies), thermodynamic stability of the lanthanum complexes (potentiometric and NMR titrations), and lipophilicity of both the ligands and the metal complexes (partition coefficient measurements). It was found that [La(pedpa)]- exhibited the most favourable overall profile for a potential drug candidate, but requires further testing before in vivo trials. Crystal structures for …
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/58567
note: LANTHANUM COMPLEXES AS THERAPEUTIC AGENTS FOR THE TREATMENT OF BONE RESORPTION DISORDERS by David Michael Weekes M.Chem. (Hons.), The University of Newcastle Upon Tyne, 2011 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Chemistry) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) July 2016 © David Michael Weekes, 2016 ii Abstract Lanthanum naturally targets and binds skeletal tissue in living systems, wherein it has the potential to treat bone resorption disorders by invoking a biological response that counteracts an imbalanced bone remodeling cycle. Because lanthanum is very poorly absorbed, the key to realizing this potential is through rational chelator design, and in this regard, a number of lanthanum complexes have been designed, synthesized, and tested in an effort to develop an orally-active drug. Previously, past group members Dr. Cheri Barta and Dr. Yasmin Mawani had identified tris-(1,2-dimetyl-3-oxypyridin-4-one) lanthanum(III) (La(dpp)3) and bis-[[bis(carboxymethyl)amino] methyl]phosphinate lanthanum(III) (La(XT)) as lead drug candidates, and – after tailoring the synthetic procedures to access large quantities of each – these compounds were tested for their thermodynamic and kinetic interactions with synthetic hydroxyapatite (HAP) by isothermal titration calorimetry (ITC) and solution depletion studies, respectively. The systems were also tested for the first time in vivo (healthy Sprague Dawley rats) by measuring lanthanum biodistribution from single-dose intravenous (IV), acute IV, and short-term IV and oral administration of either compound. Overall, it was found that La(XT) was a more viable candidate than La(dpp)3, primarily due to higher thermodynamic stability which led to better oral uptake. Four new compounds (H2dpa, H3cedpa, H4pedpa, and H7alenpa) and three of their lanthanum complexes (all but H7alenpa) were also synthesized, and tested fo…
has type: Thesis/Dissertation
date issued: 2016-09
is shown at: 10.14288/1.0307169
language: eng
degree discipline: Chemistry
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
type: Text
identifier URI: http://hdl.handle.net/2429/58567