Pharmacokinetics and pharmacodynamics of anticancer curcumin analogues in drug discovery unit
Date
2011-12-13
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
Type
Degree Level
Doctoral
Abstract
Recently, several universities including the University of Saskatchewan initiated drug design and discovery programs to meet the shift in emphasis to translational research by the major funding organizations. The nascent Drug Design and Discovery Research Group at the University of Saskatchewan initiated an anticancer drug discovery program where one of the active projects focused on the development of curcumin analogues containing the 1,5-diaryl-3-oxo-1,4-pentadienyl group as anticancer agents. This became my Ph. D. dissertation research. My current work identifies the inadequacy in the current drug design and discovery model and provides initial direction for the future design of the curcumin analogues with better pharmacokinetic and pharmacodynamic properties. A battery of pharmacokinetic tests on NC 2083, a curcumin analogue that exhibits high in vitro efficacy but does not show any effect in vivo, suggested low permeability, high plasma protein binding and rapid partitioning into RBC as the probable reasons for its inability to control tumour growth in xenografted nude mice. Solubility and permeability assays on different curcumin analogues suggest that the majority of curcumin analogues exhibit low water solubility and low permeability. Our permeability assessment tests on the curcumin analogues identified the differential effect of these curcumin analogues on Caco-2 and MDCK cell monolayer integrity where MDCK cell monolayer was adversely affected while Caco-2 was not. The comparison of physicochemical properties of our analogues with analogues from laboratories reporting preclinical success highlighted that the majority of molecules from successful laboratories conform to the Lipinski’s rule of five while most of our compounds violated it. In order to identify the mechanism of action, we tested the effect of curcumin analogues on the mRNA and protein expression of essential proteins of tumour angiogenesis. The tested curcumin analogues exhibited differential modulation of the angiogenesis mediating proteins. All these studies laid the fundamental building blocks for the anticancer drug discovery process at the College of Pharmacy and Nutrition, University of Saskatchewan and a new model of drug design and discovery was proposed. However, the efficiency of the proposed model remains to be seen.
Description
Keywords
Pharmacokinetics, Drug Discovery, Curcumin, Anticancer
Citation
Degree
Doctor of Philosophy (Ph.D.)
Department
Pharmacy and Nutrition
Program
Pharmacy