Abstracts Category : Other

Synthesis of novel flavonoid hybrids and development of their delivery systems

by Ming Han Yee

The primary aim of this project is to develop novel anti-tumor agents based on the scaffolds of two natural flavonoids phenoxodiol and (+)-catechin, and evaluate their biological properties and mechanism of action in cancer cells.The phenoxodiol scaffold was structurally modified through molecular hybridization and addition of fused-ring systems. Phenoxodiol was combined with 1-amino-2-propanol and thiosemicarbazone moieties to generate novel phenoxodiol-hybrids. The 1-amino-2-propanol and thiosemicarbazone moieties were linked with phenoxodiol through nucleophilic ring-opening of an epoxide intermediate, and through Schiff base condensation with an aldehyde or ketone intermediate. Synthesis of fused hybrid systems was carried out via an inverse electron demand Diels-Alder reaction between electron-rich dienophiles and ortho-quinone methide intermediate of phenoxodiol.In order to overcome the poor bioavailability of flavonoids, which limits their clinical use, different drug delivery vehicles for phenoxodiol and (+)-catechin were explored. Carbohydrates, -cyclodextrin and dextran, were selected for their aqueous solubility and biocompatibility. Phenoxodiol was encapsulated into -cyclodextrin via a modified co-evaporation method, and was alternatively conjugated onto dextran using an enzymatic method. (+)-Catechin was conjugated onto -cyclodextrin via a cycloaddition strategy.In vitro anti-proliferative activities of the newly synthesized compounds were evaluated against various cancer cell types. In general, most of the compounds exhibited strong anti-proliferative activities across all the tested cancer cell lines. Importantly, many of them also showed an overall increase in specificity as compared to the parent molecule.As angiogenesis plays an important role in cancer progression, the anti-angiogenic mechanism for dextran-catechin conjugate was investigated and demonstrated that it inhibited angiogenesis by disrupting copper metabolism within the endothelial cells. The conjugate was shown to generate reactive oxygen species that lead to reduction of ATOX-1 protein, which protects the cells from oxidative stress. ATOX-1 is also responsible for the transport of copper within the cell and to the VEGF promoter, which is required for angiogenesis.This study shows that structural modification and the employment of carbohydrate-based drug delivery vehicles can be an effective strategy to enhance the overall anti-tumor activity of flavonoids.Advisors/Committee Members: Kumar, Naresh, Chemistry, Faculty of Science, UNSW, Black, David, Chemistry, Faculty of Science, UNSW, Vittorio, Orazio, Children's Cancer Institute Australia for Medical Research, Faculty of Medicine, UNSW.