Chemical modulation of multidrug resistant proteins by triazole bridged flavonoid dimers

Abstract

The central theme of this thesis is the exploration of new modulators of ABC transport proteins by the design and synthesis of a series of triazole-bridged flavonoid dimers. Chapter 1 briefly introduces the background of multidrug resistance, ABC transport proteins, click chemistry as well as the objective of this thesis. Chapter 2 describes a rapid generation of a flavonoid dimer library using "click chemistry". Following this, a high-throughput screening led to the discovery of some highly potent and safe MRP1 modulators is presented. Chapter 3 elucidates the design and synthesis of a series of triazole bridged flavonoid heterodimers and homodimers. Besides, the compounds are evaluated for their potency in reversing BCRP-mediated multidrug resistance. Structure activity relationship of flavonoid dimers towards modulating BCRP is discussed. Finally, a homodimer, Ac22Az8, as a non-cytotoxic, potent and selective BCRP modulator is presented. Chapter 4 describes the design and synthesis a series of triazole bridged flavonoid heterodimers. Following this, the compounds evaluated for their potency in reversing multidrug resistance in P-gp, BCRP and MRP1. Chapter 5 describes the summary future work of this thesis.