Development of a Carborane Framework for Fragment-Based Drug Discovery

Abstract

Since the first boron-containing drug entered the clinic, there has been an increased interest in harnessing the unusual properties of this atypical element in drug design. Carboranes, an important class of boron cluster compounds, have garnered particular attention for their use as a novel drug framework. Despite this interest, however, their use in this field has remained limited in part due to an inability to access certain positions of the icosahedral cage. In this thesis, we attempt to address this synthetic barrier and report our efforts at utilising these compounds as a structural framework for fragment-based drug discovery (FBDD). In Chapter Two, we describe the development of new methods for functionalising unusual positions of the carborane cage. In so doing, an iodo protecting group for carborane B-vertices is reported for the first time. Using this protecting group, the first syntheses of closo-1,2- and closo-1,7-carborane brominated at the B8 and B5 positions, respectively, are reported. Progress towards the synthesis of two other novel closo-1,7-carboranes brominated at the B2 and B4 positions is also presented. Chapter Three details the preparation of a library of low-MW carborane fragments for use in FBDD. These compounds were subsequently tested for their ability to bind to and inhibit the function of myeloperoxidase (MPO), a haem enzyme that is an emerging target for the treatment of a range of inflammatory disorders. Surface plasmon resonance studies and in vitro inhibition assays identified new closo-carborane derivatives with μM potency that are promising lead fragments for the development of a novel MPO inhibitor. Finally, our endeavours towards increasing the potency of one of these lead fragments are presented in Chapter Four. New synthetic methods were developed which allowed the expansion of this fragment at various structural positions. Several key derivatives were synthesised, with a focus on producing hetero-disubstituted carboranes.