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Synthesis of tercyclic scaffolds as alpha helix mimetics
thesisposted on 16.02.2017, 04:13 by Lim, Zelong
The α-helix is one of the most common structural motifs in protein secondary structures, and these motifs often serve as recognition elements at the interface of protein-protein interactions (PPIs), where the interaction is mediated in particular by the side chains of the helix at the i, i+3 or i+4, and i+7 positions. These PPIs are fundamental in a wide spectrum of biological processes, such as the apoptosis signalling cascade; however, are not traditional therapeutic targets. Thus, the development of non-peptidic, small molecule α helix mimetics provides the opportunity to produce therapeutics that treat disease states, such as cancer, by modulating non-classical drug targets. Herein described is a molecular modelling-guided design and synthesis of a series of new scaffolds for the mimicry of α-helices. The synthesis of these scaffolds was conducted using a modular synthetic approach which furnished nine compounds based on a phenyl core (Chapter 3), and four compounds based on the pyrimidine core (Chapter 4). The in silico modelling directed the design of these scaffolds (Chapter 2), which provides the opportunity to install relevant functionality in suitable projections to mimic the i, i+3 or i+4, and i+7 side chains of an α-helix. This feature was demonstrated with the synthesis of the tercyclic scaffold 158 (Chapter 5), which projects a leucine-isoleucine-leucine motif for the inhibition of the apoptosis signalling proteins Bcl-xL and Mcl-1. These proteins facilitate apoptotic signalling via PPIs, and thus are pertinent in a range of cancer disease states. The scaffolds synthesised in Chapters 3 and 4 were subjected to an aqueous solubility study and determined to have ample solubility in the context of therapeutic agents. These α-helix mimetic scaffolds were then investigated for their ability to inhibit Bcl-xL and Mcl-1 (Chapter 6). These compounds were largely determined to possess inhibitory activities approaching the 300 µM IC50 range. The tercyclic scaffold 158, although incorporating a binding motif, did not exhibit superior inhibitory activity for Bcl-xL or Mcl-1. The pyridyl-phenyl-imidazole scaffold 83 surprisingly displayed agonistic properties, while the imidazole-phenyl-phenyl scaffold 67 proved to be the most active compound, inhibiting Bcl-xL and Mcl-1 with IC50 values in the 50 – 65 µM range.