The Development of Potential Therapeutic Agents: Synthesis of Mukanadins and Thienoquinolines

Abstract

Modern drug discovery includes a variety of different methods, used separately or in combination with each other. Methods include, but are not limited to natural product-directed synthesis and target-based directed drug design. The mukanadins are members of the bromopyrrole alkaloid family, of marine natural products which display numerous potent biological activities. The racemic compound 9-hydroxy mukanadin B 2.93 is one member of the mukanadin group and has been reported to exhibit strong glutamate antagonistic activity, while mukanadin F 2.83 closely resembles 9-hydroxy mukanadin B 2.93 but was isolated from nature apparently as single enantiopure. Synthetic methods to prepare mukanadin B 2.80 were developed and then applied to the preparation of mukanadin F 2.83. Racemic and enantiopure syntheses of mukanadin F 2.83 were then accomplished by trialling a variety of different protecting group strategies, with its successful preparation resulting in reassignment of the absolute stereochemistry for the natural product. It was discovered that isomerisation and racemisation of these compounds occurs under simple laboratory conditions, including solvation in methanol, which is important, as this was the solvent used to isolate the compound from marine sponges. A series of 18 analogues of mukanadin B were then prepared to allow for investigations into the structure activity relationship of these types of compounds. Thienoquinolines are a group of compounds discovered using high-throughput screening methods and were found to be promising anti-proliferative agents, with their activity suspected to be due to the inhibition of phospholipase C-γ. A series of 34 analogues were synthesised to investigate the importance of differing functionalities within these molecules, including the necessity of the 3-amino group, alterations in substitution of the aryl carboxamide and removal of hydrogen bonding interactions at C-5. Biological activity results confirmed the requirement of the 3-amino group. No particular substitution on the aryl carboxamide enhanced activity, whilst removal of the 5-keto moiety had little effect on the activity of the compounds.