Synthesis of novel analogues of dictyoquinazol A for the development of a treatment for stroke

Abstract

Stroke is a major cause of mortality and morbidity in Australia, imposing a great social and economic burden. Unfortunately, current treatments for stroke are inadequate, and so there is a high demand for new drugs. Dictyoquinazol A is a mushroom-derived natural product that exhibits neuroprotective activity. It therefore has the potential to be developed into a novel treatment for stroke. The aim of this project was to contribute to this medicinal development process. The first task in this project was to develop an efficient total synthesis of dictyoquinazol A. Two previous syntheses of this target had been published, but these methods were difficult to reproduce and are not step economical. In this project, a novel three-step synthesis of dictyoquinazol A was successfully developed, representing a substantial improvement over the existing syntheses in terms of yield and step count. Next, an even more streamlined synthesis of dictyoquinazol A was attempted, based on the insight that this target molecule possesses an element of hidden symmetry. However, this more ambitious synthetic plan was not able to be realised, since the key step in this plan (a Cannizzaro-amidation reaction sequence) did not deliver the desired product in isolable quantity. The next task in this project was to create a small library of structural analogues of dictyoquinazol A. The target analogues were designed to provide structure-activity data focusing on the primary alcohol and the methoxy groups of dictyoquinazol A. The new three-step synthesis developed above proved to be an effective method for creating these analogues. The final task in this project was to perform a preliminary biological assessment of dictyoquinazol A and analogues, using a cell-based model of stroke. It was shown that cultured nerve cells could be protected against staurosporine-induced apoptosis by co-treatment with dictyoquinazol A and analogues. This represents a previously unrecognised mode of action of these compounds. Based on this data, a preliminary structure-activity relationship profile of the molecule was created. Overall, these studies have contributed to the medicinal development of dictyoquinazol A towards a novel treatment for stroke.