Abstract:
Molecules from nature have played an important role in the drug-discovery process for millennia. Recently the scientific community’s intensifying interest in marine natural products has led to the isolation and synthesis of a growing number of molecules with potential as clinical agents against many conditions including cancer. The lamellarin family is one such class of compounds, having demonstrated anticancer activity in multiple cancer cell lines. This thesis focuses on synthetic studies towards lamellarin K 33. Three fragments were synthesised to this end, with the goal of combining the first two fragments via an acyl- Claisen rearrangement; a well-studied reaction within our research group. We found during the course of our studies, that the lithiated addition of sterically hindered aryl bromides to the acyl-Claisen rearrangement product 74 was not feasible, and despite multiple revised strategies our goal of synthesising lamellarin K 33 remained unattained. We were however successful in establishing a viable synthetic strategy to the lamellarin framework, through which the synthesis of a de-D ring analogue 234 of lamellarin K 33 was achieved. This analogue was tested for cytotoxicity and was found to have an IC50 of 2.6 μM. Through the course of our synthetic work on the lamellarin framework, we discovered the substrate-dependent auto-oxidation of methyl pyrroles at the 2-position, and conducted studies to probe the nature of the auto-oxidation process. Also, during these studies model pyrroles and pyrrole aldehydes were synthesised and were subsequently tested for bioactivity at the National Cancer Institute (USA).
