Synthetic Routes Towards Analogues of Kinase Inhibitory Natural Products (-)-TAN-2483B and Nellielloside A

<p><b>Protein kinases act as key mediators of essential biochemical pathways through the phosphorylation of protein substrates. Overactivation and abnormal functions of protein kinases are associated with a wide spectrum of diseases, many with serious health consequences. (-)-TAN-2483B (1) and nellielloside A (2) are two natural products that exhibit protein kinase inhibition. Natural product 1 is an inhibitor of Bruton’s tyrosine kinase (BTK), an established target of some cancer therapies, while 2 primarily inhibits a low number of kinases within a few families. To optimise their respective bioactivities, it is of interest to develop a structure-activity relationship (SAR) for each compound.</b></p> <p>This thesis details the investigation of synthetic routes to analogues of 1 and 2. Early steps of two proposed routes towards lactam analogues of 1 were explored, the first featuring a concise [2+2] cycloaddition and the second a Ferrier rearrangement. Both approaches showed promise, with the formation of compounds 3 and 5 as potential intermediates to achieving final analogue 4. A lactam motif is postulated to be more stable than the lactone of 1, whilst presenting opportunities for functionalisation at the nitrogen. </p> <p>Creating a diverse range of analogues of 2 is desirable to evaluate the potential of increasing the potency and selectivity of kinase inhibition. To this end, several routes to analogues of 2 were attempted, culminating in the synthesis of 7 and 8 as near-complete analogues (deprotection steps required) and 9–14 as final analogues. Several intermediates that may be used in the future to acquire further analogues were also synthesised. </p> <p>Future SAR studies of analogues related to this work will be informative in determining the influence of the introduced motifs on kinase inhibition.</p>