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

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.

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.

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.

Future SAR studies of analogues related to this work will be informative in determining the influence of the introduced motifs on kinase inhibition.