| Description |
Bryostatin 1 is a complex marine natural product isolated from bryozoan Bugula neritina by Pettit and coworkers. In recent years, bryostatin 1 has attracted a considerable amount of interest due to its biological activity towards a number of human diseases, including cancer, HIV, and Alzheimer's. Bryostatin 1's unique biological activity is thought to be due to binding and activating Protein Kinase C (PKC) isozymes with nanomolar affinity. Bryostatin 1 is unique compared to most PKC activators such as the phorbol ester in that it is non-tumor promoting. Despite its unique biological activity, the limited supply of bryostatin 1 impedes its use as a therapeutic agent. Numerous groups have tried to solve this problem through elegant syntheses of the natural bryostatins as well as structurally simplified analogues. Our group has focused primarily on a systematic approach to A,B-ring analogues, where the highly functionalized C-ring is consistant. Described herein are the synthetic efforts towards a C20 deoxygenated bryostatin analogue. This C20 deoxygenated analogue would provide a compliment to our earlier analogue Merle 24 and 25 as well as providing a direct evaluation of the C20 position with respects to its role in binding affinity and biological potency. To continue our goal of simplifying the synthesis of bryostatin analogues, phenyl rings were used as surrogates for the A,B pyran rings in Merle 40. Merle 40 displayed significantly lower binding affinity for PKC and thus, limited biological activity. Even though Merle 40 is not a good ligand, it does give us a platform for further analogue design. The poor binding affinity is thought to come from the loss of the internal hydrogen bonding network present in the natural bryostatins. The synthetic effort towards a series of aromatic analogues that systematically reinstalls the hydrogen bonding network while evaluating if aromatic rings can be used as a surrogate for the A,B-rings is described herein. |
