| Description |
Bryostatin 1 is a highly complex marine natural product originally isolated by Pettit in the 1960s. Since its structural elucidation in 1982 bryostatin 1 has attracted considerable attention for the treatment of several human diseases such as cancer, HIV, and Alzheimer's. Bryostatin 1 exerts it effect by binding to and activating Protein Kinase C (PKC) isozymes with nanomolar affinity. Bryostatin 1 is unique among the many known activators in that it is nontumor promoting. Contrastingly, the Phorbal ester PMA, which shares the same binding pocket, is one of the most potent tumor promoters known. Despite intense medical interest, the development of bryostatin 1 as a therapeutic has been impeded by its extremely low natural abundance. To address this problem numerous groups have developed elegant syntheses of the natural bryostatins. Another and perhaps more attractive solution however is the synthesis of simplified bryostatin analogues. Towards this end the Keck group synthesized the analogue Merle 23, which in cell assays demonstrated either a PMA like response or a bryostatin like response depending on the cell line. This paradoxical behavior illustrates the complexity of PKC activation as therapeutic strategy, and Merle 23 provides a valuable tool for probing the subtle differences between tumor promoting and nontumor promoting PKC ligands. Described within is the scaled synthesis of Merle 23 and it use for further probing the biological consequence of PKC activation at the transcriptional level. Merle 23 as well as two less lipophilic analogues Merle 35 and Merle 37 are also shown to be potent activators of latent HIV reservoirs. Central to the Keck group's analogue work is identifying strategies by which the synthetic burden can be reduced. In order to simplify the synthesis of new analogues the use of simple aromatic building blocks as surrogates for the A and B ring pyrans was explored. Using phenyl rings to replace the pyrans resulted in an analogue that failed to maintain high affinity binding in spite of it still containing all of the elements previously believed to be responsible for binding. |
