Synthetic and structure-function studies on bryostatin analogs

Bryostatin 1 is a member of a family of marine natural products isolated from Bugula neritina. Bryostatin 1 has shown a variety of potent biological activities and is currently being evaluated as an oncolytic agent in human clinical trials. However, the scarcity of this potential therapeutic, and consequently the limited ability to explore the structure activity relationships of bryostatin 1, has prompted the design and synthesis of bryostatin 1 analogs. These analogs retain or demonstrate greater potency than bryostatin 1 and are accessible by organic synthesis.; The chemical yield for the synthesis of a fragment of one of the lead bryostatin 1 analogs was increased from 0.23% to 7.8% and the step count was reduced from 14 steps to 11 steps. The synthesis of four new analogs was also accomplished. An analog, structurally simplified by deletion of the A ring and the C26 methyl, was synthesized. This new des-A ring analog demonstrated nearly a 6-fold increase in affinity for PKC compared to a des-A ring analog with a secondary C26 hydroxyl.; An analog of the A ring was synthesized in a convergent fashion by deletion of the A ring and making the C5-C9 linkage an amide. The use of an amide linkage at this position introduced a point of convergency to the synthesis of A ring amide analogs, allowing the facile synthesis of new analogs from commercially available amino alcohols. While this new analog did not demonstrate the desired affinity for PKC, it did provide a modular approach to structurally simplified analogs of the A ring.; An analog of the A ring was synthesized with an aryl bromide installed to allow for the late stage diversification of the completed analog. This analog was shown to be as potent a binder of PKC as bryostatin 1. The aryl bromide was successfully used to install a phenyl group on the completed analog, demonstrating the ability to use this functionality for late stage diversification, as well as generating a new analog in a single transformation. The biphenyl analog was also shown to be as potent a binder of PKC as bryostatin 1.