Scalable total synthesis of bryostatin 1 enables the design, synthesis, and biological evaluation of bryostatin analogs

Bryostatin 1 is a natural product that was originally isolated from the marine sponge Bugula neritina more than 50 years ago. Following its isolation, it has demonstrated unprecedented clinical potential across a number of indications, including HIV/AIDS eradication, the treatment of Alzheimer's disease and neurological disorders, and cancer immunotherapy. Despite this unique portfolio of indications, the natural supply of bryostatin 1 from its source organism is limited and variable and maintaining a consistent supply of the natural product has hindered its clinical advancement. To enable the continued clinical evaluation of bryostatin 1, we developed a scalable total synthesis of the natural product that can sustainably supply future clinical studies of this exciting clinical candidate. Despite its promising activity, bryostatin 1 is a marine natural product that is neither evolved nor optimized for the treatment of human disease. Historically, the scarcity of isolated material and the challenges associated with making modifications of the delicate and densely functionalized bryostatin skeleton have precluded efforts to optimize the biological activity of this natural product lead through derivatization and exploration of structure-activity relationships (SAR) around the macrocycle. Drawing on the synthetic platform we developed in our scalable synthesis of bryostatin 1, we accomplished the design, synthesis, and biological evaluation of the first close-in analogs of bryostatin 1. Using a function-oriented synthesis (FOS) strategy informed by a combination of computational and biological data surrounding bryostatin's interaction with its protein target, protein kinase C (PKC), we synthesized a series of bryostatin analogs designed to maintain PKC affinity while allowing for a systematic investigation of their biological function. By leveraging the modularity of our bryostatin 1 synthesis, we developed complementary late-stage diversification strategies that provide efficient synthetic access to parallel series of bryostatin analogs with modifications in the A- and B-rings. In agreement with our pharmacophore model, these new agents retain affinity for PKC but exhibit variable PKC translocation kinetics. We further demonstrate that select analogs potently induce increased cell surface expression of CD22, a promising target for the treatment of leukemias and lymphomas, in in vitro models of acute lymphoblastic leukemia (ALL) and AIDS-related lymphomas, highlighting the potential general use of bryostatin and bryostatin analogs for enhancing antigen-targeted cancer immunotherapies. Finally, bryostatin 1 has been shown to prevent progressive neurodegeneration in a mouse model of multiple sclerosis (MS). Working with Professors Paul Kim and Michael Kornberg at Johns Hopkins, we show that several bryostatin analogs replicate the anti-inflammatory effects of bryostatin 1 on innate immune cells in vitro and lead analog SUW133 attenuates neuroinflammation and prevents the development of MS-related neurological deficits in vivo. We further demonstrate that this activity is dependent on PKC. These findings identify bryostatin analogs as promising drug candidates for targeting innate immunity in neuroinflammation and create a platform for evaluation of synthetic PKC modulators for the treatment of MS and other neuroinflammatory diseases

Keywords: Chemistry.
Advisor: Wender Paul A.
Bertozzi Carolyn R.
Burns Noah