Supply impacting synthesis of bryostatin 1 and the design, synthesis, and evaluation of bryostatin 1 analogs

The marine derived natural product bryostatin 1 has been investigated in preclinical studies for a wide range of indications (cancer, Alzheimer's disease, HIV/AIDS eradication, multiple sclerosis, fragile X syndrome, and others). Bryostatin 1 has been evaluated in more than 40 clinical trials for three of these highly impactful indications: cancer, Alzheimer's disease, and HIV eradication. The trials in Alzheimer's disease and the eradication of HIV are ongoing, and there is a planned trial in which bryostatin 1 will act as an adjuvant to enhance CAR T cell therapy used to treat cancer. Unfortunately, the isolation of bryostatin 1 from its source organism is not economically or environmentally sustainable, placing the supply of bryostatin 1 for clinical evaluation in jeopardy. Additionally, although bryostatin 1 has impressive biologic activity, it was not evolved for human use. Bryostatin 1 has been heavily studied, but significantly less preclinical evaluation has been performed on designed bryostatin 1 analogs. These analogs have the potential to be more efficacious and have fewer off target side effects relative to the parent natural product. Prior research indicates that the putative pathway for the activity of bryostatin 1 is exogenous regulation of protein kinase C (PKC) activity. The PKC family of enzymes plays a central and complex role in both normal and diseased states. Structurally different PKC modulators have exhibited drastically different biologic activities. Further understanding how the subtle structural elements of the bryostatin 1 scaffold affect its multiple PKC mediated activities, potentially through isoform specificity or differential protein ligand orientation, could aid in the development of analog compounds with improved functional activity. This thesis details of the collaborative team effort to solve the bryostatin 1 supply problem through a step-economical and scalable total synthesis (19 longest linear sequence, 29 total steps, 4.8% yield). To reduce the number of steps in the longest linear sequence, this total synthesis convergently constructs bryostatin 1 by bringing together two similarly complex fragments late in the synthesis. This thesis focuses on the synthetic route to one of those fragments, the C-ring fragment, and the final steps in the total synthesis of bryostatin 1. The scalable nature of the bryostatin 1 total synthesis provided access to unprecedented amounts of highly complex intermediates with many of the key structural features of bryostatin 1. This thesis also describes how those intermediates were leveraged to produce a library of "close-in" analogs to bryostatin 1. These analogs were used to test hypotheses about which molecular interactions between bryostatin 1, PKC, and cellular membranes contribute to the amazing phenotypic activity of bryostatin 1. A subset of these bryostatin 1 analogs have been advanced to more complex functional assays to determine if the analogs have superior efficacy or tolerability relative to bryostatin 1.

Keywords: Chemistry.
Advisor: Wender Paul A. 
Burns Noah
Du Bois Justin