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A supply-impacting synthesis of clinical lead bryostatin 1 and the design, synthesis and evaluation of novel protein kinase C modulators as preclinical leads

Protein kinase C (PKC) modulators are currently in clinical or preclinical development for a wide range of diseases that represent major causes of mortality and morbidity worldwide. For example, the marine natural product bryostatin 1, a lead PKC modulator, is in clinical trials for HIV/AIDS eradication and Alzheimer's treatment, with a trial for its use in small molecule-enhanced CAR-T cell therapy slated for the near future. Preclinically, bryostatin 1 has been evaluated for its use in treating fragile X syndrome, multiple sclerosis, ischemic stroke and Charcot-Marie-Tooth disease, among others. Other highly active PKC modulating natural products under clinical or preclinical evaluation include the tigliane natural product prostratin and several ingenane natural products. While nature has provided bioactive compounds that, conveniently, offer solutions to hugely important problems of global health and wellness, these compounds and methods of obtaining them are by no means optimal for clinical use. Many of these natural products are extremely scarce and require one to process staggering quantities of host organism to access even milligram quantities of the natural product. This is well illustrated in the case of bryostatin 1, where 14 tons of its host organism -- a coastal marine sponge -- were processed to access only 18 grams of the natural product. Additionally, while these natural products are excellent clinical leads, nature has not optimized them for use in human medicine. These compounds can have narrow therapeutic windows, undesired on- and off-target toxicities, poor metabolic stability and problematic solubility properties. The work presented herein focuses on solving both problems presented above through design, synthesis and evaluation of natural product leads and derivatives thereof. This document should provide a clear example of the influence that synthetic chemistry can have in supporting and driving forward clinical research on some of the most challenging problems in human healthcare to-date.