Computer-Guided Design, Synthesis, and Protein Kinase C Affinity of a New Salicylate-Based Class of Bryostatin Analogs

ABSTRACT: Bryostatin 1 is in clinical trials for the treatment of cancer and Alzheimer’s disease and is a candidate for a first-in-class approach to HIV/AIDS eradication. It is neither readily available nor optimally suited for clinical use. Using a function oriented synthesis strategy, a new class of bryostatin-inspired analogs was designed with a simplified salicylate-derived subunit, enabling step-economical synthesis (23 total steps) of agents exhibiting bryostatin-like affinity to protein kinase C (PKC). The bryostatins are a family of 20 macrolide natural productsisolated from the marine bryozoan Bugula neritina.1 Extracts from these animals displayed marked antineoplastic activity when first tested against murine leukemia in the late 1960s by Pettit et al.2 The structure of bryostatin 1, the biologically active constituent, was subsequently reported in 1982 (Figure 1).3 Numerous investigations have since sought to explore the therapeutic potential of this highly potent agent