Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity

Abstract

Modern methods for the identification of therapeutic leads include chemical or virtual screening of compound libraries. Nature's library represents a vast and diverse source of leads, often exhibiting exquisite biological activities. However, the advancement of natural product leads into the clinic is often impeded by their scarcity, complexity, and nonoptimal properties or efficacy as well as the challenges associated with their synthesis or modification. Function-oriented synthesis represents a strategy to address these issues through the design of simpler and therefore synthetically more accessible analogs that incorporate the activity-determining features of the natural product leads. This study illustrates the application of this strategy to the design and synthesis of functional analogs of the bryostatin marine natural products. It is specifically directed at exploring the activity-determining role of bryostatin A-ring functionality on PKC affinity and selectivity. The resultant functional analogs, which were prepared by a flexible, modular synthetic strategy, exhibit excellent affinity to PKC and differential isoform selectivity. These and related studies provide the basic information needed for the design of simplified and thus synthetically more accessible functional analogs that target PKC isoforms, major targets of therapeutic interest.

Histone Deacetylase Inhibitors (HDACis) That Release the Positive Transcription Elongation Factor b (P-TEFb) from Its Inhibitory Complex Also Activate HIV Transcription

“…Thus, we wanted to determine whether combinations of PKC agonists and HDACis could reactivate HIV transcription in resting CD4 ϩ T cells. First we examined whether bryostatin 1, a known PKC agonist (48,49), can increase levels of P-TEFb in resting CD4 ϩ T cells, which were isolated from anonymous uninfected donors, activated, and allowed to return to a resting state in limiting amounts of IL-2 over 2 weeks. The resting state of the cells was verified by detection of low levels of CD69 and HLA-DR by FACS (data not presented).…”

Bryostatin-1 Restores Hippocampal Synapses and Spatial Learning and Memory in Adult Fragile X Mice

“…Bryostatin-1 has a much lower ED 50 for inducing PKC« translocation than its ED 50 s for PKCa or PKCd (Szallasi et al, 1994). The structural features of the bryostatins have been well defined by leading experts in function-oriented synthesis (Wender et al, 1988(Wender et al, , 2011. Bryostatin-1-like agents may represent a novel class of drugs for treating FXS.…”

Target- and Mechanism-Based Therapeutics for Neurodegenerative Diseases: Strength in Numbers

“…280 The known PKC activator bryostatin ( 90 ) promotes sAPP-α-secretase at sub-nanomolar levels; 281 analogue construction to refine pharmacological properties has garnered a great deal of attention in the literature. 282 …”