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

Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):6721-6. doi: 10.1073/pnas.1015270108. Epub 2011 Mar 17.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bryostatins / chemical synthesis
  • Bryostatins / chemistry
  • Bryostatins / pharmacology
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Drug Delivery Systems / methods
  • Drug Design*
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Mice
  • NIH 3T3 Cells
  • Protein Kinase C / antagonists & inhibitors*
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • Protein Kinase Inhibitors* / chemical synthesis
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Protein Transport / drug effects
  • Protein Transport / genetics


  • Bryostatins
  • Isoenzymes
  • Protein Kinase Inhibitors
  • Protein Kinase C