Function oriented synthesis: the design, synthesis, PKC binding and translocation activity of a new bryostatin analog.

Paul A. Wender, Jeremy L. Baryza, Stacey E. Brenner, Michael O. Clarke, Madeleine L. Craske, Joshua C. Horan, Tobias Meyer

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

Bryostatin 1 represents a novel and potent therapeutic lead with a unique activity profile. Its natural and synthetic availability is severely limited. Function oriented synthesis provides a means to address this supply problem through the design of synthetically more accessible simplified structures that at the same time incorporate improved functional activity. Pharmacophore searching and a new computer aided visualization of a possible binding mode are combined with an understanding of function and knowledge of synthesis to design and prepare a new and simplified compound with bryostatin-like function in biological systems. This new compound is a potent ligand for protein kinase C in vitro (K(i) = 8.0 nM). More significantly, the described molecule retains the functional ability to translocate a PKCdelta-GFP fusion protein in RBL cells. The extent of protein translocation and the sub-cellular localization induced by this new compound is similar to that seen in response to bryostatin 1, indicating that the new molecule retains the functional activity of the natural product but is simpler and can be synthesized in a practical fashion.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalCurrent drug discovery technologies
Volume1
Issue number1
DOIs
StatePublished - Jan 2004
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Drug Discovery

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