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 (Ki = 8.0 nM). More significantly, the described molecule retains the functional ability to translocate a PKCδ-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.
Keywords: Bryostatin, Pharmacophore, RBL cells
Current Drug Discovery Technologies
Title: Function Oriented Synthesis: The Design, Synthesis, PKC Binding and Translocation Activity of a New Bryostatin Analog
Volume: 1 Issue: 1
Author(s): Paul A. Wender, Jeremy L. Baryza, Stacey E. Brenner, Michael O. Clarke, Madeleine L. Craske, Joshua C. Horan and Tobias Meyer
Affiliation:
Keywords: Bryostatin, Pharmacophore, RBL cells
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 (Ki = 8.0 nM). More significantly, the described molecule retains the functional ability to translocate a PKCδ-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.
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Cite this article as:
Wender A. Paul, Baryza L. Jeremy, Brenner E. Stacey, Clarke O. Michael, Craske L. Madeleine, Horan C. Joshua and Meyer Tobias, Function Oriented Synthesis: The Design, Synthesis, PKC Binding and Translocation Activity of a New Bryostatin Analog, Current Drug Discovery Technologies 2004; 1 (1) . https://dx.doi.org/10.2174/1570163043484888
DOI https://dx.doi.org/10.2174/1570163043484888 |
Print ISSN 1570-1638 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6220 |
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