Function oriented synthesis: the design, synthesis, PKC binding and translocation activity of a new bryostatin analog.
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.
Wender
Paul A
PA
Department of Chemistry, Stanford University, Stanford, CA 94305, USA. wenderp@stanford.edu
Baryza
Jeremy L
JL
Brenner
Stacey E
SE
Clarke
Michael O
MO
Craske
Madeleine L
ML
Horan
Joshua C
JC
Meyer
Tobias
T
D000818:Animals; D054713:Bryostatins; D045744:Cell Line, Tumor; D015195:Drug Design; D007091:Image Processing, Computer-Assisted; D007202:Indicators and Reagents; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D015471:Leukemia, Basophilic, Acute / Q000188:drug therapy / Q000378:metabolism; D018942:Macrolides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D011485:Protein Binding; D011493:Protein Kinase C / Q000737:chemistry / Q000378:metabolism*; D051381:Rats
D054713:Bryostatins; D007202:Indicators and Reagents; D007527:Isoenzymes; D018942:Macrolides; C046785:bryostatin 1; D011493:Protein Kinase C