1. Conformationally Constrained Analogues of Diacylglycerol. 29. Cells Sort Diacylglycerol-Lactone Chemical Zip Codes to Produce Diverse and Selective Biological Activities
- Author
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Jeewoo Lee, Thushara P. Abeyweera, Damon Parrish, Alyson R. Baker, Robert J. Surawski, Matthew R. Young, Jean-Philip Truman, Nancy H. Colburn, Adriana Haimovitz-Friedman, Hee Kim, Young Ho Kim, Victor E. Marquez, Dehui Duan, Peter M. Blumberg, Nicholas A. Perry, Howard A. Young, Nancy E. Lewin, Jeffrey R. Deschamps, Noemi Kedei, Jae-Uk Chung, Megan L. Peach, James A. Kelley, Saïd El Kazzouli, Christopher C. Lai, Dina M. Sigano, and Susan A. Rotenberg
- Subjects
Binding Sites ,Protein Kinase C-alpha ,Chemical Phenomena ,Chemistry ,Molecular Conformation ,Small Molecule Libraries ,Biological activity ,Plasma protein binding ,Article ,Chemical space ,Diglycerides ,Lactones ,Structure-Activity Relationship ,Biochemistry ,Drug Discovery ,Combinatorial Chemistry Techniques ,Humans ,Molecular Medicine ,Structure–activity relationship ,Binding site ,Protein kinase C ,Protein Binding ,Diacylglycerol kinase - Abstract
Diacylglycerol-lactone (DAG-lactone) libraries generated by a solid-phase approach using IRORI technology produced a variety of unique biological activities. Subtle differences in chemical diversity in two areas of the molecule, the combination of which generates what we have termed "chemical zip codes", are able to transform a relatively small chemical space into a larger universe of biological activities, as membrane-containing organelles within the cell appear to be able to decode these "chemical zip codes". It is postulated that after binding to protein kinase C (PKC) isozymes or other nonkinase target proteins that contain diacylglycerol responsive, membrane interacting domains (C1 domains), the resulting complexes are directed to diverse intracellular sites where different sets of substrates are accessed. Multiple cellular bioassays show that DAG-lactones, which bind in vitro to PKCalpha to varying degrees, expand their biological repertoire into a larger domain, eliciting distinct cellular responses.
- Published
- 2008