Conformationally constrained analogues of diacylglycerol. 29. Cells sort diacylglycerol-lactone chemical zip codes to produce diverse and selective biological activities Journal Article
| Authors: | Duan, D.; Sigano, D. M.; Kelley, J. A.; Lai, C. C.; Lewin, N. E.; Kedei, N.; Peach, M. L.; Lee, J.; Abeyweera, T. P.; Rotenberg, S. A.; Kim, H.; Young, H. K.; El Kazzouli, S.; Chung, J. U.; Young, H. A.; Young, M. R.; Baker, A.; Colburn, N. H.; Haimovitz-Friedman, A.; Truman, J. P.; Parrish, D. A.; Deschamps, J. R.; Perry, N. A.; Surawski, R. J.; Blumberg, P. M.; Marquez, V. E. |
| Article Title: | Conformationally constrained analogues of diacylglycerol. 29. Cells sort diacylglycerol-lactone chemical zip codes to produce diverse and selective biological activities |
| 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 PKCα to varying degrees, expand their biological repertoire into a larger domain, eliciting distinct cellular responses. © 2008 American Chemical Society. |
| Keywords: | controlled study; unclassified drug; human cell; nonhuman; protein domain; mouse; animal experiment; animal model; protein binding; small molecule libraries; drug synthesis; structure-activity relationship; chemistry; biological activity; drug mechanism; cell membrane; cellular distribution; protein kinase c; binding sites; cell organelle; molecular conformation; diacylglycerol; combinatorial chemistry techniques; diglycerides; protein kinase c alpha; diacylglycerol derivative; protein kinase c-alpha; lactones; protein lipid interaction; isoenzyme; chemical composition; lactone; [2 (hydroxymethyl) 5 oxo 4 [[4 (trifluoromethyl)phenyl]methylene] 2 2,3 dihydrofuryl]methyl 2 propylpentanoate; [4 [(4 fluorophenyl)methylene] 2 (hydroxymethyl) 5 oxo 2 2,3 dihydrofuryl]methyl 2 propylpentanoate |
| Journal Title: | Journal of Medicinal Chemistry |
| Volume: | 51 |
| Issue: | 17 |
| ISSN: | 0022-2623 |
| Publisher: | American Chemical Society |
| Date Published: | 2008-09-11 |
| Start Page: | 5198 |
| End Page: | 5220 |
| Language: | English |
| DOI: | 10.1021/jm8001907 |
| PUBMED: | 18698758 |
| PROVIDER: | scopus |
| PMCID: | PMC2574997 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 10" - "Export Date: 17 November 2011" - "CODEN: JMCMA" - "Source: Scopus" |
