title: Cyclohexane diester analogues of phorbol ester as potential activators of protein kinase C.
abstract: Phospholipid-dependent, Ca2(+)-sensitive protein kinase (protein kinase C) is activated by the plant product phorbol ester at nanomolar concentrations and also in vivo at micromolar concentrations by diacylglycerols. We designed and synthesized cyclohexane diester analogues of the phorbol ester C ring as potential high-affinity activators of protein kinase C. We proposed that the necessary pharmacophore of phorbol ester could be mimicked by diesters of appropriately substituted cyclohexanediols. A series of 1,2-cyclohexanediol diesters with different substituents at position 4 was synthesized. These substituents were designed to mimic the 6,7-double bond and C-20 hydroxy of phorbol ester. Competitive binding vs [3H]phorbol dibutyrate determined that these compounds have an affinity for protein kinase C of 1 mM or more, and thus they do not bind to nor are they activators of this enzyme.
authors.affiliation: Oncogen, Seattle, Washington 98121.
authors.forename: D E
authors.initials: DE
authors.lastname: Kerr
authors.forename: L F
authors.initials: LF
authors.lastname: Kissinger
authors.forename: M
authors.initials: M
authors.lastname: Shoyab
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000494:pharmacology; D004789:Enzyme Activation; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D015240:Phorbol 12,13-Dibutyrate / Q000378:metabolism; D010703:Phorbol Esters / Q000138:chemical synthesis* / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D011955:Receptors, Drug / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D003510:Cyclohexanes; D007202:Indicators and Reagents; D010703:Phorbol Esters; D011955:Receptors, Drug; C083141:phorbol ester binding protein; C027776:phorbol ester receptor; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C