1056463-07-0Relevant academic research and scientific papers
α-Arylidene Diacylglycerol-Lactones (DAG-Lactones) as Selective Ras Guanine-Releasing Protein 3 (RasGRP3) Ligands
Ann, Jihyae,Czikora, Agnes,Saini, Amandeep S.,Zhou, Xiaoling,Mitchell, Gary A.,Lewin, Nancy E.,Peach, Megan L.,Blumberg, Peter M.,Lee, Jeewoo
, p. 6261 - 6276 (2018/06/11)
Diacylglycerol-lactones have proven to be a powerful template for the design of potent ligands targeting C1 domains, the recognition motif for the cellular second messenger diacylglycerol. A major objective has been to better understand the structure activity relations distinguishing the seven families of signaling proteins that contain such domains, of which the protein kinase C (PKC) and RasGRP families are of particular interest. Here, we synthesize a series of aryl- and alkyl-substituted diacylglycerol-lactones and probe their relative selectivities for RasGRP3 versus PKC. Compound 96 showed 73-fold selectivity relative to PKCα and 45-fold selectivity relative to PKC? for in vitro binding activity. Likewise, in intact cells, compound 96 induced Ras activation, a downstream response to RasGRP stimulation, with 8-29 fold selectivity relative to PKCδ S299 phosphorylation, a measure of PKCδ stimulation.
Conformationally constrained analogues of diacylglycerol. 30. An investigation of diacylglycerol-lactones containing heteroaryl groups reveals compounds with high selectivity for ras guanyl nucleotide-releasing proteins
Kazzouli, Sa?d El,Lewin, Nancy E.,Blumberg, Peter M.,Marquez, Victor E.
experimental part, p. 5371 - 5386 (2009/07/01)
Using a diacylglycerol-lactone (DAG-lactone) template previously developed in our laboratory as a scaffold with high binding affinity for C1 domains, we describe herein a series of novel DAG-lactones containing heterocyclic moieties (pyridines, quinolines, and indoles) as α-arylidene fragments. Some of the DAG-lactones obtained show selective binding to RasGRP3 as compared to PKCα by more than 2 orders of magnitude and possess subnanomolar affinities. Because activated C1 domains bound to their ligands (DAG or DAG-lactones) insert into membranes, the lipid composition of membranes (cellular, nuclear, and those of internal organelles) is an important determinant for specificity. Therefore, reaching a proper hydrophilic/lipophilic balance for these molecules is critical. This was achieved by carefully selecting partnering acyl fragments for the DAG-lactones with the appropriate lipophilicity. The results clearly show that the combination of chemical and physical properties in these molecules needs to be perfectly balanced to achieve the desired specificity.
