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.
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 alpha-arylidene fragments. Some of the DAG-lactones obtained show selective binding to RasGRP3 as compared to PKCalpha 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.
El Kazzouli
Saïd
S
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, 376 Boyles Street, Frederick, Maryland 21702, USA.
Lewin
Nancy E
NE
Blumberg
Peter M
PM
Marquez
Victor E
VE
D002463:Cell Membrane Permeability; D004075:Diglycerides / Q000737:chemistry*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006571:Heterocyclic Compounds; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007783:Lactones / Q000737:chemistry*; D008968:Molecular Conformation; D011485:Protein Binding; D051571:Protein Kinase C-alpha / Q000378:metabolism; D020663:ras Guanine Nucleotide Exchange Factors
C011439:1,2-diacylglycerol; D004075:Diglycerides; D020662:Guanine Nucleotide Exchange Factors; D006571:Heterocyclic Compounds; D007783:Lactones; C413212:RASGRP3 protein, human; D020663:ras Guanine Nucleotide Exchange Factors; D051571:Protein Kinase C-alpha