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.

Journal of Medicinal Chemistry
Said El KazzouliVictor E Marquez

Abstract

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.

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Citations

Feb 4, 2012·Molecular BioSystems·Narsimha MamidiDebasis Manna
Feb 22, 2012·The Journal of Biological Chemistry·Tamas GeczyPeter M Blumberg
Aug 12, 2014·Chemical & Pharmaceutical Bulletin·Nami OhashiHirokazu Tamamura
May 5, 2011·Chembiochem : a European Journal of Chemical Biology·Noemi KedeiPeter M Blumberg
May 20, 2017·Pharmaceuticals·Marta RuiSimona Collina
Nov 7, 2014·Chemical Reviews·Joydip Das, Ghazi M Rahman
Jul 20, 2021·Journal of Medicinal Chemistry·Eleonora ElhalemMaría J Comin

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