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.

[摘要]：developed in our lab. as a scaffold with high binding affinity for C1 domains, we describe herein a series of novel DAG-lactones contg. heterocyclic moieties (pyridines, quinolines, and indoles) as a-arylidene fragments. Some of the DAG-lactones obtained show selective binding to RasGRP3 as compared to PKCa by more than 2 orders of magnitude and possess subnanomolar affinities. Because insert into membranes, the lipid compn. of membranes (cellular, nuclear, and those of internal organelles) is an important determinant for specificity. Therefore, reaching a proper hydrophilic/lipophilic balance for these mols. is crit. 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 chem. and phys. properties in these mols. needs to be perfectly balanced to achieve the desired specificity.

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