Conformationally Constrained Analogues of Diacylglycerol (DAG). 17. Contrast between sn-1 and sn-2 DAG Lactones in Binding to Protein Kinase C

Abstract

In previous work, we have obtained potent protein kinase C (PK-C) ligands with low-namomolar binding affinities by constructing diacylglycerol (DAG) mimetics in which the sn-2 carbonyl of DAG was constrained into a lactone ring. An additional structural element that helped achieve high binding affinity was the presence of branched acyl or alpha-alkylidene chains. In the present study, the effects of similarly branched chains on a different lactone system, where the lactone carbonyl is now equivalent to the sn-1 carbonyl of DAG, are investigated. In this new lactone template, the two chiral centers must have the S-configuration for enzyme recognition. As with the sn-2 DAG lactones, the branched chains were designed to optimize van der Waals contacts with a group of conserved hydrophobic amino acids located on the rim of the C1 domain of PK-C. The acyl and alpha-alkylidene chains were also designed to be lipophilically equivalent (8 carbons each). Eight new compounds (7-14) representing all possible combinations of linear and branched acyl and alpha-alkylidene were synthesized and evaluated. The sn-1 DAG lactones were less effective as PK-C ligands than the sn-2 DAG lactones despite having a similar array of linear or branched acyl and alpha-alkylidene chains

Synthetic Caged DAG‐lactones for Photochemically Controlled Activation of Protein Kinase C

“…Despite the complex regulatory mechanisms of PKC activation, considerable progress in understanding isozyme‐specific functions has been made 8. Development of ligands with high specificities for PKC isozymes has been a critical issue in the medicinal field 9a–b. Enhancement of the understanding of targets and signaling pathways would provide important insights contributing to this effort.…”

Screening for Protein Kinase C Ligands Using Fluorescence Resonance Energy Transfer

“…DAG-γ-lactone derivatives have been used as racemic compounds. 14,[23][24][25] The C1b domain, residues 231 to 281 of PKCδ, was used as an acceptor molecule. Val235 was selected as the position to be labeled with fluorescein based on the following rationale: Since Val235 is located in the solvent accessible area, it is presumed that the labeled fluorescein would not disturb folding of the C1b domain (PDB ID: 1PTR).…”

Synthesis of sulfur-containing glycerophospholipids

“…Acetalization of the vicinal diol component of 11, affording 13, permitted selective methylation of the side chain alcohol. After deacetalization [40], the resulting diol (14) could be developed into lipid 12 in accordance with scheme 1. SCHEME 2 Downloaded by [The University of Manchester Library] at 02: 25 12 October 2014 SCHEME 3…”

“…Kucera et al [80] developed conditions for the selective and efficient preparation of 1-S-oleyl-2-O-oleylglycerol (50) from 2 through consecutive S-acylation, sn-3-protection, sn-2-acylation and then deprotection (scheme 14). No attempt was made towards purification until sn-2-acylation, after which the product, 3-O-dimethoxytrityl-1-S-oleyl-2-O-oleylglycerol (51), could be isolated in respectable 73% from 2 [80].…”

“…A growing interest in the synthesis of new phospholipids has been bolstered by applications in membrane engineering [9,10], the pursuit of vehicles suitable for introducing photodegradable molecules into membranes [11], and by a general ambition to surpass the bioactivity of natural compounds [12][13][14][15][16]. Sulfur-containing glycerophospholipids and phosphonolipids are important among the collection of synthetic glycerolipids.…”