Synthesis of bis-gamma-butyrolactones containing conformationally constrained (S)- and (R)-diacylglycerol structures.
The synthesis of two sets of rigid diacylglycerol (DAG) analogues with either the (S)-DAG or (R)-DAG enantiomer embedded into a bis-gamma-butyrolactone template was accomplished stereoselectively from di-O-isopropylidene-alpha-D-apiose. The key step in both syntheses was the assemblage of the bicyclic perhydrofuro[3,4-b]furan ring system via a radical exo-dig intramolecular cyclization. A lipophilic undecanyl alkyl chain attached at C-3 of the fully assembled perhydrofuro[3,4-b]furan-2,4-dione (bis-gamma-butyrolactone) template can adopt two orientations with the one directed away from the concave face of the bicyclic system favored by a 4 to 1 ratio in each case. Evaluation of the final target pairs of enantiomers as PK-C alpha ligands revealed that the template containing an embedded (R)-DAG structure was more effective. The difference in binding affinity was also modulated by the direction of the alkyl chain.
Lee
J
J
Laboratory of Medicinal Chemistry, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Lewin
N E
NE
Blumberg
P M
PM
Marquez
V E
VE
D015107:4-Butyrolactone / Q000737:chemistry*; D004075:Diglycerides / Q000737:chemistry*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015240:Phorbol 12,13-Dibutyrate / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D013237:Stereoisomerism
D004075:Diglycerides; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D015107:4-Butyrolactone