Conformationally constrained analogues of diacylglycerol. 13. Protein kinase C ligands based on templates derived from 2,3-dideoxy-L-erythro(threo)-hexono-1,4-lactone and 2-deoxyapiolactone.
In the present investigation, the last two possible modes of generating conformationally semirigid diacylglycerol (DAG) analogues embedded into five-membered ring lactones as templates III and IV are investigated. The first two templates studied in previous investigations corresponded to 2-deoxyribonolactone (template I) and 4,4-disubstituted gamma-butyrolactone (template II), with the latter producing potent protein kinase C (PK-C) ligands with low nanomolar binding affinities. The templates reported in this work correspond to 2,3-dideoxy-L-erythro- or -threo-hexono-1,4-lactone (template III) and 2-deoxyapiolactone (template IV). Compounds constructed with the dideoxy-L-erythro- or -threo-hexono-1,4-lactone template were synthesized stereospecifically from tri-O-acetyl-L-glucal and L-galactono-1,4-lactone, respectively. Compounds constructed with the 2-deoxyapiolactone template were synthesized stereoselectively from di-O-isopropylidene-alpha-D-apiose. Inhibition of the binding of [3H]phorbol-12,13-dibutyrate to PK-C alpha showed that only the threo-isomer, 5-O-tetradecanoyl-2,3-dideoxy-L-threo-hexono-1,4-lactone (2) was a good PK-C ligand (Ki = 1 microM). The rest of the ligands had poorer affinities with Ki values between 10 and 28 microM. With these results, the order of importance of five-membered ring lactones as competent templates for the construction of semirigid DAG surrogates with effective PK-C binding affinity can be established as II >> I approximately III > IV.
Lee
J
J
Laboratory of Medicinal Chemistry, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Lewin
N E
NE
Acs
P
P
Blumberg
P M
PM
Marquez
V E
VE
D004075:Diglycerides / Q000737:chemistry / Q000378:metabolism*; D006601:Hexoses / Q000737:chemistry*; D007783:Lactones / Q000737:chemistry*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010429:Pentoses / Q000737:chemistry*; D011493:Protein Kinase C / Q000378:metabolism*
C103083:2,3-dideoxyhexono-1,4-lactone; C103082:2-deoxyapiolactone; D004075:Diglycerides; D006601:Hexoses; D007783:Lactones; D008024:Ligands; D010429:Pentoses; D011493:Protein Kinase C