Conformationally constrained diacylglycerol (DAG) analogs: 4-C-hydroxyethyl-5-O-acyl-2,3-dideoxy-D-glyceropentono-1,4-lactone analogs as protein kinase C (PKC) ligands.
The (R)-DAG-lactones (5 and 7E/Z) are conformationally constrained diacylglycerol (DAG) analogs with high potency as protein kinase C (PKC) ligands. Here, we have prepared and characterized their one-carbon lengthened analogs (6 and 8E/Z). The target compounds were synthesized from 1,2-O-isopropylidene D-xylose through a key intermediate, 4-C-hydroxyethyl-2,3-dideoxy-D-glyceropentono-1,4-lactone (13); they were evaluated as competitive ligands to displace bound [(3)H]phorbol 12,13-dibutyrate (PDBU) from a recombinant single isozyme (PKC-alpha). The binding affinities of the synthesized compounds were K(i) = 2.623 microM for 6, K(i) = 1.080 microM for 8Z and K(i) = 0.92 microM for 8E, which were ca. 27, 90, and 70 times less potent than the corresponding parent compounds (5, 7Z and 7E). Molecular modeling indicated that the reduced binding affinity of the representative 3-alkylidene lactone 8Z, as compared to 7Z, may be explained by its poor fit in the sn-1 binding mode as well as by its entropic loss due to the relatively flexible hydroxyethyl group.
Lee
Jeewoo
J
Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Ku, Seoul 151-742, South Korea. jeewoo@snu.ac.kr
Kim
Su Yeon
SY
Kang
Ji-Hye
JH
Acs
Geza
G
Acs
Peter
P
Blumberg
Peter M
PM
Marquez
Victor E
VE
D001667:Binding, Competitive / Q000187:drug effects; D004075:Diglycerides / Q000138:chemical synthesis / Q000737:chemistry*; D007527:Isoenzymes / Q000737:chemistry / Q000187:drug effects; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011493:Protein Kinase C / Q000737:chemistry* / Q000187:drug effects; D051571:Protein Kinase C-alpha
D004075:Diglycerides; D007527:Isoenzymes; D007783:Lactones; D008024:Ligands; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha