Conformationally constrained analogues of diacylglycerol. 18. The incorporation of a hydroxamate moiety into diacylglycerol-lactones reduces lipophilicity and helps discriminate between sn-1 and sn-2 binding modes to protein kinase C (PK-C). Implications for isozyme specificity.
An approach to reduce the log P in a series of diacylglycerol (DAG)-lactones known for their high binding affinity for protein kinase C (PK-C) is presented. Branched alkyl groups with reduced lipophilicity were selected and combined with the replacement of the ester or lactone oxygens by NH or NOH groups. Compound 6a with an isosteric N-hydroxyl amide arm represents the most potent and least lipophilic DAG analogue known to date.
Lee
J
J
Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Shinlin Dong, Kwanak-ku, Seoul 151-742, South Korea. jeewoo@snu.ac.kr
Han
K C
KC
Kang
J H
JH
Pearce
L L
LL
Lewin
N E
NE
Yan
S
S
Benzaria
S
S
Nicklaus
M C
MC
Blumberg
P M
PM
Marquez
V E
VE
D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000737:chemistry*; D004075:Diglycerides / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D006877:Hydroxamic Acids / Q000737:chemistry*; D007527:Isoenzymes / Q000737:chemistry; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D011493:Protein Kinase C / Q000737:chemistry*; D013329:Structure-Activity Relationship
C442799:4-((N-hydroxy(tert-butylcarbonyl)amino)methyl)-4-hydroxy-3-(3-(2-methylpropyl)hexylidene)-2-oxotetrahydrofuran; D004075:Diglycerides; D006877:Hydroxamic Acids; D007527:Isoenzymes; D007783:Lactones; D008024:Ligands; D011493:Protein Kinase C; D015107:4-Butyrolactone