title: 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.
abstract: 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.
authors.affiliation: Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Shinlin Dong, Kwanak-ku, Seoul 151-742, South Korea. jeewoo@snu.ac.kr
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.forename: K C
authors.initials: KC
authors.lastname: Han
authors.forename: J H
authors.initials: JH
authors.lastname: Kang
authors.forename: L L
authors.initials: LL
authors.lastname: Pearce
authors.forename: N E
authors.initials: NE
authors.lastname: Lewin
authors.forename: S
authors.initials: S
authors.lastname: Yan
authors.forename: S
authors.initials: S
authors.lastname: Benzaria
authors.forename: M C
authors.initials: MC
authors.lastname: Nicklaus
authors.forename: P M
authors.initials: PM
authors.lastname: Blumberg
authors.forename: V E
authors.initials: VE
authors.lastname: Marquez
mesh_terms: 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
chemical_list: 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