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 g...

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Published in:Journal of medicinal chemistry 2001-12, Vol.44 (25), p.4309-4312
Main Authors: Lee, Jeewoo, Han, Kee-Chung, Kang, Ji-Hye, Pearce, Larry L, Lewin, Nancy E, Yan, Shunqi, Benzaria, Samira, Nicklaus, Marc C, Blumberg, Peter M, Marquez, Victor E
Format: Article
Language:English
Subjects:
4-Butyrolactone - analogs & derivatives
4-Butyrolactone - chemistry
Analytical, structural and metabolic biochemistry
Biological and medical sciences
Diglycerides - chemical synthesis
Diglycerides - chemistry
Drug Design
Enzymes and enzyme inhibitors
Fundamental and applied biological sciences. Psychology
Hydroxamic Acids - chemistry
Isoenzymes - chemistry
Lactones - chemical synthesis
Lactones - chemistry
Ligands
Models, Molecular
Molecular Conformation
Protein Binding
Protein Kinase C - chemistry
Structure-Activity Relationship
Transferases
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0103965