Conformationally Constrained Analogues of Diacylglycerol. 29. Cells Sort Diacylglycerol-Lactone Chemical Zip Codes to Produce Diverse and Selective Biological Activities

• Published in: Journal of medicinal chemistry Vol. 51; no. 17; pp. 5198 - 5220
• Main Authors: Duan, Dehui, Sigano, Dina M, Kelley, James A, Lai, Christopher C, Lewin, Nancy E, Kedei, Noemi, Peach, Megan L, Lee, Jeewoo, Abeyweera, Thushara P, Rotenberg, Susan A, Kim, Hee, Kim, Young Ho, Kazzouli, Saïd El, Chung, Jae-Uk, Young, Howard A, Young, Matthew R, Baker, Alyson, Colburn, Nancy H, Haimovitz-Friedman, Adriana, Truman, Jean-Philip, Parrish, Damon A, Deschamps, Jeffrey R, Perry, Nicholas A, Surawski, Robert J, Blumberg, Peter M, Marquez, Victor E
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.09.2008; Amer Chemical Soc
• Subjects: Binding Sites; Biological and medical sciences; Chemical Phenomena; Chemistry; Chemistry, Medicinal; Combinatorial Chemistry Techniques; Diglycerides - chemistry; Diglycerides - metabolism; Diglycerides - pharmacology; Humans; Immunomodulators; Lactones - chemistry; Lactones - metabolism; Lactones - pharmacology; Life Sciences & Biomedicine; Medical sciences; Miscellaneous; Molecular Conformation; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protein Binding; Protein Kinase C-alpha - metabolism; Radiation therapy and radiosensitizing agent; Science & Technology; Small Molecule Libraries; Structure-Activity Relationship; Treatment with physical agents; Treatment. General aspects; Tumors; PROTEIN-KINASE-C; GAMMA PRODUCTION; COMBINATORIAL CHEMISTRY; INDUCED APOPTOSIS; CERAMIDE SYNTHASE; PKC-ALPHA; BINDING-AFFINITY; DAG-LACTONES; AMYLOID PRECURSOR PROTEIN; PHORBOL ESTERS; Protein kinase C; Isozyme; Diacylglycerol; Molecular interaction; Selectivity; Modeling; Radiosensitization; Chemical compound library; Molecular model; Aspartic endopeptidases; Chemical synthesis; Molecular rigidity; Enzyme; Transferases; Steric hindrance; Lactone; In vitro; Biological activity; Glyceride; Immunomodulator; Peptidases; Cell motility; Biological fixation; Immunostimulant agent; Cell death; Metabolic activation; Hydrolases; Solid phase; Apoptosis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm8001907

Diacylglycerol-lactone (DAG-lactone) libraries generated by a solid-phase approach using IRORI technology produced a variety of unique biological activities. Subtle differences in chemical diversity in two areas of the molecule, the combination of which generates what we have termed “chemical zip codes”, are able to transform a relatively small chemical space into a larger universe of biological activities, as membrane-containing organelles within the cell appear to be able to decode these “chemical zip codes”. It is postulated that after binding to protein kinase C (PKC) isozymes or other nonkinase target proteins that contain diacylglycerol responsive, membrane interacting domains (C1 domains), the resulting complexes are directed to diverse intracellular sites where different sets of substrates are accessed. Multiple cellular bioassays show that DAG-lactones, which bind in vitro to PKCα to varying degrees, expand their biological repertoire into a larger domain, eliciting distinct cellular responses.