Synthetic Bryostatin Analogues Activate the RasGRP1 Signaling Pathway

• Published in: Journal of medicinal chemistry Vol. 47; no. 26; pp. 6638 - 6644
• Main Authors: Stone, James C, Stang, Stacey L, Zheng, Yong, Dower, Nancy A, Brenner, Stacey E, Baryza, Jeremy L, Wender, Paul A
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 16.12.2004
• Subjects: Animals; Antigens, CD - biosynthesis; Antigens, Differentiation, T-Lymphocyte - biosynthesis; Antineoplastic agents; Biological and medical sciences; Bryostatins; Cell Aggregation - drug effects; Cell Membrane - metabolism; Cells, Cultured; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Extracellular Signal-Regulated MAP Kinases - metabolism; General aspects; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - physiology; Humans; Immunologic Factors - chemical synthesis; Immunologic Factors - chemistry; Immunologic Factors - pharmacology; Immunomodulators; Lactones - chemical synthesis; Lactones - chemistry; Lactones - pharmacology; Lectins, C-Type; Macrolides; Medical sciences; Mice; Mutation; Pharmacology. Drug treatments; Phosphorylation; Protein Kinase C - physiology; Protein Transport - drug effects; Signal Transduction - drug effects; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; T-Lymphocytes - physiology; Tetradecanoylphorbol Acetate - pharmacology; Thymus Gland - cytology; Transfection; Antineoplastic agent; Thymocyte; Rodentia; Lactone; Oxygen heterocycle; In vitro; Biological activity; Macrocycle; Immunomodulator; Signal transduction; Vertebrata; Mammalia; Cell line; Mouse; Animal; Ras gene; Chemical synthesis; Lymphocyte
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0495069

The functional properties of four diacylglycerol (DAG) analogues were compared using cell-signaling assays based on the protein RasGRP1, a DAG-regulated Ras activator. Compounds 1 and 2, synthetic analogues of bryostatin 1, were compared to authentic bryostatin 1 and phorbol 12-myristate-13-acetate (PMA). The two “bryologues” were able to activate RasGRP1 signaling rapidly in cultured cells and isolated mouse thymocytes. They elicited expression of the T cell activation marker CD69 in human T cells. DAG analogues promptly recruited RasGRP1 to cell membranes, but they did not induce RasGRP1 proteolysis. Bryostatin 1 and compounds 1 and 2 appeared to be less potent than PMA at inducing aggregation of mouse thymocytes, a PKC-dependent, RasGRP1-independent response. In addition to sharing potential anticancer properties with bryostatin 1, compounds 1 and 2 might be clinically useful as modulators of the immune system.