Aldisine Alkaloids from the Philippine Sponge Stylissa massa Are Potent Inhibitors of Mitogen-Activated Protein Kinase Kinase-1 (MEK-1)

• Published in: Journal of medicinal chemistry Vol. 45; no. 2; pp. 529 - 532
• Main Authors: TASDEMIR, Deniz, MALLON, Robert, GREENSTEIN, Michael, FELDBERG, Larry R., KIM, Steven C., COLLINS, Karen, WOJCIECHOWICZ, Donald, MANGALINDAN, Gina C., CONCEPCIóN, Gisela P., HARPER, Mary Kay, IRELAND, Chris M.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 17.01.2002
• Subjects: Animals; Antineoplastic Agents - isolation & purification; Antineoplastic Agents - pharmacology; Azepines - isolation & purification; Azepines - pharmacology; Biological and medical sciences; Drug Screening Assays, Antitumor; Enzyme Inhibitors - isolation & purification; Enzyme Inhibitors - pharmacology; Enzyme-Linked Immunosorbent Assay; General pharmacology; Humans; MAP Kinase Kinase 1; Medical sciences; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Philippines; Phosphorylation; Porifera - chemistry; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Pyrroles - isolation & purification; Pyrroles - pharmacology; Structure-Activity Relationship; Tumor Cells, Cultured; Asia; Philippine Islands; Antineoplastic agent; Human; Imidazole derivatives; Phosphorylation; Enzyme; Nitrogen heterocycle; Pharmacognosy; Transferases; Lactam; Enzyme inhibitor; Animal origin; In vitro; Biological activity; Signal transduction; Alkaloid; Cell line; Porifera; Kinase; Bicyclic compound; Isolation; Colon; Invertebrata; Onc gene; Structural analysis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0102856

Raf/MEK-1/MAPK cascade inhibitor activity-directed fractionation of the sponge Stylissa massa afforded eight known alkaloids: aldisine (1), 2-bromoaldisine (2), 10Z-debromohymenialdisine (3), 10E-hymenialdisine (4), 10Z-hymenialdisine (5), hymenin (6), oroidin (7), and 4,5-dibromopyrrole-2-carbonamide (8). Both 4 and 5 showed significant enzyme inhibitory activity (IC(50) 3 and 6 nM, respectively). Secondary assays identified these compounds as potent MEK-1 inhibitors. Compounds 4 and 5 also inhibited the growth of human tumor LoVo cells.