aldisine and hymenialdisine

The tetrahydroazepinone pharmacophore is a component of many interesting compounds, including several marine natural products, with anti-cancer properties. The synthesis and biological evaluation of a novel series of pyrroloazepinone and indoloazepinone oximes is reported. These compounds showed promising growth inhibition activity against four human cancer cell lines but did not significantly inhibit the cell cycle regulator cyclin dependent kinase 2. The most active compounds in this series displayed improved anti-proliferative activity over the related synthetic indoloazepine kenpaullone. The structure activity relationships exhibited by the azepinone pharmacophore suggests several novel lead compounds for anti-cancer drug discovery.

Topics: Antineoplastic Agents; Azepines; Biological Products; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Indoles; MCF-7 Cells; Molecular Structure; Oximes; Pyrroles; Structure-Activity Relationship

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.

Topics: Animals; Antineoplastic Agents; Azepines; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Humans; MAP Kinase Kinase 1; Mitogen-Activated Protein Kinase Kinases; Philippines; Phosphorylation; Porifera; Protein Serine-Threonine Kinases; Pyrroles; Structure-Activity Relationship; Tumor Cells, Cultured