Aldisine alkaloids from the Philippine sponge Stylissa massa are potent inhibitors of mitogen-activated protein kinase kinase-1 (MEK-1)

J Med Chem. 2002 Jan 17;45(2):529-32. doi: 10.1021/jm0102856.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / isolation & purification
  • Antineoplastic Agents / pharmacology*
  • Azepines / isolation & purification
  • Azepines / pharmacology*
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / isolation & purification
  • Enzyme Inhibitors / pharmacology*
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • MAP Kinase Kinase 1
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Philippines
  • Phosphorylation
  • Porifera / chemistry*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Pyrroles / isolation & purification
  • Pyrroles / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Azepines
  • Enzyme Inhibitors
  • Pyrroles
  • hymenialdisine
  • Protein-Serine-Threonine Kinases
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human
  • Mitogen-Activated Protein Kinase Kinases