title: Natural sesquiterpene lactones as inhibitors of Myb-dependent gene expression: structure-activity relationships.
abstract: c-myb is a proto-oncogene encoding a transcription factor which is highly expressed in hematopoietic progenitor cells. It regulates the expression of genes important for lineage determination, cell proliferation, and differentiation. Deregulation of c-myb expression is known to be involved in the development of human tumors, especially certain types of leukemia and breast and colon cancer. The c-Myb protein has thus been identified as an interesting therapeutic target. We recently discovered that some sesquiterpene lactones suppress Myb-dependent gene expression which is a new mechanism for these natural products' potential anti-cancer activity. We developed a test system to screen compounds for inhibitory activity on Myb-inducible reporter gene activation. Using this system we have now investigated 60 sesquiterpene lactones for their capacity to inhibit c-Myb-dependent gene activation. The IC50 values were in a range between 0.7 and >30 μM. The furanoheliangolide goyazensolide and the pseudoguaianolide helenalin acetate (IC50 = 0.6 and 0.7 μM, respectively) represent the most active inhibitors of c-Myb dependent gene expression found up to present. Control measurements for cell viability (MTS assay) proved that the observed activity on c-Myb dependent gene expression is not a function of cytotoxicity/unspecific cell damage. Structure-activity relationships were investigated by a QSAR approach based on flexible alignment of the most active compounds and a common pharmacophore model. These investigations resulted in a QSAR model which indicates that the potency of inhibitory activity on c-Myb-dependent transcription does not only depend on the presence of reactive Michael-acceptor features but also on their optimal spatial arrangement in the molecule.
authors.affiliation: Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Münster, Hittorfstr. 56, D-48149 Münster, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Schomburg
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schuehly
authors.forename: Fernando B
authors.initials: FB
authors.lastname: Da Costa
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Klempnauer
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Schmidt
mesh_terms: D000123:Acetyltransferases / Q000235:genetics; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002645:Chickens; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011401:Promoter Regions, Genetic / Q000235:genetics; D000090063:Proto-Oncogene Mas; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics* / Q000378:metabolism; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D007783:Lactones; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D020598:Proto-Oncogene Proteins c-myb; D012717:Sesquiterpenes; D049452:Green Fluorescent Proteins; D000123:Acetyltransferases; C077509:mim-1 protein, Gallus gallus