title: Synthesis and biological evaluation of SANT-2 and analogues as inhibitors of the hedgehog signaling pathway.
abstract: Hedgehog (Hh) signaling plays an important role in cell signaling of embryonic development and adult tissue homeostasis. In vertebrates, the hh gene encodes three different unique proteins: sonic hedgehog (Shh), desert hedgehog (Dhh) and indian hedgehog (Ihh). Disruption of the Hh signaling pathway leads to severe disorders in the development of vertebrates whereas aberrant activation of the Hh pathway has been associated with several malignancies including Gorlin syndrome (a disorder predisposing to basal cell carcinoma, medulloblastoma and rhabdomyosarcoma), prostate, pancreatic and breast cancers. In vivo evidence suggests the antagonism of excessive Hh signaling provides a route to unique mechanism-based anti-cancer therapies. Recently the small molecule SANT-2 was identified as a potent antagonist of Hh-signaling pathway. Here, we describe the synthesis, SAR studies as well as biological evaluation of SANT-2 and its analogues. Fifteen SANT-2 derivatives were synthesized and analyzed for their interference with the expression of the Hh target gene Gli1 in a reporter gene assay. By comparison of structure and activity important molecular descriptors for Gli inhibition could be identified. Furthermore we identified derivative TC-132 that was slightly more potent than the parent compound SANT-2. Selected compounds were tested for Hh related teratogenic effects in the small teleost model medaka. Albeit Gli expression has indicated a 16-fold higher Hh-inhibiting activity than observed for the plant alkaloid cyclopamine, none of the tested compounds were able to induce the cyclopamine-specific phenotype in the medaka assay.
authors.affiliation: University of Leipzig, Institute for Organic Chemistry, Johannisallee 29, D-04103 Leipzig, Germany.
authors.forename: Anita
authors.initials: A
authors.lastname: Büttner
authors.forename: Katrin
authors.initials: K
authors.lastname: Seifert
authors.forename: Thomas
authors.initials: T
authors.lastname: Cottin
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Sarli
authors.forename: Lito
authors.initials: L
authors.lastname: Tzagkaroulaki
authors.forename: Stefan
authors.initials: S
authors.lastname: Scholz
authors.forename: Athanassios
authors.initials: A
authors.lastname: Giannis
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D015394:Molecular Structure; D015513:Oncogene Proteins / Q000235:genetics; D009990:Oryzias / Q000196:embryology / Q000235:genetics; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000235:genetics; D000071676:Zinc Finger Protein GLI1
chemical_list: D001549:Benzamides; D001562:Benzimidazoles; D053823:Hedgehog Proteins; D015513:Oncogene Proteins; C468920:SANT-2 compound; D015534:Trans-Activators; D000071676:Zinc Finger Protein GLI1