title: Inhibition of c-fos proto-oncogene induction by Sch 52900 and Sch 52901, novel diketopiperazine produced by Gliocladium sp.
abstract: Sch 52900 (1) and Sch 52901 (2), two new inhibitors of c-fos proto-oncogene induction, have been isolated from the fermentation of broth of the fungal culture (SCF-1168), Gliocladium sp. Along with compounds 1 and 2, a known compound verticillin A (3) was also obtained from the culture. Structure elucidation of 1 and 2, accomplished by analysis of spectral data in comparison with the data of 3, revealed both 1 and 2 were found to be closely related to the verticillin family of diketopiperazines. All three compounds prevented serum-stimulated transcription of the human c-fos promoter, using a fos/lac Z reporter gene assay, with IC50 values of 1.5, 18 and 0.5 microM of 1, 2 and 3, respectively. Northern analysis revealed the exposure of cells to compound 3 causes inhibition of both phorbol ester-induced c-fos induction of serum-induced JE induction in the absence of inhibiting RNA synthesis, as measured by [3H]uridine incorporation. There results suggest that this class of compounds exerts antitumor activity by blocking a signal transduction pathway that is common to and necessary for the induction of at least a subset of immediate early genes involved in cell proliferation.
authors.affiliation: Schering-Plough Research Institute, Kenilworth, NJ 07033-0359, USA.
authors.forename: M
authors.initials: M
authors.lastname: Chu
authors.forename: I
authors.initials: I
authors.lastname: Truumees
authors.forename: M L
authors.initials: ML
authors.lastname: Rothofsky
authors.forename: M G
authors.initials: MG
authors.lastname: Patel
authors.forename: F
authors.initials: F
authors.lastname: Gentile
authors.forename: P R
authors.initials: PR
authors.lastname: Das
authors.forename: M S
authors.initials: MS
authors.lastname: Puar
authors.forename: S L
authors.initials: SL
authors.lastname: Lin
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D005285:Fermentation; D015870:Gene Expression / Q000187:drug effects*; D017930:Genes, Reporter; D016762:Genes, fos; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D007763:Lac Operon; D051379:Mice; D008807:Mice, Inbred BALB C; D003904:Mitosporic Fungi / Q000378:metabolism*; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D013057:Spectrum Analysis; D013237:Stereoisomerism
chemical_list: D000903:Antibiotics, Antineoplastic; D007211:Indoles; C000715470:MAS1 protein, human; D010879:Piperazines; D000090063:Proto-Oncogene Mas; C097800:Sch 52900; C097801:Sch 52901