Inhibition of c-fos Proto-oncogene Induction by Sch 52900 and Sch 52901, Novel Diketopiperazines 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.