Inhibition of c-fos proto-oncogene induction by Sch 52900 and Sch 52901, novel diketopiperazines produced by Gliocladium sp

Sch 52900 (1) and Sch 52901 (2), two new inhibitors of c-fos proto-oncogene induction have been isolated from the fermentation broth of the fungal culture (SCF-1168), Gliocladium sp. Alone with compounds 1 and 2, a known compound verticillin A (3) was also obtained from the culture. Structure elucidation of I 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/fac Z reporter gene assay, with IC50 values of 1.5, 18 and 0.5 mu M for 1, 2 and 3, respectively. Northern analysis revealed that exposure of cells to compound 3 causes inhibition of both phorbol ester-induced c-fos induction and serum-induced JE induction in the absence of inhibiting RNA synthesis, as measured by [H-3]uridine incorporation. These 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 feast a subset of immediate early genes involved in cell proliferation.