INHIBITION OF C-FOS PROTOONCOGENE 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-onc ogene 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 cultu re. Structure elucidation of I and 2, accomplished by analysis of spec tral data in comparison with the data of 3, revealed both 1 and 2 were found to be closely related to the verticillin family of diketopipera zines. 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. Nor thern analysis revealed that exposure of cells to compound 3 causes in hibition of both phorbol ester-induced c-fos induction and serum-induc ed JE induction in the absence of inhibiting RNA synthesis, as measure d by [H-3]uridine incorporation. These results suggest that this class of compounds exerts antitumor activity by blocking a signal transduct ion pathway that is common to and necessary for the induction of at fe ast a subset of immediate early genes involved in cell proliferation.