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-1 168), 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 compoundsprevented serum-stimulated transcription of the humanc-fos promoter, using afos/lac Z reporter gene assay, with IC50 values of 1.5, 18 and 0.5fM for 1, 2 and 3, respectively. Northern analysis revealed that exposure of cells to compound3 causes inhibition of both phorbol ester-induced c-fos induction and serum-induced JE induction in the absence of inhibiting RNAsynthesis, as measured by [3H]uridine incorporation. These results suggest that this class of compounds exerts antitumor activity by blocking a signal transduction pathway that is commonto and necessary for the induction of at least a subset of immediate early genes involved in cell proliferation.

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Generation of a three-dimensional pharmacophore model (hypothesis) that correlates the biological activity of a series of farnesyl protein transferase (FPT) inhibitors, exemplified by the prototype 1-(4-pyridylacetyl)- 4-(8-chloro-5,6-dihydro-11H-benzo [5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine, Sch 44342, 1, with their chemical structure was accomplished using the three-dimensional quantitative structure-activity relationship (3D-QSAR) software program, Catalyst. On the basis of the in vitro FPT inhibitory activity of a training set of compounds, a five-feature hypothesis containing four hydrophobic and one hydrogen bond acceptor region was generated. Using this hypothesis as a three-dimensional query to search our corporate database identified 718 compounds (hits). Determination of the in vitro FPT inhibitory activity using available compounds from this "hitlist" identified five compounds, representing three structurally novel classes, that exhibited in vitro FPT inhibitory activity, IC50 < or = 5 microM. From these three classes, a series of substituted dihydrobenzothiophenes was selected for further structure-FPT inhibitory activity relationship studies. The results from these studies is discussed.

No abstract

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