CP-225,917 AND CP-263,114, NOVEL RAS FARNESYLATION INHIBITORS FROM ANUNIDENTIFIED FUNGUS .1. TAXONOMY, FERMENTATION, ISOLATION, AND BIOCHEMICAL-PROPERTIES

During the course of our screening for squalene synthase inhibitors an d Ras farnesylation inhibitors, a novel fungal culture was discovered to produce two structurally unique compounds, CP-225,917 and CP-263,11 4, as well as zaragozic acid A (squalestatin I). The two compounds are characterized by a bicyclo[4.3.1]dec-1,6-diene core plus two extended alkyl chains. CP-225,917 and CP-263,114 inhibit Ras farnesyl transfer ase from rat brain with IC50 values of 6 mu M and 20 mu M, respectivel y. CP-225,917 inhibits squalene synthase with an IC50 value of 43 mu M and CP-263,114 with an IC50 of 160 mu M. The producing organism, thou gh not fully classified, exhibits the characteristics of a sterile Pho ma species.