New fungal metabolites as potential antihypercholesterolemics and anticancer agents

Abstract

Several potent inhibitors of squalence synthetase have been discovered. Zaragozic acid A is produced by several fungi; zaragozic acid B is produced by several strains of Sporormiella intermedia; zaragozic acids C, E, and F are produced by Leptodontidium elatius; zaragozic acids D and D2 are produced by Amauroascus niger. L-731,120 and L-731,128 are minor components and coproduced with zaragozic acids A and B, respectively. Viridiofungins A, B, and C are produced by Trichoderma viride. Viridiofungin A is also produced by an unidentified sterile fungus. Several of the zaragozic acids are also potent inhibitors of farnesyl-protein transferase (FPTase). Inhibitors of FPTase may act as potential anticancer drugs. Chaetomellic acids A and B are produced by a fungus, Chaetomella acutiseta, while fusidienol is produced by Fusidium griseum. All three compounds are potent inhibitors of FPTase. Our experiences suggest that many novel inhibitors of both squalene synthase and FPTase are produced within a diverse phylogenetic array of filamentous fungi. Several of the zaragozic acids are potent inhibitors of both FPTase and squalene synthases. This is consistent with our observations that zaragozic acids and chaetomellic acids share some structural similarity. Key words: natural inhibitors, squalene synthase, farnesyl-protein transferase.