Rosalind G. Jenkins

Isolation and structure of chaetomellic acids A and B from Chaetomella acutiseta: farnesyl pyrophosphate mimic inhibitors of ras farnesyl-protein transferase

Abstract Farnesyl-Protein transferase catalyses a post-translational modification of Ras that is obligatory for the cell transforming activity of this oncogene protein. The screening of natural products to identify inhibitors of this enzyme as a potential anticancer agents, has led to the isolation of two novel dicarboxylic acids, named chaetomellic acids from Chaetomella acutiseta, as potent and selective inhibitors which appear to be the first examples of nonphosphorous containing FPP mimics.

Chaetomella acutiseta produces chaetomellic acids A and B which are reversible inhibitors of farnesyl-protien transferase

Chaetomellic acids A and B, isolated from Chaetomella acutiseta, are specific inhibitors of farnesyl-protein transferase that do not inhibit geranylgeranyl transferase type 1 or squalene synthase. Chaetomellic acids A and B are reversible inhibitors, resemble farnesyl diphosphate and probably inhibit FPTase by substituting for farnesyl diphosphate. Chaetomellic acid production appears to be widespread within the genus Chaetomella.

The isolation and structure elucidation of zaragozic acid C, a novel potent squalene synthase inhibitor.

Abstract The novel zaragozic acid C ( 1 ) has been isolated as a potent inhibitor of squalene synthase. It was found to be a competitive inhibitor of rat liver squalene synthase with an apparent K i of 45 ± 15 pM, and a broad spectrum antifungal agent against both yeast and filamentous fungi.

Distribution of zaragozic acids (squalestatins) among filamentous ascomycetes

The search for squalene synthase inhibitors of microbial origin has resulted in the discovery of a new class of fungal metabolites, the zaragozic acids (squalestatins). During our survey of representatives of most major groups of fungi and filamentous bacteria, the zaragozic acids were not found in prokaryotes Zygomycotina, or Basidiomycotina. All the fungal producers encountered to date are Ascomycotina, their related anamorphic states or sterile organisms with ascomycete affinities. Members of at least II different taxa of fungi are capable of making zaragozic acids. Zaragozic acid A (squalestatin 1) appears to be the most prevalent among the different fungal taxa. In several cases we have observed production in multiple strains of the same species; for example, nearly all strains of Sporormiella intermedia, that we have examined, produce zaragozic acid B. The discovery of the zaragozic acids illustrates how knowledge of fungal biology and biochemistry can enhance the search for new chemical entities. Simultaneous screening of fungi from diverse phylogenetic and ecological origins was emphasized to discover new zaragozic acids rather than simply relying on organisms from a single kind of substratum from geographically disparate sources.

Cylindrol A: A novel inhibitor of Ras farnesyl-protein transferase from Cylindrocarpon lucidum

Abstract Farnesylation of Ras (p21) protein by farnesyl-protein transferase (FPTase) is essential for cell-transforming activity in several tumor-types. Inhibition of FPTase activity has been shown to inhibit ras - dependent cell transformation and tumor size in nude mice thereby validating FPTase as a potential target for anticancer drugs. Our continued search for such inhibitors led to the isolation of cylindrol A, a bicyclic resorcinaldehyde cyclohexanone propionate derivative, from Cylidrocarpon lucidum . The isolation, structure elucidation by NMR and X-ray crystallographic methods, stereochemistry and FPTase activity of cylindrol A are described.

Oreganic acid: a potent novel inhibitor of ras farnesyl-protein transferase from an endophytic fungus

Abstract Inhibitors of farnesyl-protein transferase (FPTase) have the potential of being anticancer agents for tumors in which ras is found mutated and contributes to cell transformation. From the screening of the extracts of an endophytic fungus isolated from living leaves of Berberis oregana , we have discovered the tricarboxylated alkylsulfate, oreganic acid ( 1 ), as a potent (IC 50 = 14 nM) and specific inhibitor of FPTase. Its desulfated analog ( 4 ) was less active (IC 50 = 3.3μM). The trimethylester ( 2 ) and its desulfated analog ( 3 ) were inactive.

Sonomolides A and B, new broad spectrum antifungal agents isolated from a coprophilous fungus

Abstract Two novel amifungal agents, sonomolides A ( 1 ) and B ( 2 ), have been isolated and their structures determined mainly by nmr. Both compounds show inhibitory activity against a broad range of fungal pathogens.