BE-10988

The biosynthetic origin of the tumor-inhibitory derivative, BE-10988, was studied in Streptomyces sp . BA10988 by retrobiosynthetic NMR analysis using [U-(13)C6]glucose as a precursor. The isotopologue compositions of the indole moieties of BE-10988 and tryptophan were virtually identical. This indicates that tryptophan or a closely related metabolite served as a biosynthetic precursor of BE-10988 in analogy to the biosynthetic pathway of camalexin, a structurally related phytoalexin in Arabidopsis thaliana. Labeling experiments with [U-(13)C8(15)N]indole, L-[ring-(2)H5]tryptophan, or L-[U-(13)C3(15)N]cysteine confirmed this hypothesis. However, transfer of the label from [ring-(2)H5]indole pyruvic acid, but not from the known camalexin precursor, [ring-(2)H5]indole-3-acetaldoxime, showed that plants and bacteria have evolved independent mechanisms of tryptophan modification in the biosynthesis of thiazolylindole derivatives.

o-Imidoquinones, a rather rare class of compounds, are prepared from anilides by the action of Dess-Martin periodinane (DMP) and water. Their chemistry has been extensively investigated and found to lead to p-quinones and polycyclic systems of diverse molecular architectures. Applications of this methodology to the total synthesis of the naturally occurring compounds, epoxyquinomycin B and BE-10988, are described. Finally, another rare chemical entity, the ketohydroxyamide moiety, has been accessed through this DMP-based synthetic technology, and its reactivity has been studied. Among its most useful reactions is a set of cascade heterocyclic annulations leading to a variety of polycyclic systems of possible biological relevance.

Structurally related secondary products are rather rarely shared by organisms from different kingdoms. Consequently, the evolution of biosynthetic pathways of defence metabolites between distantly related organisms has not been broadly investigated. Thiazolylindoles are found in Arabidopsis thaliana, as the phytoalexin camalexin, and in a Streptomyces strain, which synthesizes a tumour-inhibitory derivative, designated BE-10988. Camalexin originates from cysteine and tryptophan, which is converted to indole-3-acetaldoxime and subsequently dehydrated to indole-3-acetonitrile. The metabolic origin of BE-10988 was determined by retrobiosynthetic NMR analysis and incorporation studies with direct precursors. Like camalexin, it is derived from tryptophan and cysteine. However, as BE-10988 is synthesized via indole-3-pyruvic acid, not via indole-3-acetaldoxime, independent mechanisms of tryptophan modification have evolved.