Biosynthesis, synthetic studies, and biological activities of the jadomycin alkaloids and related analogues.

Abstract

The jadomycins are an expanding class of compounds produced from Streptomyces venezuelae, by diverting the normal biosynthesis which provides the antibiotic chloramphenicol. In the presence of amino acids, and either by heat shock, supplementation with ethanol, or when phage SV1 is added to the culture, the formation of substituted jadomycins and benzo[b]phenanthridines can be achieved. The first part of this review provides details of intermediates involved in the biosynthesis of the jadomycins and the related benzo[b]phenanthridines. Both the jadomycins and the benzo[b]phenanthridines share biosynthetic pathways with a large class of naturally occurring compounds known as the angucyclines. The biosynthetic pathways diverge when it is postulated that an intermediate quinone, such as 3-(2-formyl-6-hydroxy-4-methylphenyl)-8-hydroxy-1,4-naphthoquinone-2-carboxylic acid is formed. The quinone then undergoes reactions with amino acids and derivatives in the culture medium to ultimately afford a library of jadomycins and a few benzo[b]phenanthridines. The second part of the review initially details synthetic efforts toward the synthesis of the naturally occurring benzo[b]phenanthridine, phenanthroviridin, and then outlines methods that have been used to assemble a selection of jadomycins. Total syntheses of jadomycin A and B, derived from l-isoleucine, are described. In addition, the synthesis of the aglycon of jadomycins M, W, S, and T is outlined. These four jadomycins were derived from l-methionine, l-tryptophan, l-serine and l-threonine respectively. As a result of these synthetic efforts, the structures of jadomycin S and T have been revised. The third part of the review describes the reported antibacterial and anticancer activities of both the jadomycins and some naturally occurring benzo[b]phenanthridines.