Novel soraphens from precursor directed biosynthesis

Abstract

Six novel halogenated soraphen analogues have been isolated from the wild-type producing organism using precursor directed biosyntheses; the best 'delivery vehicle' for the novel starter acids was cinnamate but ortho substituents were not tolerated by the soraphen PKS.

Analysis of myxobacterial secondary metabolism goes molecular

“…Consequently, the biosynthetic genes for soraphen were identified [67] and the DNA fragment encoding the loading module of the soraphen PKS was fused with elongation modules from an actinomycete biosynthetic gene cluster resulting in the production of novel phenyl substituted products after supplementation of the newly constructed strain with benzoic acid [83]. In addition, the feeding of chemically modified benzoic acid derivatives led to the formation of the expected altered compounds in the same system [13] and in the original producer [22].…”

Biosynthesis with Fluorine

“…Many polyketides and their derivatives have been commercialised as drugs. For example, synthetically fluorinated analogues of biosynthetic building blocks can be fed to polyketide-producing microbial cultures, as exemplified for erythromycin [7,8] (Scheme 1), soraphen [9] and piliformic acid. However, these are increasingly often used in medicinal chemistry.…”

“…[6] A complementary strategy for fluorinated natural products is their engineered biosynthesis. For example, synthetically fluorinated analogues of biosynthetic building blocks can be fed to polyketide-producing microbial cultures, as exemplified for erythromycin [7,8] (Scheme 1), soraphen [9] and piliformic acid. [10] A central intermediate in the biosynthesis of the rare fluorine-containing natural products is the highly toxic fluoroacetate.…”

Synthesis of C11-Desmethoxy Soraphen A1α: A Natural Product Analogue That Inhibits Acetyl-CoA Carboxylase

“…Although the natural product is readily available from fermentation (~130 mg/L), 16 the nature of structural changes that are easily accessible from the fully functionalized natural product are quite limited – such is often the case with natural product derivatization. 17–20 Soraphen A 1α ( 1 ) has been pursued as a target for total synthesis for ~20 years, with two successful syntheses being reported. 21–23 Unfortunately, these accomplishments call for synthetic sequences of 25 to ≥40 steps (longest linear sequence) and define a rather substantial barrier to the use of chemical synthesis for the discovery of novel soraphen analogs that may have better properties than 1 .…”