C−N‐Coupled Metabolites Yield Insights into Dynemicin A Biosynthesis

Abstract

The biosynthesis of the three structural subclasses of enediyne antitumor antibiotics remains largely unknown beyond a common C16‐hexaene precursor. For the anthraquinone‐fused subtype, however, an unexpected iodoanthracene γ‐thiolactone was established to be a mid‐pathway intermediate to dynemicin A. Having deleted a putative flavin‐dependent oxidoreductase from the dynemicin biosynthetic gene cluster, we can now report four metabolites that incorporate the iodoanthracene and reveal the formation of the C−N bond linking the anthraquinone and enediyne halves emblematic of this structural subclass. The coupling of an aryl iodide and an amine is familiar from organometallic chemistry, but has little or no precedent in natural product biosynthesis. These metabolites suggest further that enediyne formation occurs early in the overall biosynthesis, and that even earlier events might convert the C16‐hexaene to a common C15 intermediate that partitions to enediyne and anthraquinone building blocks for the heterodimerization.

Myxadazoles, Myxobacterium‐Derived Isoxazole–Benzimidazole Hybrids with Cardiovascular Activities

“…Besides myxadazoles, C-N coupling also serves as a port to mediate the heterodimerization of structurally complex terpene-alkaloid conidiogenone B [34] and the enediyne-anthraquinone dynemicin A. [35] The isolated myxadazoles A 1 /A 2 and B (1-3) were assayed for the activities of antibacterial (against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Acinetobacter baumannii), antifungal (against Candida albicans), anticancer (against liver carcinoma cell line HepG2, breast cancer cell line MCF-7, and hepatocyte cell line HL-7702), antioxidant (DPPH radical-scavenging), and anti-inflammatory (inhibited LPS-induced NO production in adherent cells), whereas no obvious effects were observed. We further evaluated the potential efficacy of myxadazoles on cardiovascular system in zebrafish.…”

“…Versatile C‐N coupling reaction [33] is probably a more commonplace strategy taken by nature than previously recognized, which merges distinct biosynthetic machineries and thus results in the mixed biosynthesis of a variety of chimeric NPs. Besides myxadazoles, C‐N coupling also serves as a port to mediate the heterodimerization of structurally complex terpene‐alkaloid conidiogenone B [34] and the enediyne‐anthraquinone dynemicin A [35] …”

Anthraquinone-fused enediynes: discovery, biosynthesis and development

“…42 Large-scale fermentation of the Streptomyces sp. CB03234 wild-type strain enabled the isolation and characterization of TNM D (22), a new enediyne featuring a side chain appended to C26, as well as ve Bergman cyclization products (23)(24)(25)(26)(27) related to TNM A and TNM D (Fig. 2).…”

“…Compound 56 was postulated to be generated by C-C bond formation between the Bergman cyclization radical and the most reactive position of the proximal anthracene. 25 Compound 57 is an enediyne-containing metabolite. Supplementation of 13 C-labeled 57 to the M. chersina culture showed that it was not converted to 1, and therefore it is not a biosynthetic intermediate for DYN A, presumably due to the incorrect C-C double bond position in the F-ring.…”

“…22 However, due to the lack of sufficient information on the BGCs and the biosynthetic intermediates, no signicant progress was made in the rst two and a half decades since the discovery of the rst AFE. In the past ve years, comparative studies of the BGCs 7,8,10 and the accumulated biosynthetic intermediates of AFEs have provided precious opportunities to disclose the biosynthesis of the anthraquinone moieties, 23,24 the coupling of the anthraquinones with the enediyne core, 10,25 and the late-stage tailoring steps. [26][27][28] The total synthesis of DYN A was actively pursued in the early 1990s.…”