Discoipyrroles A–D: Isolation, Structure Determination, and Synthesis of Potent Migration Inhibitors from Bacillus hunanensis

Abstract

Discoidin domain receptor 2 (DDR2) is a receptor tyrosine kinase involved in a variety of cellular response pathways, including regulation of cell growth, proliferation and motility. Using a newly developed platform to identify the signaling pathway/molecular target of natural products, we identified a family of alkaloid natural products, discoipyrroles A–D (1–4), from Bacillus hunanensis that inhibit the DDR2 signaling pathway. The structure of 1–4, determined by detailed 2D NMR methods and confirmed by X-ray crystallographic analysis has an unusual 3H-benzo[ d]pyrrolo][1,3]oxazine-3,5-dione core. Discoipyrroles A–D potently inhibit DDR2 dependent migration of BR5 fibroblasts and show selective cytotoxicity to DDR2 mutant cell lung cancer cell lines (IC50 120–400 nM). Examination of the biosynthesis has led to the conclusion that the discoipyrroles are formed through a non-enzymatic process, leading to a one-pot total synthesis of 1.

Production of Stealthin C Involves an S–N-Type Smiles Rearrangement

“…This general phenomenon has been identified in other biosynthetic pathways. 17 The relevance of 3 to kinamycin biosynthesis was established using feeding experiments, 6b and this result was the basis for the hypothesis that diazo group construction involves N–N bond formation on the benzo[ b ]fluorene scaffold. However, the 3 used for these feeding experiments was labeled on the carbon scaffold, not nitrogen, and only low levels of incorporation were observed.…”

Discovery, Characterization, and Analogue Synthesis of Bohemamine Dimers Generated by Non‐enzymatic Biosynthesis

“…Examples include the jadomycins, [1] elansolids, [2] oxazinin A, [3] ammosamides [4] and discoipyrroles. [5] For many of these families of natural products listed above, it has been possible to harness the non-enzymatic chemistry by feeding alternative precursors into the fermentation media and carrying out structure-activity relationship studies. In all of the above examples, traditional enzymatic biosynthesis gives rise to an electrophilic intermediate, such as an aldehyde, imine, iminium ion or p- quinone methide, which can then undergo a non-enzymatic reaction with a nucleophile present in the microorganisms or in the fermentation media (Figure 1).…”

Comparative mass spectrometry-based metabolomics strategies for the investigation of microbial secondary metabolites

“…231 This method was effectively able to cluster antibiotics of the same compound class and led to the identification of a novel naphthoquinone antibiotic, arromycin. 231 Gene expression profiling with either the entire transcriptome 232,233 or a subset of reporter genes 234,235 has also been used to predict modes of action for natural products. However, because these transcriptomic screens are still relatively costly, there is a great interest in applying metabolomics analyses to predict natural product modes of action using either natural product extracts 236 or purified compounds.…”