Abstract
Pyrazines (1,4-diazirines) are an important group of natural products that have tremendous monetary value in the food and fragrance industries and can exhibit a wide range of biological effects including antineoplastic, antidiabetic and antibiotic activities. As part of a project investigating the secondary metabolites present in understudied and chemically rich Actinomycetes, we isolated a series of six pyrazines from a soil-derived Lentzea sp. GA3-008, four of which are new. Here we describe the structures of lentzeacins A-E (1, 3, 5 and 6) along with two known analogues (2 and 4) and the porphyrin zincphyrin. The structures were determined by NMR spectroscopy and HR-ESI-MS. The suite of compounds present in Lentzea sp. includes 2,5-disubstituted pyrazines (compounds 2, 4, and 6) together with the new 2,6-disubstituted isomers (compounds 1, 3 and 5), a chemical class that is uncommon. We used long-read Nanopore sequencing to assemble a draft genome sequence of Lentzea sp. which revealed the presence of 40 biosynthetic gene clusters. Analysis of classical di-modular and single module non-ribosomal peptide synthase genes, and cyclic dipeptide synthases narrows down the possibilities for the biosynthesis of the pyrazines present in this strain.
Highlights
Pyrazines (1,4-diazines) are ubiquitous aromatic nitrogen-containing heterocycles distributed widely in nature, and are found in plants, insects, and diverse microorganisms
While this analysis leaves open the possibility that the lentzeacins are synthesized via a monomodular NRPS-like enzyme, it does not explain the presence of the 2,6-disubstituted compounds that occur together with their 2,5-disubstituted congeners
To the best of our knowledge, the co-occurrence of such a pair of disubstituted piperazines has been observed in fungal-derived brasiliamides isolated from Penicillium brasilianum [18] and trace amounts in the myxobacterium Chondromyces crocatus [31]
Summary
Pyrazines (1,4-diazines) are ubiquitous aromatic nitrogen-containing heterocycles distributed widely in nature, and are found in plants, insects, and diverse microorganisms. A 1H and 13C NMR were recorded in CD3OD at 500 and 125 MHz and referenced to residual solvent at δH 3.31 and δC 49.15 ppm, respectively; B 1H and 13C NMR were recorded in DMSO-d6 at 500 and 125 MHz and referenced to residual solvent at δH 2.50 and δC 39.5 ppm, respectively; C 1H and 13C NMR were recorded in CD3OD at 600 and 150 MHz and referenced to residual solvent at δH 3.31 and δC 49.15 ppm, respectively; D Chemical shifts are assigned from the HMBC spectra; E 600 MHz NMR: 15N, 0 ppm = 60.810645 MHz and 1H, 0 ppm = 600.13 MHz; 500 MHz NMR: 15N,0 ppm = 50.674693 MHz and 1H, 0 ppm = 500.1 MHz. Compounds 3 and 4 were isolated as light-yellow oils with the same molecular formula of C18H16N2O2, as established from the HR-ESI-MS(+) ions at m/z 293.1290 ([M + H]+ calculated 293.1290) and 293.1295 ([M + H]+ calculated 293.1290), respectively (see Figures S21–S26 and S27–S31 for spectral data for compounds 3 and 4, respectively). The 15N-HMBC correlations from H2-3/3 to 2-N (δN 329.3) and from H2-1/1 to 1-N (δN 336.3) confirmed compound 3 was a 2,6-disubstituted pyrazine and was named lentzeacin C. Compound 5 was a 2,6-disubstituted pyrazine compound and named lentzeacin E
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