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Pyridone Synthesis Essay

Isolation of pyridin-2-ol-degrading bacteria

The gram-negative bacterial isolate MAK1, capable of using pyridin-2-ol as a sole carbon and energy source, was isolated from soil. The 16S rRNA gene sequence of MAK1 showed similarity to that of bacteria belonging to Burkholderia sordidicola. Based on the results of 16S rRNA gene sequence analysis (Supplementary information Fig. S-I) and biochemical characterization (Supplementary information Table S-1) the strain MAK1 was identified as Burkholderia sp. MAK1.

In bacteria, pyridin-2-ol may be catabolized by two different pathways. The first pathway proceeds via formation of pyridine-2,3,6-triol, which spontaneously oxidises and dimerises to a blue pigment, 4,5,4′,5′-tetrahydroxy-3,3′-diazadiphenoquinone-(2,2′)32,35,37. The other known catabolic pathway proceeds via formation of pyridine-2,5-diol, maleamic acid, maleic acid, and fumaric acid33.

In the case of Burkholderia sp. MAK1 described here, pyridin-2-ol was catabolized without the formation of a blue pigment. Assuming that pyridine-2,5-diol is an intermediate in pyridin-2-ol catabolic pathway, the activity of pyridine-2,5-diol 5,6-dioxygenase detected in the pyridin-2-ol-induced cells of Burkholderia sp. MAK1 suggested that this strain possesses an inducible pyridin-2-ol 5-monooxygenase.

Selection of pyridine derivatives as substrates for hydroxylation with Burkholderia sp

As we found out that Burkholderia sp. MAK1 consumes pyridine-2-ol via pyridine-2,5-diol by supposedly pyridine-2-ol inducible pyridin-2-ol 5-monooxygenase we wanted to test whether Burkholderia sp. MAK1 is capable of hydroxylating other pyridine derivatives. In this study, more than 100 of pyridine, pyrimidine, and pyrazine derivatives were screened for the hydroxylation using Burkholderia sp. MAK1 as a whole-cell biocatalyst (Supplementary information Table S-2). The pyridin-2-ol-induced Burkholderia sp. MAK1 cells were incubated with a potential substrate as described in the Methods section. The progress of the reaction was followed by HPLC-MS. The efficiency of conversion of several compounds by whole cells of Burkholderia sp. MAK1 is presented as Supplementary information Table S-3.

It is worth mentioning that induction of Burkholderia sp. MAK1 hydroxylation activity was observed only in the presence of pyridin-2-ol. Several other tested compounds (pyridine, pyridine-2,5-diol, pyridin-2-amine) were not able to trigger the induction. Also no hydroxylation occurred when cells were cultivated with other sole carbon source (glucose or succinate) instead of pyridin-2-ol.

Optimization of cultivation and reaction conditions

Burkholderia sp. MAK1 grew poorly in rich nutrient medium, but the growth was observed in mineral medium (EFA or Koser) with pyridin-2-ol as a sole carbon source. The growth reached its peak after 40 h of incubation in EFA medium (OD600 = 0.4). The optimal temperature for cultivation of Burkholderia sp. MAK1 appeared to be 30 °C. At higher tested temperature (37 °C), Burkholderia sp. MAK1 cells were not able to grow. Although bacterial growth was observed at 25 °C it was rather slow compared to 30 °C. The effect of temperature on Burkholderia sp. MAK1-mediated synthesis of hydroxylated pyridine derivatives was also investigated (Fig. 1). For this experiment 4-chloropyridin-2-amine was selected due to its great conversion percentage and definite product (Table 1). During the first hour of the experiment, the bioconversion of 4-chloropyridin-2-amine was most rapid at 30 °C and 35 °C with 6-amino-4-chloro-pyridin-3-ol production rate of 7 mg (g biomass)-1 h-1 and 7.4 mg (g biomass)-1 h-1, respectively. Higher temperatures (40–45 °C) were found to be unfavorable for the synthesis, probably because of the inactivation of the biocatalyst. The conversion reached near completion (~97%) after six hours at 30 °C.

Biotransformation of various pyridin-2-ols by Burkholderia sp. MAK1 cells

The study of N-alkylpyridine transformation revealed that 1-methyl-, 1-ethyl- and 1-propylpyridin-2-ol were transformed to the final dihydroxy products by Burkholderia sp. MAK1 cells. In the chromatogram of 1-ethylpyridin-2-ol bioconversion, two dominant peaks A and B were detected (Supplementary information Fig. S-II) corresponding to the newly formed compound and the residual substrate, respectively. The absorption maximum of the product, compared with that of the substrate, shifted to longer wavelengths (~30 nm), which is characteristic of compounds with additional hydroxy group. Also, the mass of the molecular ion of the product was 16 Da higher than that of the parent compound, supporting the hydroxylation of 1-ethylpyridin-2-ol. Similar results were obtained with 1-methyl- and 1-propylpyridin-2-ol. In all cases, the formation of a single product was observed indicating the position-specific hydroxylation. Moreover, the apparent equivalence with pyridin-2-ol transformation suggested that 1-alkylpyridin-2-ols were hydroxylated at the 5-position. Of all the compounds tested, only 1-butylpyridin-2-ol remained unchanged, which is most likely due to its bulkiness. In summary, pyridin-2-ols containing small 1-alkyl substituent are hydroxylated regioselectively, but further pyridine ring opening reaction does not occur. Thus, Burkholderia sp. MAK1 is capable of producing 1-alkylpyridine-2,5-diols.

Another group of potential Burkholderia sp. MAK1 substrates comprised pyridin-2-ols substituted at position 3 (Fig. 2). HPLC-MS analysis revealed that compounds containing hydroxyl, methyl, bromo, chloro, or fluoro functional groups were completely catabolized by Burkholderia sp. MAK1 cells since no significant peaks corresponding to any hydroxylated products were detected. The latter suggests that the hydroxylated metabolites were likely further metabolized to aliphatic products. However, 3-(trifluoromethyl)pyridin-2-ol was slowly converted into a detectable new compound whose molecular mass was 16 Da higher than that of the substrate. Burkholderia sp. MAK1 cells were not able to hydroxylate pyridin-2-ols containing carboxyl or methoxy groups at position 3.

Pyridin-2-ols carrying substituents at positions 3 and 6 were also examined. The pyridin-2-ol-induced cells were able to metabolize 2-hydroxy-6-methyl-pyridine-3-carbonitrile: substrate concentration decreased over time, and no new products were detectable by HPLC-MS. After incubation of Burkholderia sp. MAK1 with 3-amino-6-methyl-pyridin-2-ol, a new compound with a molecular mass of 278 Da accumulated in the reaction mixture. Since the molecular mass of the expected 3-amino-6-methyl-pyridin-2-ol hydroxylation product is 140 Da, it is likely that the oxidation of the substrate is followed by the spontaneous dimerization. When Burkholderia sp. MAK1 cells were incubated with 3-bromo-6-methyl-pyridin-2-ol, neither hydroxylation, nor any other transformation occurred suggesting that 3-bromo functional group disrupted the proper orientation of the substrate.

Pyridin-2-ols substituted at positions 4 and/or 6 were also used as substrates in this study (Fig. 3). Pyridine-2,4-diol was completely oxidized by Burkholderia sp. MAK1 cells after 20 hours of incubation. However, the intermediate product accumulating in the reaction mixture was detected by HPLC-MS and its absorption spectra as well as molecular mass ([M + H]+ = 128.05, [M + H2O + H]+ = 146.10, [2M+ H]+ = 255.05) were consistent with those of hydroxylated pyridine-2,4-diol (Supplementary information Fig. S-III). Using 4-cyano, 4-chloro, 4-bromo, or 4-trifluomethyl substituted pyridin-2-ols, hydroxylation of the pyridine ring did not occur suggesting that the nature of a substituent at position 4 is important for the hydroxylation process.

Pyridine-2,6-diol was transformed by Burkholderia sp. MAK1 to a blue pigment. Previously, Holmes with colleagues described dimerization of pyridine-2,3,6-triol, which led to the formation of a blue pigment38. Following this observation, the hydroxylation of the symmetric pyridine-2,6-diol by Burkholderia sp. MAK1 cells likely occurred at position 3 of the pyridine ring and the resulting pyridine-2,3,6-triol spontaneously dimerized to a blue compound. Moreover, if the sixth position of pyridin-2-ol was occupied by a small and uncharged functional group, the pyridine ring cleavage probably followed the hydroxylation event.

Summarizing experiments with substituted pyridin-2-ols we can make the statement that most of the substrates were consumed without detectable products. Although we were unable to provide any data about structures of the detectible product there were strong evidences suggesting regioselective hydroxylation at 5-position (Table 2).

Screening of pyridin-2-amines as potential substrates for regioselective hydroxylation by Burkholderia sp. MAK1 cells

The ability of Burkholderia sp. MAK1 to transform various pyridin-2-ols encouraged us to study pyridin-2-amines as another group of potential substrates. During the initial experiments, the cells were incubated with pyridin-2-amine for 20 hours. HPLC-MS analysis revealed that pyridin-2-amine was completely consumed, and the new peak in the chromatogram belonged to the expected product. The molecular mass of the product, which was 16 Da higher than that of pyridin-2-amine, confirmed the notion that hydroxylation of the substrate occurred. The UV-Vis spectrum of the product was compared with spectra of commercially available reference standards (pyridin-2-amine hydroxylated at position 3, 4, or 6), yet none of these spectra matched that of the product (Supplementary information Fig. S-IV). From this we presume that in the case of Burkholderia sp. MAK1, pyridin-2-amine undergoes hydroxylation at position 5.

Next, pyrazin-2-amine, a homolog of pyridin-2-amine containing two nitrogen atoms in the aromatic ring, was chosen as a substrate for the bioconversion. HPLC-MS analysis showed that the molecular mass of the biotransformation product was 16 Da higher than that of pyrazin-2-amine, suggesting that Burkholderia sp. MAK1 cells are also capable of pyrazin-2-amine hydroxylation.

Pyridin-2-amines with methyl, nitro, chloro, bromo, or fluoro substituent at position 3 (Fig. 4a) were all transformed by Burkholderia sp. MAK1. Moreover, the pyridin-2-ol-induced cells were also capable of hydroxylating ethyl-2-aminopyridine-3-carboxylate, a compound with a bulky functional group at the 3-position. The conversion product of 3-chloropyridin-2-amine was purified as described in the Materials and Methods section, and its structure was analysed by 1H NMR, 13C NMR, and HPLC-MS analyses. The molecular mass of the product (145 Da) corresponded to that of 6-amino-5-chloro-pyridin-3-ol. The compound showed four peaks in the 1H NMR spectrum (DMSO-d6, ppm): δ = 5.51 (s, 2 H, NH2), 7.11 (d, J = 2.6 Hz, 1H, CH), 7.56 (d, J = 2.6 Hz, 1H, CH), 9.24 (brs, 1H, OH), and five peaks in the 13C NMR spectrum (DMSO-d6, ppm): δ = 113.58, 125.21, 133.73, 146.21, 149.46), identifying the product as 6-amino-5-chloro-pyridin-3-ol. The production yield of 6-amino-5-chloro-pyridin-3-ol was 34%.

Both pyridine-2,3-diamine and 2-aminopyridin-3-ol were transformed into colored compounds, with a molecular mass of 213 Da (yellow-brown) and 214 Da (yellow-green), respectively. The retention time, UV-Vis spectra, and ionisation profile of the oxidation product of 2-aminopyridin-3-ol matched those of the analytical standard (2-amino-3H-dipyrido[3,2-b:2′,3′-e][1,4]oxazine-3-one) suggesting that Burkholderia sp. MAK1 catalyzes the oxidative dimerization of 2-aminopyridin-3-ol. Also, although another analytical standard, pyridine-2,3-diamine derivative, is commercially unavailable, our results indicate, that MAK1 catalyzes dimerization of pyridine-2,3-diamine as well. These dimers are potential anticancer and antimicrobial drugs39.

Next, the ability of Burkholderia sp. MAK1 cells to transform pyridin-2-amines substituted at position 4 was investigated. Compounds with methyl, chloro, bromo, or fluoro substituents were hydroxylated. In all cases, the molecular mass of reaction products, as estimated by HPLC-MS, was 16 Da higher than that of parent compounds indicating that oxidation of substrates had occurred.

In the case of 4-methyl-pyridin-2-amine, 4-chloro-pyridin-2-amine, and 4-fluoro-pyridin-2-amine, the biotransformation catalyzed by the pyridin-2-ol-induced Burkholderia sp. MAK1 cells resulted in the formation of a single product. The products of all three reactions were purified by a reverse phase chromatography (C18 cartridges, water/methanol mixture, 10:0 → 10:5), and their structures were analysed by 1H NMR and 13C NMR. 6-Amino-4-methyl-pyridin-3-ol (1H NMR (DMSO-d6, ppm): δ = 2.18 (s, 3H, CH3), 6.41 (dd, J = 6.6, 2.3 Hz, 1H, CH), 6.61 (d, J = 2.3 Hz, 1H, CH), 6.70 (s, 2H, NH2), 7.87 (d, J = 6.6 Hz, 1H, CH), 13C NMR (DMSO-d6, ppm): δ = 20.52, 109.39, 113.72, 136.73, 138.00, 150.61), 6-amino-4-chloro-pyridin-3-ol (1H NMR (DMSO-d6, ppm): δ = 6.66 (dd, J = 7.0, 2.9 Hz, 1H, CH), 6.84–6.83 (m, 1H, CH), 7.0 (s, 2H, NH2), 8.04 (d, J = 7.0 Hz, 1H, CH), 13C NMR (DMSO-d6, ppm): δ = 108.17, 112.44, 131.29, 138.34, 151.70) and 6-amino-4-fluoro-pyridin-3-ol (1H NMR (DMSO-d6, ppm): δ = 6.54 (td, J = 7.3, 3.4 Hz, 1H, CH), 6.62 (dd, J = 9.1, 3.2 Hz, 1H, CH), 7.11 (s, 2H, NH2), 8.07 (dd, J = 7.2, 6.0 Hz, 1H, CH), 13C NMR (DMSO-d6, ppm): δ = 95.45, 100.74, 139.03, 158.91, 161.39) were formed by whole cells of Burkholderia sp. MAK1 with the yield of 34%, 50% and 68%, respectively (Fig. 4b). In addition, 4-chloropyrimidin-2-amine, pyrimidine-2,4-diamine, and 2-aminopyrimidin-4-ol were also hydroxylated by the pyridin-2-ol-induced Burkholderia sp.MAK1 cells. According to the 1H NMR and 13C NMR analyses, the purified product of 2-aminopyrimidin-4-ol conversion was 2-aminopyrimidine-4,5-diol, and the conversion yield was 18%. To our knowledge, biocatalytical production of 6-amino-4-methyl-pyridin-3-ol has never been described previously. Moreover, there is no available information concerning the synthesis of 6-amino-4-chloro-pyridin-3-ol or 6-amino-4-fluoro-pyridin-3-ol. By analogy to aminophenols, the new compounds described in this study have great potential as materials for the production of dyes, drugs, pesticides, and etc.40.

The compounds substituted at position 6 (Fig. 4c) were also transformed by Burkholderia sp. MAK1. HPLC-MS analysis showed that pyridine-2,6-diamine was consumed; however, no new compounds were detected. Nevertheless, in the case of pyridine-2,6-diamine, the reaction mixture turned brown suggesting that after oxidation, further transformations (e. g. polymerisation) occurred. The compounds with 6-chloro or 6-bromo substituents were converted to the corresponding hydroxylated products. The product of oxidation of 6-chloropyridin-2-amine, 6-amino-2-chloropyridin-3-ol, was purified and identified by 1H NMR (DMSO-d6, ppm): δ = 5.90 (s, 2H, NH2), 6.38 (d, J = 7.8 Hz, 1H, CH), 6.84 (d, J = 7.8 Hz, 1H, CH), 9.79 (brs 1H, OH). While 6-fluoropyridin-2-amine conversion was very slow, the transformation of 6-methoxypyridin-2-amine did not occur at all. The conversion of 6-aminopyridin-2-ol led to several compounds suggesting that the substrate is hydroxylated at position 3 and/or 5, so that a mixture of several products in varying proportions results.

Unlike the aforementioned pyridin-2-ols, the products of hydroxylation of 6-substituted pyridin-2-amines were not metabolised further suggesting that Burkholderia sp. MAK1 may be applied for the regioselective synthesis of 6-substituted 2-aminopyridinols (Table 1).

Oxyfunctionalization of pyridine, pyrazine and their derivatives using whole-cell biocatalyst

The study on pyridin-2-amine and pyridin-2-ol bioconversion by Burkholderia sp. MAK1 cells showed that the pyridin-2-ol-inducible pyridin-2-ol 5-monooxygenase has broad substrate specificity and strict regiospecificity since it catalyzes hydroxylation at position 5 on the aromatic ring. With very few exceptions, microbial hydroxylation of pyridine-2-amines has been scarcely studied. One such exception is the study on the biotransformation of 4-methyl-3-nitro-pyridin-2-amine using whole-cells of fungus Cunninghamella elegans ATCC 26269. During this biotransformation, a mixture of three products, 6-amino-4-methyl-5-nitropyridin-3-ol, 2-amino-4-hydroxymethyl-3-nitropyridine, and 2-amino-4-methyl-3-nitropyridine-1-oxide was obtained suggesting that both aromatic and aliphatic positions as well as the heterocyclic nitrogen atom undergo oxidation41. In the case of Burkholderia sp. MAK1 cells, oxidation of the heterocyclic nitrogen atom was not observed when pyridin-2-ols were used as substrates. To determine if these bacteria were capable of producing N-oxides, various pyridine and pyrazine compounds without amino or hydroxy group at position 2 were tested as substrates for pyridin-2-ol-induced Burkholderia sp. MAK1 cells. HPLC-MS analysis showed that pyridine was transformed into a single product whose molecular mass was 16 Da higher than that of the parent compound. The UV spectrum of the product was very similar to that of pyridine yet did not match with the spectra of 2-, 3-, or 4-hydroxy-substituted pyridines at position suggesting that the product of pyridine biotransformation is pyridine-1-oxide (pyridine-N-oxide). The retention time, UV spectrum and ionisation profile of the bioconversion product matched those of analytical standard, pyridine-N-oxide, suggesting that Burkholderia sp. MAK1 catalyzes pyridine oxidation at position 1. Induction of cells with pyridin-2-ol was necessary for the oxidation of pyridine as well as for pyridin-2-ol and pyridin-2-amine transformation indicating that the same enzyme of Burkholderia sp. MAK1 is responsible for all these biotransformations.

A group of pyridines and pyrazines containing a methyl group attached to the aromatic ring at different positions (Fig. 5) was studied as potential substrates for Burkholderia sp. MAK1. The test revealed that the whole cells of Burkholderia sp. MAK1 catalyzed the transformation of 2-methyl-, 3-methyl-, and 4-methylpyridine into corresponding N-oxides whose structures were confirmed by HPLC-MS using analytical standards (Table 3). Burkholderia sp. MAK1 was also capable of transforming di- and trimethyl pyridines, except those in which both positions adjacent to nitrogen were occupied.

Based on HPLC-MS analysis, the biotransformation of pyrazine resulted in the formation of two products with molecular masses that were 16 Da and 32 Da higher than that of the parent compound. 1H and 13C NMR analysis allowed identification of these products as pyrazine-1-oxide (1H NMR (DMSO-d6, ppm): δ = 8.34–8.36 (m, 2H, CH), 8.54–8.57 (m, 2H, CH); 13C NMR (DMSO-d6, ppm): δ = 134.85, 148.94) and pyrazine-1,4-dioxide (1H NMR (DMSO-d6, ppm): δ = 8.28 (s, 4H, CH); 13C NMR (DMSO-d6, ppm): δ = 137.21).

Our research revealed that Burkholderia sp. MAK1 has also the ability to oxidize various methylpyrazines. For the oxidation of methylated pyrazines the single free position adjacent to either one of nitrogen atoms was a sufficient condition, e. g. the cells could oxidize 2,3,5-trimethylpyrazine, but not 2,3,5,6-tetramethylpyrazine.

To date, only a few reports regarding the microbial N-hydroxylation of pyridines have been published. The formation of pyridine N-oxides has been observed in fungi Cunninghamella elegans ATCC 2626941, Verticillium sp. GF3931, and other fungi42 as well as in bacteria Methylococcus capsulatus29 and Diaphorobacter sp. J5-5143. Also, the purified aromatic peroxygenase from fungus Agrocybe aegerita has been found to be active towards pyridine and its derivatives30. In this context, the results of this study not only broaden our understanding of microbial transformation but also provide a versatile tool that can be used in a regioselective oxyfunctionalization of various pyridine derivatives.

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