4-Hydroxy-3-methyl-2(1h)-quinolone, originally discovered from a brassicaceae plant, produced by a soil bacterium of the genus burkholderia sp.: Determination of a preferred tautomer and antioxidant activity

Article abstract of DOI:10.3762/bjoc.16.124

4-Hydroxy-3-methyl-2(1H)-quinolone (1), a molecule known for a long time and recently discovered from a Brassicaceae plant Isatis tinctoria without providing sufficient evidence to support the structure, was isolated from a fermentation extract of Burkholderia sp. 3Y-MMP isolated from a soil by a Zn2+ enrichment culture. Detailed spectroscopic analyses by MS and NMR, combined with 13C chemical shift comparison with literature values of the related compounds and a synthetic preparation of 1, allowed its first full NMR characterization and identification of 2-quinolone but not 2-quinolinol (2) as the preferred tautomer for this heterocyclic system. While the metal-chelating activity was negligible, compound 1 at 10 μM, a concentration lower than that in liquid production cultures, quenched hydroxy radical-induced chemiluminescence emitted by luminol by 86percent. Because some Burkholderia species are pathogenic to plants and animals, the above result suggests that 1 is a potential antioxidant to counteract reactive oxygen species-based immune response in the host organisms.

Full text of DOI:10.3762/bjoc.16.124

4-Hydroxy-3-methyl-2(1H)-quinolone, originally discovered
from a Brassicaceae plant, produced by a soil bacterium of
the genus Burkholderia sp.: determination of a preferred
tautomer and antioxidant activity
Dandan Li1, Naoya Oku1, Yukiko Shinozaki2, Yoichi Kurokawa3 and Yasuhiro Igarashi*1
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 1489–1494.
1Biotechnology Research Center and Department of Biotechnology,
doi:10.3762/bjoc.16.124
Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama
9
39-0398, Japan, 2National Institute of Technology, Toyama College,
3 Hongo-machi, Toyama City, Toyama 939-8630, Japan and
Received: 10 April 2020
Accepted: 08 June 2020
Published: 26 June 2020
1
3Department of Bioscience and Biotechnology, Fukui Prefectural
University, Eiheiji-cho, Fukui, Japan
Associate Editor: J. S. Dickschat
Email:
Yasuhiro Igarashi* - yas@pu-toyama.ac.jp
© 2020 Li et al.; licensee Beilstein-Institut.
License and terms: see end of document.
*
Corresponding author
Keywords:
antioxidant; Burkholderia sp; quinolone; soil bacterium; Zn2+
enrichment culture
Abstract
4
-Hydroxy-3-methyl-2(1H)-quinolone (1), a molecule known for a long time and recently discovered from a Brassicaceae plant
Isatis tinctoria without providing sufficient evidence to support the structure, was isolated from a fermentation extract of Burk-
holderia sp. 3Y-MMP isolated from a soil by a Zn2+ enrichment culture. Detailed spectroscopic analyses by MS and NMR,
combined with 13C chemical shift comparison with literature values of the related compounds and a synthetic preparation of 1,
allowed its first full NMR characterization and identification of 2-quinolone but not 2-quinolinol (2) as the preferred tautomer for
this heterocyclic system. While the metal-chelating activity was negligible, compound 1 at 10 μM, a concentration lower than that
in liquid production cultures, quenched hydroxy radical-induced chemiluminescence emitted by luminol by 86%. Because some
Burkholderia species are pathogenic to plants and animals, the above result suggests that 1 is a potential antioxidant to counteract
reactive oxygen species-based immune response in the host organisms.
Findings
4
-Hydroxy-2(1H)-quinolone (3) is a unique structural motif ing 2,4-dihydroxyquinoline (4) [3-5], although which form to be
mostly found in alkaloids from rutaceous plants (family taken seems not always be correctly identified in some of the
Rutaceae) [1,2]. This motif has several tautomeric forms includ- studies [6-8]. Currently, 229 compounds are known to contain
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Beilstein J. Org. Chem. 2020, 16, 1489–1494.
this unit as a part or a whole of the structure, among which only The producing strain 3Y-MMP was cultured in King’s B medi-
1
2 originated from organisms other than rutaceous plants [9]. um [18] for 4 days and the production culture was extracted
Examples from microbes include chymase inhibitors SF2809-I with 1-BuOH. The butanolic extract was partitioned between
to VI from an actinomycete of the genus Dactylosporangium CH2Cl2 and 60% MeOH, and the latter layer was flash-chro-
[
10], a quorum sensing signaling molecule 2,4-dihydroxyquino- matographed on ODS followed by reversed-phase HPLC to
line (DHQ, 4) from Gram-negative bacteria Pseudomonas yield 1 (5.2 mg) with sufficient purity for structure characteriza-
aeruginosa and Burkholderia thailandensis, [7], and 4-O-β-ᴅ- tion.
glucopyranosyl-2,3,4-trihydroxyquinoline (5) from an
ascomycete of the genus Alternaria [8].
The molecular formula of 1 was determined to be C10H9NO2
based on a sodium adduct molecular ion peak at m/z 198.0525
The genus Burkholderia sensu lato, within the class Betapro- observed by a HRESITOFMS measurement (calcd 198.0526).
teobacteria, represents a polyphyletic group of bacteria, which The broad IR absorption band around 3100 cm−1 and an intense
undergoes reclassification into several lineages [11]. Members peak at 1600 cm−1 indicated the existence of hydroxy and aro-
of this group are basically free-living aerobes inhabiting soil matic groups, respectively.
and freshwater, but some are also found in the tissues of
animals, plants, or fungi as pathogens or beneficial symbionts The 1H and 13C NMR spectra in DMSO-d6 displayed 6 and 10
[
12]. Not only as the subjects of human/animal health care and resonances, respectively, and by combining with the results of
plant pathology [13], but they are now gathering significant 1H,1H coupling constants and COSY and HSQC spectroscopic
attention as an emerging source of bioactive molecules. Many analysis, following 8 molecular pieces were revealed: a consec-
new structure classes, even after being spun off as a new genus utive four aromatic methines (δC 129.8, 122.7, 121.2, 115.0;
from Pseudomonas in 1992 [14], have been discovered from δH 7.85, 7.41, 7.23, 7.12), two heteroatom-substituted nonproto-
this group, which, along with their large genomes comparable nated sp2 carbons (δC 164.0 and 157.4), three sp2 nonproto-
to those of actinomycetes or myxobacteria, demonstrate a nated carbons (δC 137.4, 115.8, and 106.9), an allylic methyl
higher capacity of secondary metabolism [15].
group (δC 9.6/δH 1.98 s), and a singlet exchangeable proton
δH 11.30). The four methine unit (C5–C6–C7–C8) was
(
In the course of our continuing studies on bioactive metabolites connected to the two quaternary carbons (δC 137.4 and 115.8:
of less studied bacterial taxa [16], Burkholderia sp. 3Y-MMP, C8a and C4a) to form a disubstituted benzene ring by HMBC
isolated from soil by an exhaustive enrichment culture under correlations H5/C8a, H6/C4a, H7/C8a, H8/C4a, and H8/C8a.
Zn2+-load, was selected for a detailed chemical study, which On the other hand, the remaining parts were assembled into a
resulted in the isolation of 4-hydroxy-3-methyl-2(1H)- C4 enol-amidyl or enol-imidic acyl unit based on HMBC corre-
quinolone (1, Figure 1). This compound was recently reported lations from the methyl proton H39 to the three nonprotonated
from the root of woad (Isatis tinctoria, family Brassicaceae) carbons C4 (δ 157.4), C3 (δ 106.9), and C2 (δ 164.0). Connec-
with no details of structure characterization [17]. Herein we tion of this unit to C4a of the benzene ring was implied by an
describe the isolation, unequivocal structure characterization, HMBC correlation from H39 to C4a, and correlations from the
and antioxidant activity of compound 1.
exchangeable proton to C4a and C3 supported this linkage as
well as hydroxylation at the benzylic position. Finally, the
chemical shift of C8a at 137.4 ppm was in favor of N-substitu-
tion, and comparison with the literature values from 4-methoxy-
1
,3-dimethyl-2(1H)-quinolone (6, δ 138.4) [19], N-methyl-2-
pyridone 7 (δ 139.5) [20], 2,4-dimethoxy-3-methylquinoline (8,
δ 147.0) [21], and 2-methoxypyridine 9 (δ 147.2) [22] sup-
ported a 2-quinolone form 1 but not 2-quinolinol 2 (Figure 2,
Table 1). The same structure was synthesized from diethyl
malonate and aniline (see Supporting Information File 1 for full
experimental data), which substantiated this assignment.
Although compound 1 has repeatedly been synthesized since
1
921 [23] and enumerated chemical shifts for 1H and 13C reso-
nances were available [24], one-on-one assignments of the reso-
nances to each structural part have not been made until this
work. In addition, HMBC correlations from the enol proton and
Figure 1: Structures of compounds 1–5.
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Beilstein J. Org. Chem. 2020, 16, 1489–1494.
Figure 2: COSY-deduced spin-system (bold lines) and key HMBC correlations (arrows) for compound 1, and structures for compounds 6–10 with a
13C chemical shift at the C8a position.
Table 1: 1H (500 MHz) and 13C (125 MHz) NMR data of compound 1 in DMSO-d6 (297 K).
1
No.
13C
1H multiplicity, (J in Hz), integration
HMBC (→13C)
1
2
3
4
4
4
5
6
7
8
8
9
a
164.0
106.9
157.4
-OH
11.30 brs, 1H
3, 4a
a
115.8
122.7
121.2
129.8
115.0
137.4
9.6
7.85 dd (7.9, 1.0), 1H
7.12 ddd (7.9, 7.2, 0.7), 1H
7.41 ddd (8.1, 7.2. 1.2), 1H
7.23 d (8.1), 1H
4, 7, 8a
4a, 5, 7, 8, 8a
5, 8, 8a
4, 4a, 6, 7, 8a
a
1.98 s, 3H
2, 3, 4, 4a
aSignal for amide proton not observed.
the comparison of the chemical shift of the carbon adjacent to of this class are classified into two lineages, those with or with-
the nitrogen with the literature values unequivocally deter- out a 3-methyl group, and the former lineages are unique to
mined 2-quinolone to be a preferred tautomer of this hetero- Burkholderia producers [28]. These metabolites are shown to be
cyclic system. The same C8a carbons of compounds 4 and 5 biosynthesized by head-to-head condensation of anthranilate
resonate at 139.2 [25] and 133.4 ppm [8], respectively (Figure 1 and β-ketoacylate precursors, followed by a modification at C3
and Figure 2), which indicates that both also exist as or nitrogen by putative monooxygenases or methyltransferase
2
4
-quinolone and hence should more precisely be called as [27]. Entry of malonate as the acylate precursor into this path-
-hydroxy-2(1H)-quinolone (4HQ, 3) and 4-O-β-ᴅ-glucopyra- way is proposed to yield 3 (4 in the original literature) [29].
nosyl-3,4-dihydroxy-2-quinolone (10), respectively.
Thus, 1 is very likely to be biosynthesized by the same mecha-
nism followed by additional methylation on C3.
Though not alkylated, the close structural similarity to 3 sug-
gests that 1 is also a member of the 2-alkyl-4-quinolone class Compound 1 is reportedly inhibitory to Mycobacterium tuber-
signaling molecules/antibiotics known from Pseudomonas culosis H37Ra at IC90 6.8 μM while weakly cytotoxic to MRC-
aeruginosa and some Burkholderia species [26,27]. Quinolones 5 human lung-derived fibroblasts with GI50 84.7 μM [30]. It did
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Beilstein J. Org. Chem. 2020, 16, 1489–1494.
not inhibit the production of nitric oxide in RAW 264.7 murine ment using Chrome Azurol S-Fe3+ (CAS) [45], which required
macrophage-like cells [31]. In our hands, 1 was inactive against a 1600 times higher concentration for metal-chelation. Thus,
any of the tested strains including Staphylococcus aureus compound 1 was found to be another example of the antioxi-
FDA209P JC-1 (Gram-positive bacterium), Rhizobium dant from Burkholderia. Detailed studies on the antioxidation
radiobacter NBRC14554, Ralstonia solanacearum SUPP1541, mechanism of 1 is now underway.
Tenacibaculum maritimum NBRC16015 (Gram-negative
Experimental
bacteria), Candida albicans NBRC0197, and Saccharomyces
cerevisiae S100 (yeasts).
General experimental procedures
UV and IR spectra were obtained on a Hitachi U-3210 and
Oxidative burst, which is a transient production of massive a Perkin Elmer Spectrum 100, respectively. NMR spectra
reactive oxygen species (ROS), is implemented in eukaryotic were collected on a Bruker AVANCE 500 spectrometer in
cells, including protists [32], as an innate immune response to DMSO-d6 and CDCl3 referenced at δH/δC 2.49/39.8 and
deactivate foreign substances or as part of phagocytic digestion 7.27/77.0, respectively. HRESITOFMS were recorded on a
of internalized nutrients [33]. Pathogenic microbes are equipped Bruker micrOTOF focus mass spectrometer. Chemilumines-
with a multitude of strategies to circumvent host immunity [33], cence was measured on a Molecular Devices SpectraMax M2
among which redox enzymes and antioxidants are the direct microplate reader.
countermeasures to neutralize the toxicity of ROS [34]. Limited
examples of antioxidants include catecholamine melanin from a Microorganism
fungus Cryptococcus neoformans [35], 1,8-dihydroxynaphtha- Burkholderia sp. 3Y-MMP was isolated from a soil sample
lene melanin from fungi Wangiella dermatitidis and Alternaria collected in Toyama, central Japan, in June 2015 by a proce-
alternata [36], staphyloxanthin from a firmicute Staphylo- dure similar to that described in [46]. One mM of ZnCl2,
coccus aureus [37], vitamin B6 from fungi Cercospora nico- instead of CoCl2, was used as a selection pressure during the
tianae, [38] and Rhizoctonia solani [39], and a melanin-like initial exhaustive enrichment culture stage. The 16S rDNA se-
pigment from Burkholderia cenocepacia [40].
quence of strain 3Y-MMP was determined by a DNA analysis
service (Tsuruga Bio, Toyobo Co. Ltd., Osaka, Japan) using a
The antioxidant activity of 1 was evaluated using the luminol primer set 10F (5′-GTTTGATCCTGGCTCA-3′) and 800R
chemiluminescence extinction assay [41,42]. This assay quanti- (5′-TACCAGGGTATCTAATCC-3′). A partial sequence with a
fies the presence of the most detrimental ROS, hydroxy radical length of 800 bp (accession number LC508727) thus read was
[
43,44], as intensity of luminescence emitted by oxidation of queried against the Basic Local Alignment Search Tool
luminol. Compound 1 at 10 μM, which is lower than a concen- program (BLAST) available at the DNA Data Bank of Japan
tration in production liquid cultures (15 μM), decreased lumi- (DDBJ) website, which reported 99.9% homology to Burk-
nescence to 14% of the control reaction (Figure 3). Because the holderia cepacia strain N1_1_43 (accession number
Fenton reaction catalyzed by Cu2+ was used to generate the MN691134). This strain will be deposited in NBRC once it
hydroxy radicals, entrapment of Cu2+ by 1 was initially resumes services, which is currently suspended due to a nation-
suspected as the mechanism of chemiluminescence inhibition. wide State of Emergency regarding COVID-19 declared on
However, this speculation was ruled out by a titration experi- April 16 by the Government of Japan.
Fermentation and isolation
A cell mass of Burkholderia sp. 3Y-MMP, scraped off from an
agar plate, was inoculated into 500 mL K-flasks each contain-
ing 100 mL King’s B medium composed of peptone 2%, glyc-
erin 1%, K2HPO4 0.41%, and MgSO4·7H2O 0.15%. The pro-
duction cultures thus made were rotary shaken at 200 rpm at
3
0 °C for 4 days. After fermentation, an equal amount of 1-bu-
tanol was added to each flask, shaken for additional 1 h, and
then centrifuged at 6000 rpm. The butanol layer was collected
and dried in vacuo to give a solid (2.7 g) from a 2 L culture.
The extract was partitioned between 60% aqueous MeOH and
CH2Cl2, and the former layer was fractionated on ODS eluted
sequentially with a step gradient of MeCN/0.1% HCOOH
mixed in ratios of 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, and 8:2, respec-
Figure 3: Extinction of luminol chemiluminescence by 1.
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Beilstein J. Org. Chem. 2020, 16, 1489–1494.
tively. A fraction eluted by 30% MeCN was evaporated to Acknowledgements
provide 69.4 mg of a solid, which was purified by HPLC on an We thank Prof. Yasufumi Hikichi and Dr. Ayami Kanda at
ODS column (Cosmosil AR-II, 1 × 25 cm) eluted with 16% Kochi University for providing R. solanacearum SUPP1541.
MeCN containing 0.1% HCO2H at a flow rate of 4 mL/min,
which yielded 1 (5.2 mg, tR 31.3 min) with sufficient purity for Funding
NMR-based structure characterization.
This work was supported in part by JSPS KAKENHI Grant
Number 18K05827 to N. O. and President’s Fund Initiative at
4
-Hydroxy-3-methyl-2(1H)-quinolone (1): UV (MeOH) λmax Toyama Prefectural University FY2019.
nm (ε): 312 (2300), 226 (12000); IR (ATR) νmax: 3268, 3186,
2
6
958, 2927, 1595, 1486, 1387, 1354, 1243, 1026, 772, 761, 692, ORCID® iDs
64 cm−1; HRESITOFMS (m/z): [M + Na]+ calcd for
Dandan Li - https://orcid.org/0000-0002-0384-989X
Naoya Oku - https://orcid.org/0000-0002-2171-2168
Yasuhiro Igarashi - https://orcid.org/0000-0001-5114-1389
C10H9NNaO2, 198.0526, found: 198.0525 ; 1H and 13C NMR
data are shown in Table 1.
Evaluation of Fe3+ binding activity
Preprint
The iron-binding activity was evaluated by the CAS assay de-
veloped by Schwyn and Neilands [45]. Compound 1 (2.5 mg) in
DMSO (20 μL) was mixed with a blue-colored CAS stock solu-
A non-peer-reviewed version of this article has been previously published
as a preprint doi:10.3762/bxiv.2020.48.v1
tion (50 μL) and further brought up to 100 μL with H2O (final References
concentration of 1: 160 mM). After 10 min at an ambient tem-
perature, the solution turned orange due to the loss of Fe3+ from
the indicator CAS dye, indicating positive to the iron-binding
ability of 1. A prolonged reaction caused biphasic separation of
the mixture.
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