Ribosides and Ribotide of a Fairy Chemical, Imidazole-4-carboxamide, as Its Metabolites in Rice

Article abstract of DOI:10.1021/acs.orglett.9b02833

The metabolism of imidazole-4-carboxamide (ICA) in plants has been unknown. Two metabolites (1 and 2) were isolated from ICA-treated rice, and their structures were determined by spectroscopic analysis including the single-crystal X-ray diffraction technique and synthesis. The ribotide of ICA (3), whose existence was predicted, was also synthesized and detected from the treated rice by LC-MS/MS. These results indicated that rice might interconvert ICA, 1, and 3 to regulate the biological activity.

Full text of DOI:10.1021/acs.orglett.9b02833

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ribosides and Ribotide of a Fairy Chemical, Imidazole-4-
carboxamide, as Its Metabolites in Rice
Jae-Hoon Choi,†,‡ Nobuo Matsuzaki,§ Jing Wu,‡ Mihaya Kotajima,† Hirofumi Hirai,†,‡ Mitsuru Kondo,‡
Tomohiro Asakawa,∥ Makoto Inai,⊥ Hitoshi Ouchi,⊥ Toshiyuki Kan,⊥
and Hirokazu Kawagishi*,†,‡,§
†Graduate School of Integrated Science and Technology, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529, Japan
‡Research Institute of Green Science and Technology, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529, Japan
§Graduate School of Science and Technology, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529, Japan
∥Tokai University Institute of Innovative Science and Technology, 4-1-1 Kitakaname, Hiratsuka City, Kanagawa 259-1292, Japan
⊥School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
S
* Supporting Information
ABSTRACT: The metabolism of imidazole-4-carboxamide
(ICA) in plants has been unknown. Two metabolites (1 and
2) were isolated from ICA-treated rice, and their structures
were determined by spectroscopic analysis including the
single-crystal X-ray diffraction technique and synthesis. The
ribotide of ICA (3), whose existence was predicted, was also
synthesized and detected from the treated rice by LC−MS/
MS. These results indicated that rice might interconvert ICA,
1, and 3 to regulate the biological activity.
in agriculture.3,4,9 All of the above-mentioned results allowed
airy rings are zones of promoted or suppressed grass
Fgrowth due to the interaction between a fungus and a
us to conclude that FCs are biosynthesized on the novel purine
metabolic pathway in plants. We have formulated a hypothesis
that FCs are a new family of plant hormones, and the
plant.1 Since the first scientific article about fairy rings in 1675
and subsequent studies reviewed in Nature in 1884,2 this
phenomenon had been attributed to unknown “fairies” before
our studies. Our work has disclosed that the fairies, the plant-
growth promoter and suppresser produced by a fairy-ring-
forming fungus Lepista sordida, are 2-azahypoxanthine (AHX)
and imidazole-4-carboxamide (ICA), respectively.3 After the
two compounds were found, 2-aza-8-oxohypoxanthine (AOH)
was isolated as a common metabolite of AHX in plants, and
this compound also stimulated plant growth like AHX.4 The
three compounds were named fairy chemicals (FCs) after the
title of the article in Nature that prefaced our study.5 We have
also reported the endogenous existence of FCs in plants and
the discovery of new routes in the purine metabolic pathway in
which FCs are biosynthesized.4,6 These results indicated that
FCs are probably common members of the purine metabolic
pathway in plants and microorganisms.4,6−8
FCs exhibit growth regulatory activity against all of the
plants tested regardless of their belonging families and
conferred tolerance to various and continuous stress (low or
high temperature, salt, drought, etc.) on the plants.3,4
Furthermore, the yields of rice, wheat, or other crops were
increased by the treatment with each FC in a greenhouse or in
field experiments, suggesting the possibility of FC applications
elucidation of metabolic pathway of FCs is critical to prove the
hypothesis.8,10,11 Recently, N-glucosides of AHX and AOH
were discovered as their metabolites in rice.12 However, the
metabolism of ICA in plants has not been revealed. Herein we
describe the discovery of three metabolites of ICA in rice
(Figure 1).
First of all, to know the metabolism of ICA in plants, rice,
cucumber, tomato, lettuce, and komatsuna (Brassica rapa L. cv.
Rakuten) were incubated with ICA. High-Performance Liquid
Chromatography (HPLC) analysis with photodiode array
(PDA) detection of the ICA-treated rice indicated that ICA
was converted into some metabolites, mainly compounds 1
and 2 (Figure S1a). The conversion of ICA to 1 was also
observed in the other plants tested (Figure S1b−e).
Therefore, we tried to isolate the metabolites from rice. Rice
was cultivated in ICA-containing culture broth for 2 weeks;
then, the rice was divided into roots and shoots. EtOH extracts
of the roots were fractionated by octadecyl-silica (ODS) flash
Received: August 9, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02833
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Letter
was determined from the HMBC cross-peak (H-1′/C-2, C-5).
All of the data of the isolated 1 and the synthetic one,
25
including specific optical rotation values (isolated 1, [α]D
−39 (c 0.28 MeOH); synthetic 1, [α]D26 −41 (c 0.28 MeOH))
and NMR data (Figures S3 and S4), were identical to each
other, indicating that the sugar part of 1 was D-ribose.
Although 1 has been synthesized and its antiviral activity
against HV/1, RV/13, and PIV/3 and inhibitory activity
against nucleotide biosynthesis and adenosine deaminase have
been reported, this is the first isolation of the compound from
a natural source.13 The complete assignment of all of the
proton and carbon signals of NMR was accomplished as shown
in Table 1.
Compound 2 was purified as a pale-yellow, amorphous
material. The molecular formula was determined as
C15H23N3O10 by HRESIMS (m/z 428.1281 [M + Na]+;
calcd for C15H23N3NaO10, 428.1281), indicating the presence
of six degrees of unsaturation in the molecule. The structure of
2 was elucidated by the interpretation of NMR data including
DEPT, DQF-COSY, HMQC, and HMBC (Figures S5−S8).
The DEPT experiment indicated the presence of 2 methylenes,
11 methines, and 2 quaternary carbon atoms. The molecular
formula, the unsaturation degrees, the 13C NMR data (δC 60.7,
69.4, 83.0, 86.0, 90.7 121.0, 129.5, 136.4, 161.6), and the
DEPT data indicated that 2 was a kind of ICA−riboside like 1.
The skeleton of the riboside part (C-2 to C-6; C-1′ to C-5′)
was constructed by the DQF-COSY correlations (H-1′/H-2′;
H-2′/H-3′; H-3′/H-4′; H-4′/H-5′) (Figure 2 and Figure S7)
and the HMBC correlations (H-1′/C-2, C-5, C-2′; H-2′/C-1′,
C-4′; H-3′/C-1′,C-5′; H-5′/C-3′,C-4′) (Figure 2 and Figure
S8). However, this compound possessed an additional six
carbon atoms compared with 1. The presence of glucose (C-1″
to C-6′′) was suggested by the characteristic 13C NMR
chemical shifts at δC 60.3, 69.2, 73.1, 75.4, 76.0, and 103.0, 1H
NMR chemical shifts, and coupling constants: δH 3.22 (H-5″,
m), 3.25 (H-2′′, m), 3.27 (H-4′′, m), 3.36 (H-3′′, dd, J = 9.2,
9.2 Hz), 3.51 (H-6″a, dd, J = 12.0, 4.0 Hz), 3.53 (H-6″b, dd, J
= 12.0, 3.5 Hz), and 4.46 (H-1″, d, J = 8.0 Hz). The HMBC
cross-peaks (H-1″/C-2′, H-2′/C-1′′) and the coupling
constant of the anomeric proton (J = 8.0 Hz) indicated that
the glucose was connected to the ribose at C-2′ via a β-
glucosidic bond. The relative configuration of 2 was confirmed
by single-crystal X-ray analysis (Figure 3). 2 was hydrolyzed
with β-glucosidase to give 1, indicating that the sugars in 2
were D-ribose and D-glucose (Figure S9). Compound 2 was a
novel compound. The complete assignment of all of the proton
and carbon signals of NMR was accomplished as shown in
Table 1.
Figure 1. Structures of ICA and its metabolites.
column chromatography, followed by HPLC to yield
compounds 1 and 2.
Compound 1 was purified as a pale-yellow, amorphous
material. The molecular formula was determined as
C9H13N3O5 by high-resolution electrospray ionization mass
spectrometry (HRESIMS) (m/z 266.0724 [M + Na]+; calcd
for C9H13N3NaO5, 266.0753), indicating the presence of five
degrees of unsaturation in the molecule. The structure of 1 was
elucidated by the interpretation of nuclear magnetic resonance
(NMR) spectra including distortionless enhancement by
polarization transfer (DEPT), double-quantum-filtered corre-
lation spectroscopy (DQF-COSY), heteronuclear multiple-
quantum correlation (HMQC), and heteronuclear multiple
bond correlation (HMBC). The DEPT experiment indicated
the presence of one methylene, six methines, and two
quaternary carbon atoms. 13C NMR data (δC 122.1, 137.5,
138.1, 167.2) indicated that 1 had the same skeleton as ICA.3b
However, this compound possessed five more carbon atoms
than ICA. As the skeleton of the additional moiety, a pentose
(C-1′ to C-5′), was constructed by the characteristic 13C NMR
chemical shifts at δC 62.8, 72.2, 77.7, 87.4, and 92.0, the DQF-
COSY correlations (H-1′/H-2′; H-2′/H-3′; H-3′/H-4′; H-4′/
H-5′), and the HMBC correlations (H-1′/C-2′; H-2′/C-1′; H-
3′/C-1′; H-4′/C-3′; H-5′/C-3′, C-4′) (Figure 2). The NMR
data of the pentose moiety in 1 were very similar to those of
ribose. The linkage position between the aglycon and ribose
Members of a plant hormone family, cytokinins, are
interconvertible to their ribosides and ribotides. Hence, we
postulated that it was possible that ICA−ribotide (3) was also
produced by plants. Therefore, to confirm the existence of 1
and 3 in rice, chemical synthesis was investigated. The
synthesis of 1 and 3 was commenced with protected AICA−
riboside (4) (Scheme 1), which was readily obtained from the
commercially available inosine.14 After the removal of the
dinitrophenyl group of 4, the deamination reaction was carried
out by the treatment with sodium nitrite under acidic
conditions to provide the protected ICA−riboside (5).
Although utilizing a similar condition as the dinitrophenyl-
protected derivative, the diazonium salt formation and
subsequent cyclization to the triazine ring proceeded,14 and
deamination occurred in this case. Subsequently, the treatment
Figure 2. DQF-COSY and HMBC correlations of 1 and 2.
B
DOI: 10.1021/acs.orglett.9b02833
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1
Table 1. H and 13C NMR Data for 1 and 2
1 (in D2O)
2 (in D2O)
1H
13C
1H
δH (mult, J in Hz)
8.75 (s)
13C
position
δH (mult, J, Hz)
δC, type
δC, type
2
4
5
6
1′
2′
3′
4′
5′a
5′b
1″
2″
3″
4″
5″
6″a
6″b
7.93 (d, 1.4)
138.1 CH
137.5 C
122.1 CH
167.2 C
92.0 CH
77.7 CH
72.2 CH
87.4 C
136.4 CH
129.5 C
121.0 CH
161.6 C
90.7 CH
83.0 CH
69.4 CH
86.0 CH
60.7 CH2
7.92 (d, 1.4)
8.12 (s)
5.67 (d, 5.5)
6.01 (d, 4.6)
4.26 (dd, 5.5, 5.5)
4.20 (dd, 5.5, 3.4)
4.07 (ddd, 3.4, 3.4, 3.5)
3.71 (dd, 12.2, 3.4)
3.79 (dd, 12.2, 3.5)
4.55 (dd, 4.6, 5.2)
4.36 (dd, 5.2, 4.6)
4.18 (ddd, 4.6, 4.0, 3.2)
3.70 (dd, 12.8, 4.0)
3.79 (dd, 12.8, 3.2)
4.46 (d, 8.0)
3.25 (m)
3.36 (dd, 9.2, 9.2)
3.27 (m)
62.8 CH2
103.0 CH
73.1 CH
75.4 CH
69.2 CH
76.0 CH
60.3 CH2
3.22 (m)
3.51 (dd, 12.0, 4.0)
3.53 (dd, 12.0, 3.5)
and is biosynthesized in plants like AHX and AOH.3 The
existence of 1−3 in intact rice was also examined by LC−MS/
MS. As a result, 1 and 3 were detected in the extracts of intact
rice, indicating the endogenous existence of the compounds in
rice (Figure S12). In general, each member on the purine
pathway is metabolized to other ones as a ribotide; therefore,
ribotides are important intermediates of bioactive free bases on
their biosynthetic pathways. ICA may be further metabolized
to unknown base(s) via its ribotide 3 in plants.
To examine the metabolism of 1 and 2, rice was treated with
1 or 2. Conversions from 1 to ICA and 2 and from 2 to ICA
and 1 were observed in both the shoots and roots, suggesting
that the interconversion among ICA, 1, and 2 was reversible in
rice (Figure 4 and Figure S13). Adenosine kinases have
revealed the predominant activity responsible for phosphor-
ylation for AICA−riboside in the eukaryotic cells.16 In general,
purine nucleotides are converted to their nucleosides by 5′-
nucleotidase. The interconversion of 1 and 3 may react with
the above enzymes in plants.
Figure 3. ORTEP drawing of 2. The structure was solved by a direct
method, SHELXL-97 (1), and refined using the SHELXL-97 tool.
Crystallographic data have been deposited at The Cambridge
Crystallographic Data Centre and allocated the deposition number
CCDC 1531773.
Scheme 1. Synthesis of ICA−Riboside (1) and ICA−
Ribotide (3)
The plant growth regulatory activity of 1 and 2 was
examined using rice. Both of the compounds showed inhibition
activity against the shoots only at high concentration (0.1 mM)
and showed no significant effect on the roots (Figure S14). As
previously mentioned, cytokinins are interconvertible to their
ribosides and ribotides, and those glycosides are the inactive
forms of the corresponding free base forms.17 The free base
forms are usually more active than the corresponding ribosides
and ribotides in various bioassays, which may be related to
rapid uptake and high intrinsic activity.18 The inhibitory
activity of 1 and 2 might be due to ICA that was converted
from 1 and 2 in rice (Figure 4 and Figures S13 and S14). Many
enzymes involved in cytokinin biosynthesis, interconversion,
inactivation, and degradation have been identified and play
very important roles in the regulation of endogenous cytokinin
homeostasis. The above results suggest that the interconver-
sion among ICA, 1, and 2 regulates the homeostasis of ICA in
rice.
of 5 with NH4F to remove the tert-butyldimethylsilyl (TBS)
groups provided 1. On the contrary, the synthesis of 3 was
demonstrated by utilizing 5. After the selective removal of the
TBS group on the primary alcohol, the incorporation of
phosphate ester was carried out by the phosphoramidite
method15 and stepwise deprotection of the TBS and benzyl
groups to give 3 (Figure S10).
In the LC−MS/MS analysis using the synthetic 3 as the
authentic standard, this compound was detected in the extracts
of the ICA-treated rice (Figure S11). ICA exists endogenously
In conclusion, we discovered three metabolites of ICA,
ribosides (1 and 2) and ribotide (3), from ICA-treated rice,
and the endogenous existence of 1 and 3 in rice was proved.
C
DOI: 10.1021/acs.orglett.9b02833
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by a Grant-in-Aid for
Scientific Research on Innovative Areas “Frontier Research on
Chemical Communications” (JP17H06402) from MEXT to
H.K. and a Grant-in-Aid for Young Scientists A (JP16H06192)
from MEXT to J.-H.C. We thank K. Okamoto (Ushio ChemiX
Co. Ltd.) for providing ICA.
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Figure 4. Novel purine metabolic pathway in rice. The route
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02833.
Experimental section, synthesis, HPLC profiles, NMR
spectra, plant growth regulatory effect, metabolism, and
endogenous existence (PDF)
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Accession Codes
CCDC 1531773 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kawagishi.hirokazu@shizuoka.ac.jp.
ORCID
Makoto Inai: 0000-0001-7074-0520
Toshiyuki Kan: 0000-0002-9709-6365
Hirokazu Kawagishi: 0000-0001-5782-4981
D
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