Isoxazole derivatives as new nitric oxide elicitors in plants

Article abstract of DOI:10.3762/bjoc.13.65

Several 3,5-disubstituted isoxazoles were obtained in good yields by regiospecific 1,3-dipolar cycloaddition reactions between aromatic nitrile oxides, generated in situ from the corresponding hydroxyimidoyl chlorides, with non-symmetrical activated alkyn

Full text of DOI:10.3762/bjoc.13.65

Isoxazole derivatives as new nitric oxide elicitors in plants
Anca Oancea1, Emilian Georgescu2, Florentina Georgescu3, Alina Nicolescu4,5,
Elena Iulia Oprita1, Catalina Tudora1, Lucian Vladulescu3,
Marius-Constantin Vladulescu3, Florin Oancea6 and Calin Deleanu*4,5
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 659–664.
1
National Institute of Research and Development for Biological
Sciences, Spl. Independentei 296, RO-060031 Bucharest, Romania,
Research Center Oltchim, Str. Uzinei 1, RO-240050, Ramnicu
doi:10.3762/bjoc.13.65
2
Received: 31 December 2016
Accepted: 16 March 2017
Published: 06 April 2017
Valcea, Romania, 3Research Dept., Teso Spec SRL, Str. Muncii 53,
RO-915200 Fundulea, Calarasi, Romania, 4Petru Poni Institute of
Macromolecular Chemistry, Romanian Academy, Aleea Grigore
Ghica Voda 41-A, RO-700487 Iasi, Romania, 5C. D. Nenitescu Centre
of Organic Chemistry, Romanian Academy, Spl. Independentei
This article is part of the Thematic Series "Chemical biology".
Guest Editor: H. B. Bode
2
02-B, RO-060023 Bucharest, Romania and 6National Research &
Development Institute for Chemistry & Petrochemistry – ICECHIM,
Spl. Independentei 202, RO-060021 Bucharest, Romania
© 2017 Oancea et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Email:
Calin Deleanu* - calin.deleanu@yahoo.com
*
Corresponding author
Keywords:
chemical elicitor; 1,3-dipolar cycloaddition; isoxazole; nitric oxide;
nitrile oxide; reactive oxygen species
Abstract
Several 3,5-disubstituted isoxazoles were obtained in good yields by regiospecific 1,3-dipolar cycloaddition reactions between aro-
matic nitrile oxides, generated in situ from the corresponding hydroxyimidoyl chlorides, with non-symmetrical activated alkynes in
the presence of catalytic amounts of copper(I) iodide. Effects of 3,5-disubstituted isoxazoles on nitric oxide and reactive oxygen
species generation in Arabidopsis tissues was studied using specific diaminofluoresceine dyes as fluorescence indicators.
Introduction
Isoxazoles are an interesting class of N-heterocyclic com- activities. Several isoxazole derivatives have GABAA antago-
pounds intensely studied mainly due to their wide range of bio- nist [14] and T-type Ca2+ channel blocking activities [15].
logical activity [1,2]. Isoxazole compounds show antiviral [3,4], Commercial drugs featuring an isoxazole moiety include the
antithrombotic [5-9], analgesic [9], COX-2 inhibitory [10,11], COX-2 inhibitor Valdecoxib and the β-lactam antibiotics
anti-inflamatory [9,11], antinociceptive [12] and anticancer [13] Cloxacillin and Dicloxacillin. An isoxazole derivative, namely
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Beilstein J. Org. Chem. 2017, 13, 659–664.
3
,5-difluorophenyl-[3-methyl-4-(methylsulfonyl)isoxazol-5- benzo[1,3]dioxole framework is a constituent of some
yl]methanone, was recently reported as an inducer of nitric fragrances and flavors [44], and several bioactive compounds
oxide producing elicitor in plants [16,17]. Nitric oxide (NO), with a broad spectrum of applications [45-48]. The thiophene is
which has been demonstrated to be a major gasotransmitter in a core system of a large number of bioactive molecules such as
mammals, is also involved in the orchestration of various plant antineoplastic agents [49], non-steroidal anti-inflammatory
physiological responses, playing an important role in the regula- drugs [50] or compounds with antibacterial activities against
tion of interactions between plant and microorganisms and in several Gram-positive strains [51]. Thus, 3,5-disubstituted isox-
plant defense mechanisms against stresses [18,19]. Conse- azole derivatives were obtained by regioselective 1,3-dipolar
quently, there is interest in the biological evaluation of further cycloaddition reactions of aromatic nitrile oxides to non-sym-
isoxazole derivatives.
metrical activated alkyne derivatives in the presence of catalyt-
ic amounts of copper(I) iodide.
Many synthetic approaches towards the isoxazole core include
the reactions of hydroxylamine with aryl-β-diketones [20], α,β-
unsaturated carbonyl compounds [21], or α,β-unsaturated
Results and Discussion
Synthesis of 3,5-disubstituted isoxazole
nitriles [22], and 1,3-dipolar cycloaddition reactions between derivatives
alkenes or alkynes and nitrile oxides [23-25].
The regioselective cooper(I)-catalyzed 1,3-dipolar cycloaddi-
tion reactions of aromatic nitrile oxides, generated in situ from
Nitrile oxides are known as reactive 1,3-dipoles involved in 1,3- the corresponding crude imidoyl chlorides, and non-symmetri-
dipolar cycloaddition reactions with various dipolarophiles cally activated alkynes led to 3,5-disubstituted isoxazole deriva-
generating five-membered heterocyclic compounds, such as tives. For this, aromatic aldehydes 1 are first converted to the
isoxazoles, isoxazolines, oxadiazoles, oxadiazolines, dioxazo- corresponding aldoximes 2, via reactions with hydroxylamine,
lidines etc. [23-25]. Intermediate nitrile oxides are usually and the crude reaction products are transformed to the corre-
generated in situ by the oxidative dehydrogenation of aldoximes sponding imidoyl chlorides 3 which are directly used in the next
in the presence of various oxidants [26-29], or by the dehydro- step without purifications. Catalytic amounts of copper(I) iodide
halogenation of hydroxyiminoyl halides promoted by organic or and a base, such as KHCO3, are added to an aqueous solution
inorganic bases [30-32]. A less used synthetic procedure containing the crude imidoyl chlorides 3 and the non-symmetri-
involves the oxidative dehydration of primary nitro compounds cal activated alkynes 4. The in situ generated aromatic nitrile
with isocyanates in the presence of tertiary alkylamines [33].
oxides 5 undergo an addition to copper(I) acetylides formed in
situ to give the 3,5-disubstituted isoxazoles 6–11 as single
Generally, the cycloaddition reactions of nitrile oxides to isomers, in moderate to good yields (Scheme 1).
alkenes yield isoxazolines or a mixture of isoxalines and isoxa-
zoles. Cycloaddition reactions of nitrile oxides to alkynes yield All reactions between crude imidoyl chlorides 3 and the non-
isoxazoles directly, without a catalyst, but the yields of isoxa- symmetrical activated alkynes 4 are carried out in aqueous solu-
zole products are quite low because of side reactions and both tions at room temperature. The final 3,5-disubstituted isoxa-
regioisomers are generally obtained [23-25]. The one-pot 1,3- zoles are easily separated by filtration, washed with water and
dipolar cycloaddition reaction of a nitrile oxide, generated in recristallysed. The synthesized 3,5-disubstituted isoxazoles are
situ from the corresponding hydroxymoyl chloride, with an in presented in Table 1.
situ brominated electron-deficient alkene led to the intermedi-
ate bromoisoxazoline from which, by loss of HBr, a 3,5-disub- 3,5-Disubstituted isoxazoles 6, 7, 9 and 10 (Table 1) have been
stituted isoxazole derivative is formed as major regioisomer previously prepared by different synthetic procedures, but com-
[
34]. Based on the copper(I)-catalyzed click reactions of pounds 6 [52], 7 [49] and 10 [53] have been only partly charac-
organic azides with terminal acetylenes [35], different terized, while for compound 9 [54] no characterization data
copper(I)-catalyzed synthetic procedures towards isoxazole de- have been reported.
rivatives were developed [36,37].
3
,5-Disubstituted isoxazole structures were unambiguously
As part of our continued efforts to develop simple synthetic assigned on the basis of chemical and spectral analysis (IR, 1H,
routes towards bioactive heterocyclic compounds [38-43], we 13C and 15N NMR spectra). NMR spectra clearly indicated the
report here the synthesis of several 3,5-isoxazole derivatives, presence of only one regioisomer for all synthesized 3,5-disub-
bearing benzo[1,3]dioxole and thiophene scaffolds respectively, stituted isoxazoles. Signals in 1H and 13C NMR spectra were
as well as their inductor effect on the generation of nitric fully assigned based on H,C-HSQC and H,C-HMBC experi-
oxide and reactive oxygen species in plant tissues. The ments. The 3,5-disubstitution was also experimentally proven
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Beilstein J. Org. Chem. 2017, 13, 659–664.
Scheme 1: Synthetic route to 3,5-disubstituted isoxazoles.
Table 1: Reported 3,5-disubstituted isoxazoles.
Compound
Ar
R
mp (º)
59–160;
41–142 [51]
100–101.5
135–137
Yield (%)
81
1
6
Me
1
7
8
OEt
Ph
70
78
9
Me
OEt
Ph
113–115
78–80
73
67
74
10
1
1
90–91
by NOE experiments which indicated through space interaction the flowering plant with the largest amount of knowledge on
between the H-4 proton and the protons from both 3- and 5- cellular and molecular biology and it has a relatively short life
substituents.
cycle. The Arabidopsis leaves were sprayed with fine suspen-
sions of isoxazole inductors 6–11 at two different concentra-
tions (10 μg/mL and 50 μg/mL, respectively) and collected after
Biological activity
We investigated the inductor effects of 3,5-disubstituted isoxa- 24 h. Collected leaves were washed with distilled water and in-
zoles 6–11 on NO and reactive oxygen species (ROS) produc- cubated with the specific fluorescence indicator for histochem-
tion in plant tissues. Usually, NO and ROS, such as O2−, OH· ical analysis of ROS and NO by fluorescence microscopy.
and H2O2, together are required to induce the activation of Arabidopsis leaves untreated with inductor suspensions have
various defense-related enzymes in plants [55]. Plant cells been used as negative controls. As positive control, we used
contain oxygen radical detoxifying enzymes and nonenzymatic chitosan (β-1,4 linked glucosamine) with average molecular
antioxidants which have an essential role in protection of plant weight, a fungal elicitor with known effect as NO and ROS
cells from oxidative damages at the sites of ROS and NO gener- inductor on A. thaliana [61].
ation [56,57]. Measuring the ROS and NO levels in plant tissues
is often difficult due to high reactivity and extremely short Intracellular ROS was visualized using 2’,7’-dichlorodihydro-
physiological half-life of these free radicals [58,59].
fluorescein diacetate (H2DCF DA) as fluorescence indicator.
The method is based on the oxidation of the non-fluorescent
In this work, generation of both NO and ROS was proven by probe of 2’,7’-dichlorodihydrofluorescein diacetate to the
fluorescence microscopy using specific fluorescence indicators highly fluorescent 2’,7’-dichlorofluorescein diacetate [62,63].
that help to exactly define the sites of generation. We used
Arabidopsis thaliana wild type seeds, cultivated for six weeks Intracellular NO was visualized using 4-amino-5-methylamino-
in laboratory in Arasystem [60]. Arabidopsis thaliana was 2’,7’-dichlorodihydrofluorescein diacetate (DAF-FM diacetate),
selected as model organisms for NO inductors because this is a non-fluorescent compound, which reacts with NO to form a
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Beilstein J. Org. Chem. 2017, 13, 659–664.
fluorescent benzotriazole and does not react with any ROS [64- Acknowledgments
6
7].
This work was supported by the Ministry of National Educa-
tion – Research Activity, UEFISCDI, Project PN-II-PT-PCCA-
Fluorescence microscopy images of all 3,5-disubstituted isoxa- 2013-4-0267 – SAFE-SEL, contract 186/2014. Access to
zoles-treated Arabidopsis leaves showed a pronounced pres- research infrastructure developed in the “Petru Poni” Institute of
ence of ROS at both concentrations of inductors (10 μg/mL and Macromolecular Chemistry through the European Social Fund
5
0 μg/mL). Strong fluorescence densities were observed espe- for Regional Development, Competitiveness Operational
cially at higher concentration (50 μg/mL) of 3,5-disubstituted Programme Axis 1, Project InoMatPol (ID P_36_570, Contract
isoxazoles. Intensities of fluorescence revealed differences be- 142/10.10.2016, cod MySMIS: 107464) is gratefully acknowl-
tween tested compounds. These compounds can be listed in the edged.
increasing order of ROS generation efficacy as follows:
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