Synthesis and pharmacological properties of naturally occurring prenylated and pyranochalcones as potent anti-inflammatory agents

Article abstract of DOI:10.1016/j.cclet.2016.01.043

An efficient approach has been developed for the synthesis of naturally occurring prenylated chalcones viz. kanzonol C (1), stipulin (2), crotaorixin (3), medicagenin (4), licoagrochalcone A (5) and abyssinone D (6) along with the pyranochalcones paratocarpin C (7), anthyllisone (8) and 3-O-methylabyssinone A (9). The key step of the synthesis is a Claisen-Schmidt condensation. Subsequently, their anti-inflammatory effects were investigated in lipopolysaccharides (LPSs)-induced RAW-264.7 macrophages. Of the synthesized chalcones, compounds 5 (IC₅₀ = 10.41 μmol/L), 6 (IC₅₀ = 9.65 μmol/L) and 8 (IC₅₀ = 15.34 μmol/L) show remarkable activity with no cytotoxicity. Compound 9 (IC₅₀ = 4.5 μmol/L) exhibits maximum (83.6%) nitric oxide (NO) inhibition, but shows slight cytotoxicity. The results reveal that the chalcones bearing the prenyl group at 3- and/or 5-position on ring A (acetophenone moiety), i.e., 1-4 and 7 show weak, or no inhibition activity, whereas chalcones having the prenyl group only on ring B (aldehyde part), i.e., 5, 6 and 8 show significant activity on the production of inflammatory mediated NO with no cytotoxicity.

Full text of DOI:10.1016/j.cclet.2016.01.043

Accepted Manuscript
Title: Synthesis and pharmacological properties of naturally
occurring prenylated and pyranochalcones as potent
anti-inflammatory agents
Author: Kongara Damodar Jin-Kyung Kim Jong-Gab Jun
PII:
S1001-8417(16)00058-9
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.cclet.2016.01.043
CCLET 3571
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
4-8-2015
4-12-2015
15-1-2016
Please cite this article as: K. Damodar, J.-K. Kim, J.-G. Jun, Synthesis and
pharmacological properties of naturally occurring prenylated and pyranochalcones
as potent anti-inflammatory agents, Chinese Chemical Letters (2016),
http://dx.doi.org/10.1016/j.cclet.2016.01.043
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Graphical Abstract
Synthesis and pharmacological properties of naturally occurring prenylated and pyranochalcones as potent anti-inflammatory
agents
Kongara Damodar a, Jin-Kyung Kimb, Jong-Gab Juna *
aDepartment of Chemistry and Institute of Natural Medicine, Hallym University, Chuncheon 200-702, Korea
b Department of Biomedical Science, College of Natural Science, Catholic University of Daegu, Gyeungsan-Si 700-702, Korea
O
O
R4
R1
HO
OH
OH
HO
OH
O
R3
R2
R2
R1
1
2
3
4
5
6
R1, R3 = prenyl, R2, R4 = H (kanzonol C)
R1, R4= prenyl, R2, R3 = H (stipulin)
7
R1 = H, R2 = prenyl (paratocarpin C)
R1 = prenyl, R2 = H (anthyllisone)
8
R
1 = OMe, R3 = prenyl, R2, R4 = H (crotaorixin)
R1 = OMe, R2 = H (3-O-methylabyssinone A)
9
R1, R2 = H, R3, R4 = prenyl (medicagenin)
R1 = prenyl, R2, R3, R4 = H (licoagrochalcone A)
R
1 = prenyl, R2 = OMe, R3, R4 = H (abyssinone D)
A facile approach for the synthesis of naturally occurring prenylated and pyranochalcones is achieved using Claisen-Schmidt
condensation as a key step. Subsequently, their anti-inflammatory study revealed that the chalcones bearing the prenyl group at
3- and/or 5-position on ring A (acetophenone moiety), i.e., 1-4 and 7 show weak, or no inhibition activity, whereas chalcones
having the prenyl group only on ring B (aldehyde part), i.e., 5, 6 and 8 show significant activity on the production of
inflammatory mediated NO with no cytotoxicity.
Page 1 of 6

Original article
Synthesis and pharmacological properties of naturally occurring prenylated and
pyranochalcones as potent anti-inflammatory agents
Kongara Damodar a, Jin-Kyung Kimb, Jong-Gab Juna
aDepartment of Chemistry and Institute of Natural Medicine, Hallym University, Chuncheon 200-702, Korea
b Department of Biomedical Science, College of Natural Science, Catholic University of Daegu, Gyeungsan-Si 700-702, Korea
ARTICLE INFO
ABSTRACT
Article history:
An efficient approach has been developed for the synthesis of naturally occurring prenylated
chalcones viz. kanzonol C (1), stipulin (2), crotaorixin (3), medicagenin (4), licoagrochalcone A
(5) and abyssinone D (6) along with the pyranochalcones paratocarpin C (7), anthyllisone (8)
and 3-O-methylabyssinone A (9). The key step of the synthesis is a Claisen-Schmidt
condensation. Subsequently, their anti-inflammatory effects were investigated in
lipopolysaccharides (LPSs)-induced RAW-264.7 macrophages. Of the synthesized chalcones,
compounds 5 (IC50 = 10.41 µmol/L), 6 (IC50 = 9.65 µmol/L) and 8 (IC50 = 15.34 µmol/L) show
remarkable activity with no cytotoxicity. Compound 9 (IC50 = 4.5 µmol/L) exhibits maximum
(83.6%) nitric oxide (NO) inhibition, but shows slight cytotoxicity. The results reveal that the
chalcones bearing the prenyl group at 3- and/or 5-position on ring A (acetophenone moiety), i.e.,
1-4 and 7 show weak, or no inhibition activity, whereas chalcones having the prenyl group only
on ring B (aldehyde part), i.e., 5, 6 and 8 show significant activity on the production of
inflammatory mediated NO with no cytotoxicity.
Received 4 August 2015
Received in revised form 4 December 2015
Accepted 15 January 2016
Available online
Keywords:
Prenylated chalcone
Pyranochalcone
Claisen-Schmidt condensation
Anti-inflammatory
Nitric oxide (NO)
1. Introduction
In multi-cellular organisms, inflammation is an early, protective, homeostatic response of a host against a pathogenic challenge [1]
and is indicative of either acute or chronic inflammation. In normal conditions, this process is automatically regulated by the limiting
expression levels of pro-inflammatory cytokines, but under pathological conditions, macrophage stimulation leads to an increase of
nitric oxide (NO) production. NO, short-lived free radical, can regulate various physiological functions in the cardiovascular, nervous
and immune system [2]. Its Endogenous secretion from L-arginine is catalyzed by a family of nitric oxide synthase (NOS) enzymes
viz. neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS). The first two are constitutively expressed and can
generate physiologically vital amounts of NO involved chiefly in nerve function and blood regulation whereas the later one (i.e. iNOS)
produces larger amounts (nano molar) in response to various proinflammatory stimuli. Overproduction of NO causes cell damage
because of its highly reactive nature. Therefore, effective control of NO accumulation by iNOS inhibition represents a beneficial
therapeutic strategy.
Nonsteroidal anti-inflammatory drugs (NSAIDs) and classical steroidal anti-inflammatory drugs (SAIDs) are currently used to treat
acute inflammation. Treatment of chronic inflammation with these SAIDs and NSAIDs is not absolutely successful due to unexpected
side effects associated with these developed compounds. Hence, there is a need for the identification and development of safe, effective
and novel anti-inflammatory agents.
Bacterial lipopolysaccharides (LPSs) are the major outer surface membrane components present in almost all Gram-negative
bacteria and can induce the production of inflammatory mediators including iNOS in diverse eukaryotic species ranging from insects to
humans [3]. Therefore, reducing the expression levels of LPS-inducible inflammatory mediators is a promising method to attenuate a
variety of disorders derived from inflammation triggered by activated macrophages. RAW 264.7 is a murine macrophage cell line
which has been established as an excellent model to screen anti-inflammatory activity of bioactive compounds.
Chalcones, as members of the flavonoid family, are a distinguished class of naturally occurring, bioactive compounds with 1,3-
diaryl-2-propen-1-one skeleton. They are abundantly present in edible plants and are important precursors in the biosynthesis of
flavonoids and isoflavonoids [4]. Primitive therapeutic applications of these plant-related, secondary metabolites can be associated with
the thousand-year old use of plants and herbs for the treatment of different medical disorders. These small and non-chiral chemical
templates possess a conjugated double bond and an entirely delocalized π-electron system on both benzene rings which gives the
———
Corresponding author.
E-mail address: jgjun@hallym.ac.kr
Page 2 of 6

compounds non-linear optical properties [5]. Recently, chalcones have been a subject of great interest around the globe in view of their
availability in nature, effortless synthesis, accessible structural modifications and multifarious biological activities. Various natural and
non-natural chalcones have been investigated as anti-inflammatory [6], antioxidant [7], anticancer [8], antiprotozoal [9], antimicrobial
[10], antiviral [11], antibacterial [12], antihyperglycemic [13], antiplatelet aggregation [14], antiangiogenic [15], antiulcerative [16],
antitubercular [17], and antiplasmodial [18] agents. They have also shown inhibitory effects on several enzymes [19].
Continuing our interest on the synthesis and biological evaluation of chalcones as anti-inflammatory agents [20], herein we describe
the synthesis of natural prenylated and pyranochalcones using a Claisen–Schmidt condensation as a key step and present the
assessment of their anti-inflammatory effects.
Natural prenylated chalcones under the current study viz. kanzonol C (1) [21], stipulin (2) [22], crotaorixin (3) [23], medicagenin (4)
[24], licoagrochalcone A (5) [25] and abyssinone D (6) [26] were isolated from Glycyrrhiza eurycarpa, Dalbergia stipulacea,
Crotalaria orixensis, Crotalaria medicaginea, Glycyrrhiza glabra, and Erythrina abyssinica, respectively (Fig. 1). Pyranochalcones
include in this investigation are paratocarpin C (7) [27], anthyllisone (8) [28] and 3-O-methylabyssinone A (9) [29] which were
isolated from Paratocarpus Venezosa Zoll, Anthyllis hermanniae and Lonchocarpus nicou, respectively (Fig. 1). Synthesis of these
interesting compounds was not yet been reported, except for compounds 4 [30] and 5 [31].
2. Experimental
All chemicals were obtained from commercial suppliers and were used without further purification unless noted otherwise. All
solvents used for reactions were freshly distilled from proper dehydrating agents under nitrogen gas. All solvents used for
chromatography were purchased and directly used without further purification. The 1H NMR spectra were recorded at Varian Mercury-
300 MHz FT-NMR and 75 MHz for 13C NMR, with the chemical shift (δ) reported in parts per million (ppm) downfield relative to
TMS and the coupling constants (J) quoted in Hz. CDCl3/CD3OD/CD3COCD3 was used as solvent and an internal standard. Mass
spectra were recorded using Agilent-5977E spectrometer. Melting points were measured on a MEL-TEMP II apparatus and were
uncorrected. Thin-layer chromatography (TLC) was performed on DC-Plastikfolien 60, F254 (Merck, layer thickness 0.2 mm) plastic-
backed silica gel plates and visualized by UV light (254 nm) or staining with p-anisaldehyde. Chromatographic purification was
carried out using Kieselgel 60 (60-120 mesh, Merck).
2.1 General procedure for Claisen-Schmidt condensation reaction
To a stirred solution of acetophenone (0.25 mmol) and aromatic aldehyde (0.3 mmol, 1.2 equiv.) in MeOH (2 mL) and H2O (1 mL)
was added KOH (0.309 g, 5.5 mmol, 22 equiv.) and the mixture was stirred at room temperature for 72 h. After completion of the
reaction, H2O (25 mL) was added and extracted with EtOAc (3 × 25 mL). The combined organic layer was washed with brine (2 × 40
mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude was purified by column chromatography (EtOAc/hexane =
1/20 to 1/5) to obtain the allyl protected chalcone.
2.2 General procedure for allyl group deprotection
To a stirred solution of di- or tri-allyloxy chalcone (0.15 mmol) in anhydrous MeOH (2.5 mL) were added K2CO3 (0.124 g, 0.9
mmol, 6 equiv.) and Pd(PPh3)4 (2 mmol%) at room temperature and degassed for 2 min. The reaction mixture was stirred at 60o C for 1-
1.5 h. After completion of the reaction, solvent was removed in vacuo. H2O (15 mL) was added to the crude, neutralized with slow
addition of 1 mol/L HCl (1.5 mL) at 0 oC and then extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with
brine (2 × 40 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude was purified by column chromatography
(EtOAc/hexane = 1/5 to 1/1, v/v) to obtain the pure chalcone.
Physical and spectroscopic characterization data of the compounds described in this article were given in Supporting information.
3. Results and discussion
3.1 Chemistry
Our approach for the synthesis of the chalcones 1-9 is outlined in Schemes 1-4. The synthesis commenced with the prenylation of
2,4-dihydroxyacetophenone (10) following the literature procedure [31b] (Scheme 1).
Treatment of compound 10 with BF3.Et2O followed by 2-methyl-but-3-en-2-ol addition at room temperature afforded compounds
11-13. Subsequently, allyl protection of 10 along with the prenylated acetophenones 11-13 was accomplished with Cs2CO3/NaI and
allyl bromide in DMF at 60o C and the resulting products 14-17 were each obtained in high yields.
Next, 4-hydroxybenzaldehyde (18) and vanillin (19) were transformed to their prenyl derivatives (Scheme 2). Treatment of 18 and
19 with 3,3-dimethylallyl bromide using 1 mol/L NaOH afforded the aldehydes 20 and 21, respectively. Later, aldehydes 18-21 were
reacted with allyl bromide in the presence of Cs2CO3/NaI to generate the allyl protected aldehydes 22-25 in high yields, respectively.
Page 3 of 6

Aldehyde part of pyranochalcones 7-9 was obtained from aldehydes 18, 20 and 19 respectively (Scheme 3). Reaction of aldehydes
18-20 with 3-chloro-3-methyl-1-butyne using K2CO3/KI and catalytic CuI in acetone under reflux gave compounds 26-28 which were
subsequently converted to compounds 29-31, respectively.
Keeping the allyl protected acetophenones (14-17) and aromatic aldehydes (22-25 and 29-31) in hand, next we executed the Claisen-
Schmidt condensation (Scheme 4). Treatment of the suitable acetophenone with 1.2 equiv. of aromatic aldehyde using excess KOH in
MeOH:H2O (2:1) at room temperature produced the allyl protected chalcones (32-40) in good to high yields. Finally, allyl group
deprotection was achieved using K2CO3 and catalytic Pd(PPh3)4 (2 mol%) in anhydrous MeOH at 60o C to furnish the desired natural
prenylated and pyranochalcones 1-9. All the products 1-9 were structurally confirmed by their spectral (1H NMR & 13C NMR and MS)
data.
3.2. Pharmacology
To examine the anti-inflammatory effect of the synthesized chalcones 1-9, we selected an in vitro model with murine RAW 264.7
macrophage cell line, which is an established model for anti-inflammatory drug screening. We assayed the ability of compounds 1-9 to
decrease NO release after LPS stimulation. The RAW 264.7 cells were incubated with LPS and 1 µmol/L & 10 µmol/L concentrations
of compounds 1-9 for 24 h. Later, culture media were harvested and the amount of NO was measured. Compounds 1-4 and 7 exhibited
weak, or no suppression of NO production at 10 µmol/L level (Table 1). On the other hand, chalcones 5, 6, 8 and 9 were shown to
exhibit a moderate to good level of activity.
Next, cell viability was analyzed to check whether the inhibitory effect was due to cytotoxicity. All of the prepared chalcones
displayed no toxic effects, except compound 9, which showed a slight cytotoxicity at 10 µmol/L level (Table 1). The IC50 values of
these natural chalcones 1-9 were evaluated by using GraphPad Prism 4.0 software and the values were 56.75, 35.40, 41.39, 29.09,
10.41, 9.65, 52.71, 15.34 and 4.50 µmol/L, respectively. Based upon the results, it can be concluded that chalcones bearing the prenyl
group only on ring B (aldehyde part), i.e., 5, 6 and 8 are fruitful to show good anti-inflammatory activity by effective inhibition of NO
production with no cytotoxicity.
4. Conclusion
We have developed a simple and efficient approach for the synthesis of naturally occurring prenylated and pyranochalcones 1-9
using the Claisen-Schmidt condensation as a key step. Later, their anti-inflammatory effects were evaluated in lipopolysaccharides
(LPSs)-stimulated RAW-264.7 macrophages. Of the chalcones prepared in this study, compounds 5, 6 and 8 showed remarkable
activities with no cytotoxicity. Compound 9 (IC50 = 4.5 µmol/L) exhibited maximum (83.6%) nitric oxide (NO) inhibition, but showed
a slight cytotoxicity. The results revealed that the chalcones bearing the prenyl group at 3- and/or 5-position on ring A (acetophenone
part), i.e., 1-4 and 7 showed weak or no inhibition activities, whereas chalcones holding prenyl group only on ring B (aldehyde part),
i.e., 5, 6 and 8 showed significant activities on the production of inflammatory mediated NO with no cytotoxicity.
Acknowledgment
This research was financially supported by Priority Research Centers Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and Technology (NRF-2009-0094071).
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O
O
R4
R1
HO
OH
OH
HO
OH
O
R3
R2
R2
R1
1
2
3
4
5
6
R1, R3 = prenyl, R2, R4 = H (kanzonol C)
R1, R4= prenyl, R2, R3 = H (stipulin)
R1 = OMe, R3 = prenyl, R2, R4 = H (crotaorixin)
R1, R2 = H, R3, R4 = prenyl (medicagenin)
R1 = prenyl, R2, R3, R4 = H (licoagrochalcone A)
R1 = prenyl, R2 = OMe, R3, R4 = H (abyssinone D)
7
R1 = H, R2 = prenyl (paratocarpin C)
R1 = prenyl, R2 = H (anthyllisone)
R1 = OMe, R2 = H (3-O-methylabyssinone A)
8
9
Fig. 1. Structures of naturally occurring prenylated and pyranochalcones (1-9).
O
O
O
O
a
+
+
HO
OH
HO
OH
HO
OH
HO
OH
10
11 (23%)
13 (17%)
12
(14%)
O
b
b
b
b
O
O
O
O
O
O
O
O
O
O
O
14 (98%)
15 (94%)
16
(92%)
17
(71%)
Scheme 1. Synthesis of prenyl substituted acetophenones. Reagents and conditions: (a) 2-methyl-but-3-en-2-ol, BF3.Et2O, 1,4-dioxane, r.t., 1 h. (b) allyl
bromide, Cs2CO3/NaI, DMF, 60 oC, 5 h.
Page 5 of 6

CHO
CHO
a
HO
HO
R
R
18 R = H
19 R = OMe
20 R = H (24%)
21 R = OMe (18%)
R'
CHO
R'
CHO
b
HO
O
R
R
22 R, R' = H (98%)
18 R, R' = H
23 R = OMe, R' = H (98%)
24 R = H, R' = prenyl (97%)
25 R = OMe, R' = prenyl (96%)
19 R = OMe, R' = H
20 R = H, R' = prenyl
21 R = OMe, R' = prenyl
Scheme 2. Synthesis of prenyl substituted benzaldehydes. Reagents and conditions: (a) 3,3-dimethylallyl bromide, 1 mol/L NaOH, 0o C – r.t., 2 h. (b) allyl
bromide, Cs2CO3/NaI, DMF, 60o C, 2 h.
CHO
CHO
CHO
c
d
O
HO
O
R
R
R
18 R = H
26 R = H (82%)
29 R = H (92%)
19 R = OMe
20 R = prenyl
27 R = OMe (97%)
28 R = prenyl (88%)
30 R = OMe (93%)
31 R = prenyl (79%)
Scheme 3. Synthesis of substituted 2,2-dimethyl-2H-chromene-6-carbaldehydes. Reagents and conditions: (a) 3-chloro-3-methyl-1-butyne, K2CO3/KI, acetone,
reflux, 4.5 h. (b) N, N-diethylaniline, sealed tube, 210 oC, 1.5 h.
O
O
O
R4
O
R1
O
R4
R1
16 + 24
15 + 24
b
a
16 23
+
HO
OH
OH
R3
R2
R2
R3
17 + 22
1-6
14 24
+
32 R1, R3 = prenyl, R2, R4 = H
R1, R4 = prenyl, R2, R3 = H
14 + 25
33
34 R1, = OMe, R3 = prenyl, R2, R4 = H
35 R1, R2 = H, R3, R4= prenyl
36 R1 = prenyl, R2, R3, R4 = H
37 R1, = OMe, R2 = prenyl, R3, R4 = H
O
O
16 + 29
14 + 31
14 + 30
b
a
O
HO
OH
7-9
O
O
O
R1
R2
R1
R2
R1 = H, R2 = prenyl
R1 = prenyl, R2 = H
40 R1 = OMe, R2 = H
38
39
Scheme 4. Synthesis of naturally occurring prenylated and pyranochalcones.Reagents and conditions: (a) KOH, MeOH/H2O (2:1), r.t., 72 h, 58%-90%. (b)
K2CO3, Pd(PPh3)4, MeOH, 60 oC, 1-1.5 h, 51%-89%.
Table 1.
Anti-inflammatory activities of naturally occurring prenylated and pyranochalcones 1-9.
Compd
NO Production (% inhibition)a,b
Proliferationc
I µmol/L
99.77 ± 4.23
112.35 ± 15.75
108.03 ± 11.72
112.35 ± 15.75
108.03 ± 9.41
99.24 ± 0.63
IC50 (µmol/L)
1 µmol/L
10 µmol/L
10 µmol/L
99.77 ± 4.23
93.56 ± 5.91
157.63 ± 8.06*
113.36 ± 8.80
99.25 ± 2.71
111.37 ± 11.13
103.85 ± 2.0
97.43 ± 2.22
98.24 ± 10.12
92.74 ± 1.40*
Medium
1.13 ± 0.87 (98.87)***
131.54 ± 2.6 (-31.54) ***
124.14 ± 1.43 (-24.14) ***
124.98 ± 6.49 (-24.98) ***
116.27 ± 2.95 (-16.27) ***
125.30 ± 4.79 (-25.3)***
120.10 ± 2.03 (-20.1)***
124.2 ± 2.91 (-24.2)***
119.20 ± 0.64 (-19.2)***
107.21 ± 3.51 (-7.21)**
99.99 ± 3.76 (0.01)
1.13 ± 0.87 (98.87)***
124.48 ± 10.29 (-24.48)***
103.13 ± 5.1 (-3.13)
1
2
3
4
5
6
7
8
9
56.75
35.40
41.39
29.09
10.41
9.65
52.71
15.34
4.50
99.72 ± 11.36 (0.28)
82.26 ± 0.8 (17.74)***
53.58 ± 2.41 (46.42)***
39.59 ± 4.31 (60.41)***
129.9 ± 2.52 (-29.9)***
58.09 ± 0.94 (41.91)***
16.45 ± 0.89 (83.55)***
99.99 ± 3.76 (0.01)
99.16 ± 3.26
105.45 ± 6.96
108.47 ± 2.86
106.66 ± 5.82
LPS
a The results are reported as mean value ± SEM for n = 3. Statistical significance is based on the difference when compared with LPS-treated groups (**P <
0.01, ***P < 0.001).
b Inhibition is based on LPS as shown in parenthesis.
c The results are reported as mean value ± SEM for n = 3. Statistical significance is based on the difference when compared with Medium groups (*P < 0.05).
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