Synthesis and insect antifeedant activity of aurones against spodoptera litura larvae

Article abstract of DOI:10.1021/jf062562t

A series of aurones were prepared from various phenols via phenoxy acetic acids and coumaranones and evaluated for insect antifeedant activity against the common cutworm (Spodoptera litura). The naturally occurring aurone was most active at an ED₅₀ of 0.12 μmol/cm². The synthetic precursor, coumaranones, showed that the introduction of methoxyl and methyl groups to the benzene ring increased insect antifeedant activity. Similarly, the tested aurones showed that the introduction of methoxyl group to the A and/or B rings increased the insect antifeedant activity, but 4,5,6- and 3 ,4 ,5 -trisubstituted compounds did not show this activity in this test. The hydroxylation of aurones in the B ring should be disadvantageous for insect antifeedant activity against S. litura. Although the melting points did not correlate well with the insect antifeedant activity, compounds that were nearly inactive had high melting points. A significant correlation was noted between biological activity (pED₅₀) and a hydrogen-bonding parameter calculated from the R_f value obtained from SiOH thin-layer chromatography and a lipophilicity parameter (log k) calculated from the retention time in ODS high-performance liquid chromatography. The respective correlation coefficients (r) were -0.83 and -0.70. The introduction of alkoxy and alkyl groups along with adequate hydrogen bonding seems to contribute to the antifeedant activity of the compounds tested.

Full text of DOI:10.1021/jf062562t

700 J. Agric. Food Chem. 2007, 55, 700−705
Synthesis and Insect Antifeedant Activity of Aurones against
Spodoptera litura Larvae
MASANORI MORIMOTO,* HIROMI FUKUMOTO, TOKI NOZOE, AI HAGIWARA,
AND KOICHIRO KOMAI
Department of Applied Biological Chemistry, Faculty of Agriculture, Kinki University,
3327-204 Nakamachi, Nara, Japan
A series of aurones were prepared from various phenols via phenoxy acetic acids and coumaranones
and evaluated for insect antifeedant activity against the common cutworm (Spodoptera litura). The
naturally occurring aurone was most active at an ED50 of 0.12 µmol/cm2. The synthetic precursor,
coumaranones, showed that the introduction of methoxyl and methyl groups to the benzene ring
increased insect antifeedant activity. Similarly, the tested aurones showed that the introduction of
methoxyl group to the A and/or B rings increased the insect antifeedant activity, but 4,5,6- and 3′,4′,5′-
trisubstituted compounds did not show this activity in this test. The hydroxylation of aurones in the B
ring should be disadvantageous for insect antifeedant activity against S. litura. Although the melting
points did not correlate well with the insect antifeedant activity, compounds that were nearly inactive
had high melting points. A significant correlation was noted between biological activity (pED50) and
a hydrogen-bonding parameter calculated from the Rf value obtained from SiOH thin-layer
chromatography and a lipophilicity parameter (log k) calculated from the retention time in ODS high-
performance liquid chromatography. The respective correlation coefficients (r) were -0.83 and -0.70.
The introduction of alkoxy and alkyl groups along with adequate hydrogen bonding seems to contribute
to the antifeedant activity of the compounds tested.
KEYWORDS: Aurones; insect antifeedant; SAR; Spodoptera litura
INTRODUCTION
zopyranone) (9) and aurone (benzofuranone) suggests that
aurones may show insect antifeedant activity (Figure 1).
Because natural 3′,4,4′,6-tetramethoxyaurone showed insect
antifeedant activity against Spodoptera litura larvae, structure-
activity relationships are also discussed.
In plant-insect interaction, phytophenolics including fla-
vonoids and phenylpropanoids can attract pollinators and provide
chemical defense to avoid damage from phytophagous insects
(1). The flavonoids are some of the most common pigments
among naturally occurring phytophenolics. Occasionally, fla-
vones and isoflavones also provide chemical defense against
herbivores. Aurones (2-benzylidene-coumaran-3-ones) are fla-
vonoids that are closely associated with the yellow color of
flowers; for example, in Scrophulariaceae and Compositae, they
are found in heartwood as well as in flowers (2). Aurones are
obtained from chalcone by aurone synthase as well as through
the biosynthesis of other flavonoids (3). Aurones have been
reported to show cytotoxicity (4) and antiparasitic (5) and
antifungal activity (6). 3′,4,4′,6-Tetramethoxyaurone is one of
several constituents that has been isolated from the methanolic
extract of Cyperus radians (Cyperaceae). This Cyperaceae
produces large amounts of which polymethylated aurones may
be part of a chemical defense system. Because both coumaran
(dihydrobenzofuran) and chromene (benzopyran) are known to
exhibit insect antifeedant activity (7, 8), a similar corresponding
relationship between the chemical structures of flavone (ben-
MATERIALS AND METHODS
1
Synthesis. General. H and 13C NMR spectra were measured on a
JEOL 270EX (270 MHz) spectrometer using tetramethylsilane as an
internal standard. Mass spectra were taken at 70 eV (DEI probe) with
a JEOL QMS-K9. High-resolution mass spectra (HREIMS) were
obtained on a JEOL JMS-700. The synthetic compounds were purified
by column chromatography on silica gel, Fuji silysia chemical BW-
127ZH and BW-300 (Fuji Silysia Chemical Ltd., Japan). Melting points
were measured on a Yanaco model MP apparatus. Thin-layer chro-
matography (TLC) involved the use of silica gel plates with a
fluorescent indicator (Merck Silica Gel 60 F254 0.25 mm thick).
General Procedure for Preparation of Tested Aurones. To a solution
of 3,5-dimethoxyphenol (1.086 mmol) in acetone (20 mL) was added
Na (8.351 mmol) at room temperature. The solution was kept under
the same conditions with stirring until hydrogen was no longer
generated. 2-Bromoethylacetate (6.313 mmol) was added to the mixture,
and reflux conditions were maintained for several hours. After the
starting material had disappeared by TLC analysis, the solution was
cooled, ethanol (0.3 mL) was added to dissolve sodium completely,
and 0.1 N NaOH(aq) (15 mL) was poured into the solution. The
* To whom correspondence should be addressed. Tel: +81-742-43-7162.
Fax: +81-742-43-1445. E-mail: masanori@nara.kindai.ac.jp.
10.1021/jf062562t CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/10/2007

Synthesis and Insect Antifeedant Activity of Aurones
J. Agric. Food Chem., Vol. 55, No. 3, 2007 701
δ 172.5, 158.5, 135.7 (overlapped), 122.6, 114.0 (overlapped), 65.0.
DEIMS (70 eV) m/z (relative intensity): 220 (M+, 100%), 175 (79.8%),
145 (32.7%). HREIMS m/z (M+), 219.9705; calcd for C8H6O5Cl2,
219.9694.
3,4,5-Trimethoxyphenoxyacetic Acid (4). Yield, 23.9%; pale brown
1
crystal; mp, 96-99 °C. H NMR (270 MHz, CDCl3): δ 6.50-6.99
(1H, br. s, -COOH), 6.17 (2H, s, C2, C6), 4.63 (2H, s, -O-CH2-),
3.81 (6H, s, Ar-OCH3 × 2), 3.77 (3H, s, Ar-OCH3). 13C NMR (270
MHz, CDCl3): δ 173.3, 154.1, 153.7 (overlapped), 133.0, 92.6
(overlapped), 65.2, 61.0, 56.1 (overlapped). DEIMS (70 eV) m/z
(relative intensity): 242 (M+, 28.4%), 183 (2.9%), 168 (13.8%), 153
(2.3%), 125 (4.8%), 69 (100%). HREIMS m/z (M+), 242.0797; calcd
for C11H14O6, 242.0790.
4,6-Dimethoxycoumaranone (5). Yield, 18.9%; yellow crystal; mp,
1
126-128 °C. H NMR (270 MHz, CDCl3): δ 6.11 (1H, d, J ) 1.8
Figure 1. Structural similarity of benzofurans and benzopyranes in this
text.
Hz, C7), 5.96 (1H, d, J ) 1.8 Hz, C5), 4.54 (2H, s, -O-CH2-), 3.87
(3H, s, Ar-OCH3), 3.83 (3H, s, Ar-OCH3). 13C NMR (270 MHz,
CDCl3): δ 194.8, 177.1, 169.8, 158.9, 104.8, 93.0, 89.0, 75.5, 56.0,
55.9. DEIMS (70 eV) m/z (relative intensity): 194 (M+, 16.4%), 165
(6.7%), 151 (5.1%), 48 (100%). HREIMS m/z (M+), 194.0583; calcd
for C10H10O4, 194.0579.
synthetic ester was hydrolyzed at 80 °C. The solution was adjusted to
pH 8-9 and washed with chloroform to remove residual ester from
the solution. The solution was then adjusted to below pH 3, extracted
with chloroform, dried with anhydrous sodium sulfate, and concentrated
to dryness to give the 3,5-dimethoxyphenoxyacetic acid (1) in 81%
yield, which was used directly in the next reaction without further
purification. These phenoxy acetic acids were obtained in a yield of
23.9-86.0% in this reaction (10).
Coumaranones were prepared by polyphosphoric acid (PPA)-
mediated cyclization of the corresponding phenoxyacetic acid. Com-
pound 1 (2.245 mmol) was added to PPA (26.2 g), and the mixture
was stirred using a mechanical stirrer at 100 °C for 8 h. The reaction
product was then cooled, and distilled water was poured into the same
pot. The reaction product was extracted with chloroform, dried with
anhydrous sodium sulfate, and concentrated to dryness to give the 4,6-
dimethoxycoumaranone (5) (0.424 mmol) in 18.9% yield. These
coumaranones were obtained in yields of 15.9-36.5% in this cyclization
reaction (10).
4,6-Dimethylcoumaranone (6). Yield, 15.9%; yellow crystal; mp,
1
51-53 °C. H NMR (270 MHz, CDCl3): δ 6.68 (1H, s, C5), 6.59
(1H, s, C7), 4.51 (2H, s, -O-CH2-), 2.50 (3H, s, Ar-CH3), 2.33
(3H, s, Ar-CH3). 13C NMR (270 MHz, CDCl3): δ 199.8, 174.8, 149.1,
138.9, 124.6, 116.9, 110.7, 74.7, 22.2, 17.5. DEIMS (70 eV) m/z
(relative intensity): 162 (M+, 28.1%), 148 (5.0%), 120 (2.0%), 105
(10.5%), 48 (100%). HREIMS m/z (M+), 162.0683; calcd for C10H10O2,
162.0681.
4,5,6-Trimethoxycoumaranone (7). Yield, 36.5%; pale brown
1
crystal; mp, 129-131 °C. H NMR (270 MHz, CDCl3): δ 6.31 (1H,
s, C7), 4.56 (2H, s, -O-CH2-), 4.15 (3H, s, Ar-OCH3), 3.93 (3H, s,
Ar-OCH3), 3.78 (3H, s, Ar-OCH3). 13C NMR (270 MHz, CDCl3): δ
195.1, 171.9, 162.5, 150.5, 135.7, 106.6, 90.6, 75.3, 61.9, 61.4, 56.3.
DEIMS (70 eV) m/z (relative intensity): 224 (M+, 55.3%), 209 (61.2%),
195 (8.9%), 181 (17.2%), 167 (8.4%), 151 (6.5%), 48 (100%). HREIMS
m/z (M+), 224.0688; calcd for C11H12O5, 224.0685.
Each aurone was prepared by a known method, and only the Z form
was obtained (11). Basic active alumina for chromatography (Chame-
leon special reagent for chromatography, 300 mesh, Kishida Chemical
Co. Ltd., Japan) (1 g) was added to a dichloromethane solution (1.5
mL) of 5 (0.206 mmol) and benzaldehyde (0.4695 mmol) and allowed
to stand overnight at room temperature. The progress of the reaction
was monitored by TLC analysis. After the alumina powder was removed
by filtration with celite, the solvent was removed under reduced pressure
to obtain crude product. Crystallization from chloroform-hexane gave
pure aurone, 4,6-dimethoxyaurone (Z) (21), in 84.3% yield as pale
yellow crystals. The determination of E-Z isomer was achieved by
Aurone (Z) (8). Yield, 22.8%; yellow crystalline; mp, 98-99 °C.
1H NMR (270 MHz, CDCl3): δ 7.89-7.93 (2H, m, C2′, C6′), 7.81
(1H, dd, J ) 7.6, 1.3 Hz, C4), 7.65 (1H, ddd, J ) 8.3, 7.3, 1.3 Hz,
C6), 7.36-7.49 (3H, m, C3′, C4′, C5′), 7.32 (1H, d, J ) 8.3 Hz, C7),
7.21 (1H, dd, J ) 7.6, 7.3 Hz, C5), 6.89 (1H, s, benzylic). 13C NMR
(270 MHz, CDCl3): δ 184.7, 166.2, 147.0, 136.8, 132.4 (overlapped),
131.5, 129.8 (overlapped), 128.9, 124.7, 123.5, 121.7, 113.0, 112.9.
DEIMS (70 eV) m/z (relative intensity): 222 (M+, 100%), 134 (36.3%),
120 (19.2%). HREIMS m/z (M+), 222.0688; calcd for C15H10O2,
222.0681.
1
examining the chemical shift value of the C2′ aryl proton in the H
2′-Methoxyaurone (Z) (9). Yield, 82.4%; yellow crystal; mp, 167-
1
NMR spectrum. These synthetic aurones were obtained in a yield of
13.2-97.0% in this reaction (Figure 2).
170 °C. H NMR (270 MHz, CDCl3): δ 8.31 (1H, dd, J ) 7.8, 1.7
Hz, C4), 7.81 (1H, dd, J ) 7.9, 1.2 Hz, C7), 7.63 (1H, ddd, J ) 7.8,
7.8, 1.2 Hz, C5), 7.48 (1H, s, benzylic), 7.36 (1H, ddd, J ) 7.9, 7.8,
1.7 Hz, C6), 7.31 (1H, d, J ) 8.3 Hz, C6′), 7.20 (1H, dd, J ) 8.2, 6.6
Hz, C4′), 7.06 (1H, dd, J ) 8.3, 6.6 Hz, C5′), 6.92 (1H, d, J ) 8.2 Hz,
C3′), 3.90 (3H, s, Ar-OCH3). 13C NMR (270 MHz, CDCl3): δ 184.7,
165.9, 158.8, 146.9, 136.6, 132.0, 131.5, 124.6, 123.3, 121.8, 121.2,
120.8, 112.9, 110.7, 107.3, 55.6. DEIMS (70 eV) m/z (relative
intensity): 252 (M+, 24.9%), 237 (7.8%), 221 (100%), 92 (17.6%), 76
(11.3%). HREIMS m/z (M+), 252.0762; calcd for C16H12O3, 252.0786.
3′-Methoxyaurone (Z) (10). Yield, 75.2%; yellow crystal; mp, 117-
3,5-Dimethoxyphenoxyacetic Acid (1). Yield, 81.0%; pale brown
1
crystal; mp, 118-122 °C. H NMR (270 MHz, CDCl3): δ 6.14 (1H,
d, J ) 2.0 Hz, C4), 6.10 (2H, d, J ) 2.0 Hz, C2, C6), 4.53 (2H, s,
-O-CH2-), 4.43-5.15 (1H, br. s, -COOH), 3.76 (6H, s, Ar-OCH3
× 2). 13C NMR (270 MHz, CD3OD): δ 172.7, 163.2 (overlapped),
161.3, 94.7, 94.6 (overlapped), 66.0, 55.9 (overlapped). DEIMS (70
eV) m/z (relative intensity): 212 (M+, 57.5%), 167 (7.4%), 137 (13.4%),
107 (7.6%), 95 (9.6%), 69 (100%). HREIMS m/z (M+), 212.0684; calcd
for C10H12O5, 212.0685.
1
3,5-Dimethylphenoxyacetic Acid (2). Yield, 35.8%; white crystal;
mp, 100-104 °C. 1H NMR (270 MHz, CDCl3): δ 7.05-7.24 (1H, br.
s, -COOH), 6.66 (1H, s, C4), 6.54 (2H, s, C2, C6), 4.64 (2H, s, -O-
CH2-), 2.29 (6H, s, Ar-CH3 × 2). 13C NMR (270 MHz, CDCl3): δ
176.3, 159.4, 141.5 (overlapped), 125.9, 114.3 (overlapped), 66.7, 23.4
(overlapped). DEIMS (70 eV) m/z (relative intensity): 180 (M+, 61.9%),
163 (6.0%), 135 (29.1%), 105 (42.8%), 91 (29.9%), 58 (100%).
HREIMS m/z (M+), 180.0780; calcd for C10H12O3, 180.0786.
3,5-Dichlorophenoxyacetic Acid (3). Yield, 86.0%; white crystal;
119 °C. H NMR (270 MHz, CDCl3): δ 7.81 (1H, dd, J ) 7.6, 1.3,
Hz, C4), 7.66 (1H, ddd, J ) 8.3, 7.3 1.3 Hz, C6), 7.48-7.51 (2H, m,
C2′, C6′), 7.37 (1H, dd, J ) 8.3, 7.9 Hz, C5′), 7.33 (1H, dd, J ) 8.3,
0.7 Hz, C7), 7.22 (1H, ddd, J ) 7.6, 7.3, 0.7 Hz, C5), 6.96 (1H, ddd,
J ) 8.3, 2.6, 1.0 Hz, C4′), 6.86 (1H, s, benzylic), 3.88 (3H, s, Ar-
OCH3). 13C NMR (270 MHz, CDCl3): δ 184.7, 166.2, 159.9, 147.0,
136.9, 133.6, 129.8, 124.7, 124.3, 123.5, 121.7, 116.6, 115.8, 113.0,
112.9, 55.4. DEIMS (70 eV) m/z (relative intensity): 252 (M+, 72.8%),
237 (17.5%), 221 (77.1%), 209 (15.2%), 132 (13.0%), 76 (100%).
HREIMS m/z (M+), 252.0761; calcd for C16H12O3, 252.0786.
1
mp, 109-113 °C. H NMR (270 MHz, CD3OD): δ 7.03 (1H, t, J )
1.7 Hz, C4), 6.25 (2H, d, J ) 1.7 Hz, C2, C6), 5.64-6.15 (1H, br. s,
3′-Chloroaurone (Z) (11). Yield, 66.2%; pale yellow crystal; mp,
-COOH), 4.66 (2H, s, -O-CH2-). 13C NMR (270 MHz, CD3OD):
98-99 °C. H NMR (270 MHz, CDCl3): δ 7.94 (1H, s, C2′), 7.80
1

702 J. Agric. Food Chem., Vol. 55, No. 3, 2007
Morimoto et al.
Figure 2. Synthesis of substituted aurones.
(1H, dd, J ) 7.6, 1.3 Hz, C4), 7.73 (1H, dd, J ) 8.1, 1.7 Hz, C4′),
7.68 (1H, ddd, J ) 7.5, 7.3, 1.3 Hz, C6), 7.34-7.42 (3H, m, C5′, C6′,
C7), 7.24 (1H, dd, J ) 7.3, 7.6 Hz, C5), 6.79 (1H, s, benzylic). 13C
NMR (270 MHz, CDCl3): δ 184.6, 166.2, 147.3, 137.2, 134.8, 134.0,
130.9, 130.0, 129.7, 129.6, 124.7, 123.7, 121.3, 113.0, 111.1. DEIMS
(70 eV) m/z (relative intensity): 256 (M+, 100%), 221 (75.6%), 92
(90.3%), 76 (38.4%). HREIMS m/z (M+), 256.0277; calcd for C15H9O2-
Cl, 256.0291.
4′-Hydroxy-3′-methoxyaurone (Z) (17). Yield, 82.0%; orange
crystal; mp, 199-201 °C. H NMR (270 MHz, CDCl3): δ 7.82 (1H,
1
dd, J ) 7.6, 1.5 Hz, C4), 7.65 (1H, ddd, J ) 8.3, 8.2, 1.5 Hz, C6),
7.50 (1H, d, J ) 2.0 Hz, C2′), 7.49 (1H, dd, J ) 2.0, 8.8 Hz, C6′),
7.32 (1H, d, J ) 8.3 Hz, C7), 7.22 (1H, dd, J ) 8.2, 7.6 Hz, C5), 7.00
(1H, d, J ) 8.8, C5′), 6.87 (1H, s, benzylic), 5.99 (1H, s, Ar-OH),
4.00 (3H, s, Ar-OCH3). 13C NMR (270 MHz, CDCl3): δ 184.5, 165.7,
147.8, 146.7, 145.8, 136.5, 126.6, 124.9, 124.6, 123.3, 121.9, 115.0,
113.9, 113.3, 112.8, 56.0. DEIMS (70 eV) m/z (relative intensity): 268
(M+, 100%), 225 (15.9%), 197 (10.3%), 104 (9.8%), 92 (50.7%).
HREIMS m/z (M+), 268.0714; calcd for C16H12O4, 268.0736.
3′-Bromoaurone (Z) (12). Yield, 37.3%; pale yellow crystal; mp,
1
115-117 °C. H NMR (270 MHz, CDCl3): δ 8.08 (1H, d, J ) 2.0,
C2′), 7.80 (1H, d, J ) 7.9 Hz, C4′), 7.78 (1H, dd, J ) 7.3, 1.3 Hz,
C4), 7.66 (1H, ddd, J ) 8.3, 7.9, 1.3 Hz, C6), 7.51 (1H, dd, J ) 7.9,
2.0 Hz, C6′), 7.34 (1H, d, J ) 8.3 Hz, C7), 7.30 (1H, t, J ) 7.9 Hz,
C5′), 7.22 (1H, dd, J ) 7.3, 7.9 Hz, C5), 6.77 (1H, s, benzylic). 13C
NMR (270 MHz, CDCl3): δ 184.5, 166.3, 147.4, 137.1, 134.4, 133.9,
132.6, 130.3, 129.9, 124.8, 123.7, 123.0, 121.5, 113.0, 110.9. DEIMS
(70 eV) m/z (relative intensity): 301 (M+, 25.7%), 221 (64.1%), 120
(61.3%), 92 (100%), 76 (40.2%). HREIMS m/z (M+), 299.9780; calcd
for C15H9O2Br, 299.9786.
3′-Ethoxy-4′-hydroxyaurone (Z) (18). Yield, 68.9%; brown crystal;
1
mp, 121-123 °C. H NMR (270 MHz, CDCl3): δ 7.80 (1H, dd, J )
7.6, 1.3 Hz, C4), 7.63 (1H, ddd, J)8.3, 7.3, 1.3 Hz, C6), 7.47 (1H, d,
J ) 1.8 Hz, C2′), 7.47 (1H, dd, J ) 1.8, 8.7 Hz, C6′), 7.30 (1H, d,
J ) 8.3 Hz, C7), 7.20 (1H, dd, J ) 7.3, 7.6 Hz, C5), 6.99 (1H, d, J )
8.7 Hz, C5′), 6.84 (1H, s, benzylic), 6.07 (1H, s, Ar-OH), 4.21 (2H,
q, J ) 6.9 Hz, -O-CH2-), 1.50 (3H, t, J ) 6.9 Hz, -CH3). 13C NMR
(270 MHz, CDCl3): δ 184.4, 165.8, 148.1, 146.0, 145.8, 136.4, 126.5,
124.8, 124.6, 123.3, 122.0, 115.0, 114.4, 113.9, 112.8, 64.7, 14.8.
DEIMS (70 eV) m/z (relative intensity): 282 (M+, 100%), 253 (72.3%),
225 (23.9%), 197 (15.7%), 92(45.4%), 76(16.6%). HREIMS m/z (M+),
282.0865; calcd for C17H14O4, 282.0892.
4′-Methoxyaurone (Z) (13). Yield, 75.3%; yellow crystal; mp, 120-
122 °C. 1H NMR (270 MHz, CDCl3): δ 7.88 (2H, d, J ) 8.7 Hz, C2′,
C6′), 7.80 (1H, dd, J ) 7.6, 1.3 Hz, C4), 7.62 (1H, ddd, J ) 8.3, 7.3,
1.3, Hz, C6), 7.31 (1H, dd, J ) 8.3, 0.6 Hz, C7), 7.20 (1H, ddd, J )
7.6, 7.3, 0.6 Hz, C5), 6.98 (2H, d, J ) 8.7 Hz, C3′, C5′), 6.88 (1H, s,
benzylic), 3.86 (3H, s, Ar-OCH3). 13C NMR (270 MHz, CDCl3): δ
184.5, 165.9, 161.1, 145.9, 136.4, 133.4 (overlapped), 125.1, 124.5,
123.2, 122.0, 114.5 (overlapped), 113.3, 112.8, 55.4. DEIMS (70 eV)
m/z (relative intensity): 252 (M+, 100%), 237 (29.4%), 221 (38.5%),
135 (62.8%), 77 (73.5%). HREIMS m/z (M+), 252.0772; calcd for
C16H12O3, 252.0786.
3′,5′-Dimethoxyaurone (Z) (19). Yield, 97.0%; yellow crystal; mp,
1
153-155 °C. H NMR (270 MHz, CDCl3): δ 7.79 (1H, d, J ) 7.9
Hz, C4), 7.64 (1H, dd, J ) 6.9, 8.6 Hz, C6), 7.30 (1H, d, J ) 8.6 Hz,
C7), 7.21 (1H, dd, J ) 6.9, 7.9 Hz, C5), 7.08 (2H, s, C2′, C6′), 6.80
(1H, s, benzylic), 6.53 (1H, s, C4′), 3.85 (6H, s, Ar-OCH3 × 2). 13C
NMR (270 MHz, CDCl3): δ 184.6, 166.2, 161.2 (overlapped), 147.0,
136.8, 133.9, 124.7, 123.5, 121.7, 112.9 (overlapped), 109.6 (over-
lapped), 102.5, 55.4 (overlapped). DEIMS (70 eV) m/z (relative
intensity): 282 (M+, 73.0%), 251 (100%), 208 (8.5%), 92 (11.4%), 76
(16.8%). HREIMS m/z (M+), 282.0869; calcd for C17H14O4, 282.0892.
3′,4′,5′-Trimethoxyaurone (Z) (20). Yield, 64.2%; yellow crystal;
3′4′-Dimethoxyaurone (Z) (14). Yield, 65.8%; yellow crystal; mp,
1
175-178 °C. H NMR (270 MHz, CDCl3): δ 7.80 (1H, dd, J ) 7.6,
1.3 Hz, C4), 7.63 (1H, ddd, J ) 8.3, 7.2, 1.3 Hz, C6), 7.53 (1H, d,
J ) 2.0 Hz, C2′), 7.49 (1H, dd, J ) 8.3, 2.0 Hz, C6′), 7.30 (1H, d, J
) 8.3 Hz, C7), 7.21 (1H, dd, J ) 7.6, 7.3 Hz, C5), 6.94 (1H, d, J )
8.3 Hz, C5′), 6.89 (1H, s, benzylic), 3.97 (3H, s, Ar-OCH3), 3.94 (3H,
s, Ar-OCH3). 13C NMR (270 MHz, CDCl3): δ (ppm) 184.3, 165.8,
151.0, 149.2, 146.0, 136.4, 126.0, 125.4, 124.6, 123.3, 122.0, 114.1,
113.5, 112.8, 114.4, 56.0 (overlapped). DEIMS (70 eV) m/z (relative
intensity): 282 (M+, 63.9%), 267 (27.3%), 251 (17.9%), 134 (59.7%),
105 (64.7%). HREIMS m/z (M+), 282.0886; calcd for C17H14O4,
282.0892.
1
mp, 173-174 °C. H NMR (270 MHz, CDCl3): δ 7.79 (1H, dd, J )
7.6, 1.3 Hz, C4), 7.63 (1H, ddd, J ) 8.3, 8.2, 1.3 Hz, C6), 7.30 (1H,
d, J ) 8.3 Hz, C7), 7.22 (1H, dd, J ) 8.2, 7.6 Hz, C5), 7.19 (2H, s,
C2′, C6′), 6.82 (1H, s, benzylic), 3.95 (6H, s, Ar-OCH3 × 2), 3.93
(3H, s, Ar-OCH3). 13C NMR (270 MHz, CDCl3): δ 184.4, 165.9,
153.4 (overlapped), 146.4, 140.5, 136.6, 127.7, 124.6, 123.5, 121.8,
113.2, 112.8, 109.3 (overlapped), 60.9, 56.3 (overlapped). DEIMS (70
eV) m/z (relative intensity): 312 (M+, 100%), 297 (61.1%), 266
(15.5%), 223 (7.9%), 92 (35.3%), 76 (15.1%). HREIMS m/z (M+),
312.0975; calcd for C18H16O5, 312.0998.
3′,4′-Methylendioxyaurone (Z) (15). Yield, 79.9%; yellow crystal;
1
mp, 185-188 °C. H NMR (270 MHz, CDCl3): δ 7.80 (1H, dd, J )
7.6, 1.7 Hz, C6′), 7.65 (1H, ddd, J ) 8.6, 8.3, 1.7 Hz, C6), 7.60 (1H,
d, J ) 1.7 Hz, C2′), 7.34 (1H, dd, J ) 8.3, 1.7 Hz, C4), 7.33 (1H, d,
J ) 7.6 Hz, C5′), 7.22 (1H, dd, J ) 8.3, 8.6 Hz, C5), 6.89 (1H, d, J
) 8.3, C7), 6.84 (1H, s, benzylic), 6.05 (2H, s, -OCH2O-). 13C NMR
(270 MHz, CDCl3): δ 184.5, 165.8, 149.3, 148.2, 145.9, 136.6, 127.6,
126.6, 124.6, 123.4, 121.8, 113.4, 112.9, 110.6, 108.8, 101.6. DEIMS
(70 eV) m/z (relative intensity): 266 (M+, 100%), 252 (19.2%), 146
(20.0%), 120 (35.9%), 92 (59.5%), 76 (28.3%). HREIMS m/z (M+),
266.0561; calcd for C16H10O4, 266.0579.
4,6-Dimethoxyaurone (Z) (21). Yield, 84.3%; pale yellow crystal;
1
mp, 145-146 °C. H NMR (270 MHz, CDCl3): δ 7.86 (1H, dd, J )
8.3, 2.4 Hz, C2′), 7.87 (1H, dd, J ) 7.8, 1.8 Hz, C6′), 7.33-7.47 (3H,
m, C3′, C4′, C5′), 6.78 (1H, s, benzylic), 6.39 (1H, d, J ) 1.8 Hz, C7),
6.13 (1H, d, J ) 1.8 Hz, C5), 3.96 (3H, s, Ar-OCH3), 3.92 (3H, s,
Ar-OCH3). 13C NMR (270 MHz, CDCl3): δ 180.7, 169.1, 169.0, 159.4,
147.8, 132.5, 131.1 (overlapped), 129.3, 128.8 (overlapped), 110.8,
105.2, 94.0, 89.2, 56.2, 56.1. DEIMS (70 eV) m/z (relative intensity):
282 (M+, 100%), 239 (9.2%), 118 (5.7%), 106 (7.9%), 77 (6.2%).
HREIMS m/z (M+), 282.0869; calcd for C17H14O4, 282.0892.
3′,4′-Dihydroxyaurone (Z) (16). Yield, 13.2%; orange crystal; mp,
225-228 °C. 1H NMR (270 MHz, CDCl3): δ 7.63-7.92 (2H, m, C4,
C6), 7.68 (1H, s, benzylic), 7.53 (1H, d, J ) 8.3 Hz, C5′), 7.34-7.45
(2H, m, C5, C7), 6.96 (1H, dd, J ) 8.3, 1.5 Hz, C6′), 6.93 (1H, d,
J ) 1.5 Hz, C2′). 13C NMR (270 MHz, CDCl3): δ 186.0, 167.1, 149.9,
146.8, 146.7, 138.6, 126.9, 125.4, 125.2, 124.7, 122.9, 119.2, 116.7,
116.3, 114.0. DEIMS (70 eV) m/z (relative intensity): 254 (M+, 100%),
237 (26.7%), 134 (5.6%), 120 (18.3%), 92 (33.6%), 76 (21.4%).
HREIMS m/z (M+), 254.0564; calcd for C15H10O4, 254.0579.
3′,4,4′,6-Tetramethoxyaurone (Z) (22). Yield, 71.2%; yellow
1
crystal; mp, 166-168 °C. H NMR (270 MHz, CDCl3): δ 7.45 (1H,
d, J ) 2.0 Hz, C2′), 7.43 (1H, dd, J ) 8.2, 2.0 Hz, C6′), 6.91 (1H, d,
J ) 8.2 Hz, C5′), 6.72 (1H, s, benzylic), 6.33 (1H, d, J ) 2.0 Hz, C7),
6.12 (1H, d, J ) 2.0 Hz, C5), 6.89 (1H, s, benzylic), 3.95 (3H, s, Ar-
OCH3), 3.95 (3H, s, Ar-OCH3), 3.92 (3H, s, Ar-OCH3), 3.90 (3H, s,
Ar-OCH3). 13C NMR (270 MHz, CDCl3): δ 180.4, 168.7, 159.4, 150.5,
149.1, 146.9, 125.6, 125.4, 113.9, 111.4, 111.1, 94.0, 89.2, 56.2, 56.0

Synthesis and Insect Antifeedant Activity of Aurones
J. Agric. Food Chem., Vol. 55, No. 3, 2007 703
(overlapped), 55.9. DEIMS (70 eV) m/z (relative intensity): 342 (M+,
100%), 311 (56.3%), 296 (8.3%), 77(2.5%). HREIMS m/z (M+),
342.1086; calcd for C19H18O6, 342.1103.
calculated from the area of the leaf disk consumed. A straight line was
fitted to the points obtained by the bioassay, and the ED50 was calculated
as the dose that corresponded to the midpoint between complete
inhibition and no effect.
3′,4,4′,5,6-Pentamethoxyaurone (Z) (23). Yield, 84.7%; yellow
1
crystal; mp, 161-162 °C. H NMR (270 MHz, CDCl3): δ 7.47 (1H,
Measurement of Physicochemical Properties of Tested Aurones.
The lipophilicity of a substance is closely related to its ability to
penetrate a biological membrane. Log P is conventionally used to
determine lipophilicity by the shaking-flask method using octanol and
water. However, this method is difficult to apply to lipophilic
substances, such as aurones and flavonoids (12). Therefore, we used
log k to reflect lipophilicity in this paper. Log k for the insect antifeedant
activity of aurones was calculated from the experimentally determined
high-performance liquid chromatography (HPLC) retention time of the
aurone toward a marker KI(tR): k ) (tR - t0)/t0. HPLC analyses of
aurones were performed with a VP10 (Shimadzu, Japan) and a
Shimadzu UV/vis detector at 390 nm; column: Imtakt cadenza CD-18
(100 mm × φ 4.6 mm). The eluent was acetonitrile:water (6:4) at a
flow rate of 1 mL/min.
d, J ) 2.0 Hz, C2′), 7.45 (1H, dd, J ) 2.0, 8.9 Hz, C6′), 6.93 (1H, d,
J ) 8.9 Hz, C5′), 6.74 (1H, s, benzylic), 6.51 (1H, s, C7), 4.26 (3H, s,
Ar-OCH3), 3.99 (3H, s, Ar-OCH3), 3.97 (3H, s, Ar-OCH3), 3.94
(3H, s, Ar-OCH3), 3.83 (3H, s, Ar-OCH3). 13C NMR (270 MHz,
CDCl3): δ 180.6, 163.7, 161.4, 151.6, 150.4, 148.9, 146.6, 136.6, 125.4,
125.3, 113.5, 111.7, 111.1, 107.2, 90.4, 62.4, 61.6, 56.6, 56.0, 55.9.
DEIMS (70 eV) m/z (relative intensity): 372 (M+, 100%), 357 (77.5%),
314 (7.3%), 299 (7.5%), 195 (17.8%), 167 (36.5%), 151 (10.3%).
HREIMS m/z (M+), 372.1190; calcd for C20H20O7, 372.1209.
4,6-Dimethoxy-3′,4′-dimethylaurone (Z) (24). Yield, 34.5%; yellow
1
crystal; mp, 184-186 °C. H NMR (270 MHz, CDCl3): δ 7.61 (1H,
d, J ) 7.6 Hz, C6′), 7.59 (1H, s, C2′), 7.17 (1H, d, J ) 7.6 Hz, C5′),
6.72 (1H, s, benzylic), 6.37 (1H, d, J ) 1.7 Hz, C7), 6.37 (1H, d, J )
1.7 Hz, C5), 3.94 (3H, s, Ar-OCH3), 3.90 (3H, s, Ar-OCH3), 2.31
(3H, s, Ar-CH3), 2.29 (3H, s, Ar-CH3). 13C NMR (270 MHz,
CDCl3): δ 180.6, 169.0, 168.8, 159.4, 147.4, 138.5, 136.9, 132.3, 130.2,
130.1, 128.7, 111.1, 105.4, 94.0, 89.2, 56.1, 56.0, 19.8, 19.7. DEIMS
(70 eV) m/z (relative intensity): 310 (M+, 48.0%), 295 (88.1%), 133
(43.7%), 48 (100%). HREIMS m/z (M+), 310.1199; calcd for C19H18O4,
310.1205.
The TLC Rf values of the tested aurones developed with EtOAc:
Hexane (1:1) on a SiOH plate (developing length, 6 cm; Merck Silica
Gel 60 F254 0.25 mm thick) were evaluated to assess their effect on
biological activity. The hydrogen-bonding parameter (HB) showed that
a smaller Rf value meant stronger hydrogen bonding to SiOH; thus,
the compound might act strictly at taste receptors or other receptors
by hydrogen bonding (9).
4,6,3′,4′-Tetramethylaurone (Z) (25). Yield, 84.1%; yellow crystal;
1
mp, 176-178 °C. H NMR (270 MHz, CDCl3): δ 7.66 (1H, d, J )
7.6 Hz, C6′), 7.63 (1H, s, C2′), 7.20 (1H, d, J ) 7.6 Hz, C5′), 6.93
(1H, s, C5), 6.74 (2H, s, benzylic, C7), 2.62 (3H, s, Ar-CH3), 2.41
(3H, s, Ar-CH3), 2.31 (3H, s, Ar-CH3), 2.30 (3H, s, Ar-CH3). 13C
NMR (270 MHz, CDCl3): δ 185.0, 166.8, 148.0 (overlapped), 147.0,
139.4, 138.8, 137.0, 132.4, 130.1, 128.9, 126.0, 117.6, 111.9, 110.2,
22.4, 19.9, 19.8, 17.8. DEIMS (70 eV) m/z (relative intensity): 278
(M+, 57.3%), 263 (100%), 148 (24.8%), 120 (11.0%). HREIMS m/z
(M+), 278.1301; calcd for C19H18O2, 278.1307
RESULTS AND DISCUSSION
Previously, we reported that the insect antifeedant activities
of benzopyranones, flavones, and chromone against S. litura
larvae were decreased by the introduction of a hydroxyl group
(9). In this study, we evaluated the insect antifeedant activities
of various aurones (Z form) and their synthetic precursors,
coumaranones, against S. litura larvae by a dual-choice leaf disk
bioassay. Among the 23 test compounds, 3′,4,4′,6-tetramethoxyau-
rone (22) was the most active compound with an ED50 of 0.12
µmol/cm2 (Table 1). B ring-eliminated compounds, coumara-
nones, showed that the introduction of methoxyl and methyl
groups to a benzene ring increased biological activity, and 4,5,6-
trisubstituted compounds showed the strongest activity, with an
ED50 of 0.41 µmol/cm2. Similarly, the tested aurones showed
that the introduction of methoxyl group to the A and/or B rings
increased the insect antifeedant activity, while 4,5,6- and 3′,4′,5′-
trisubstituted compounds did not show this activity in this test
(Table 1). This result differed from that with coumaranone but
was similar to previous results using by flavones and chromones
(9). The methoxyl group located at the 6-position (C6) of
flavone, which corresponds to the 5-position (C5) of aurone,
was easy to demethylate by S. litura larvae (13). This suggests
that the introduction of a methoxyl group at the C5 of the aurone
A ring may have the same effect as introducing a hydroxyl
group, and as a result, the biological activity disappeared. While
the introduction of 3′- or 4′-monosubstituted, catechol type
disubstituted, or methylenedioxy groups to the B ring increased
this activity, the introduction of 2′-monosubstituted and electron-
withdrawing groups, such as 3′-Br or 3′-Cl derivatives, did not
show this activity. In a B ring-substituted derivative, the most
effective compounds were 3′-methoxyaurone (10) and 3′4′-
dimethoxyaurone (14) (Table 1). It has been reported that the
hydrophobic and steric properties of the 6- and 3′-positions of
flavone are important for binding to the GABA receptor (14).
The relationship between compounds that affect the GABA
receptor and insect antifeedants has already been reported (15).
As compared to 14, the corresponding hydroxylated aurone (16)
showed remarkably decreased activity, and the addition of a
hydroxyl group to an active compound (10) gave similar results.
3′,4′-Dimethoxy-4,6-dimethylaurone (Z) (26). Yield, 94.8%; yellow
1
crystal; mp, 134-135 °C. H NMR (270 MHz, CDCl3): δ 7.53 (1H,
d, J ) 1.5 Hz, C2′), 7.46 (1H, dd, J ) 1.5, 8.5 Hz, C6′), 6.93 (1H, d,
J ) 8.5 Hz, C5′), 6.91 (1H, s, C5), 6.76 (1H, s, C7), 6.75 (1H, s,
benzylic), 3.98 (3H, s, Ar-OCH3), 3.94 (3H, s, Ar-OCH3), 2.64 (3H,
s, Ar-CH3), 2.42 (3H, s, Ar-CH3). 13C NMR (270 MHz, CDCl3): δ
184.8, 166.9, 150.4, 149.0, 147.9, 146.5, 139.5, 126.0, 125.6, 125.5,
117.7, 113.5, 111.9, 111.1, 110.1, 55.9, 55.8, 22.4, 17.7. DEIMS (70
eV) m/z (relative intensity): 310 (M+, 100%), 295 (25.1%), 267
(15.5%), 252 (20.7%), 132 (3.4%), 120 (7.2%). HREIMS m/z (M+),
310.1193; calcd for C19H18O4, 310.1205.
Insect Antifeedant Assay. Insects. Common cutworms (S. litura
F.) were purchased from Sumika Technoservice Co. Ltd. (Takarazuka,
Japan). The insects were reared on an artificial diet (Insecta LF, Nihon
Nosan Kogyo Co., Japan) in a controlled environment at 26.5 °C and
60% humidity.
Antifeedant Bioassay. For the insect antifeedant test against common
cutworms, leaf disks, 2 cm in diameter, were prepared with a cork
borer from fresh sweet potato (Ipomoea batata cv. narutokintoki) leaves
that had been cultivated in the farm at Kinki University (Nara Pref.
Japan). Two disks were treated with test compound in an acetone
solution, and two other disks were treated with acetone only as a control.
After the acetone was completely evaporated, the four disks were set
in alternating positions in the same petri dish, 9.5 cm in diameter, with
moistened filter paper on the bottom. Fifteen larvae (third instar) were
released into the dish. The dishes were then kept in an insect-rearing
room at 26.5 °C in the dark for 5-6 h. Partially consumed leaf disks
were digitized by a PC scanner. Data were analyzed on a PC using
NIH Image (http://rsb.info.nih.gov/nih-image/). For each experiment,
the data for an intact disk were measured and compared to those of a
treated disk. To measure the activities of test compounds, we used an
antifeedant index: AFI ) % of treated disks consumed/(% of treated
disks consumed + % of control disks consumed) × 100. The AFI value
was converted to the inhibitory rate (%): inhibitory rate (%) ) (50 -
AFI) × 2. The insect antifeedant potency of test compounds was
evaluated in terms of the ED50 value for the rate of feeding inhibition

704 J. Agric. Food Chem., Vol. 55, No. 3, 2007
Morimoto et al.
Table 1. Insect Antifeedant Activity of Coumaranones, Aurones, and Salannin on S. litura Larvaea
A ring
R2
B ring
ED50
mol/cm2)
pED50
(mol/cm2)
compd
R1
R3
R4
R5
R6
R7
(
µ
5
6
7
OCH3
CH3
OCH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OCH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OCH3
CH3
OCH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3.87
0.68
0.41
inactive
inactive
inactive
1.01
inactive
4.21
2.03
0.86
1.61
inactive
inactive
1.96
3.45
inactive
0.85
5.41
6.17
6.39
coumaranone
8
9
H
OCH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OCH3
Cl
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
salannin
6.00
5.38
5.69
6.07
5.79
OCH3
OCH3
OCH3
−O
−CH2−O
−
OH
OH
OH
OH
H
OCH3
H
OCH3
OCH3
CH3
CH3
OCH3
OCH3
OC2H3
OCH3
OCH3
H
OCH3
OCH3
CH3
5.71
5.46
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
CH3
CH3
H
H
OCH3
H
H
OCH3
OCH3
OCH3
OCH3
CH3
CH3
H
H
H
H
H
H
6.07
6.92
0.12
inactive
inactive
inactive
1.02
H
H
CH3
OCH3
H
5.99
7.18
0.066
a Salannin, positive control isolated from neem oil; inactive, antifeedant activity was less than 40% at 0.33 mg (ca. 1.52
µ
mol)/cm2 disk treatment.
Table 2. Physicochemical Properties and Insect Antifeedant Activity of
Active Compounds against S. litura Larvae
physicochemical properties
compd
mp
Rf
log K
10
12
13
14
15
18
19
21
22
118.0
116.0
131.5
154.0
186.5
122.0
154.0
145.5
167.0
0.61
0.61
0.55
0.54
0.44
0.45
0.54
0.33
0.07
0.737
1.047
0.689
0.741
0.624
0.382
0.741
0.560
0.277
These results suggest that the hydroxylation of aurones is
disadvantageous for insect antifeedant activity against S. litura
larvae, as well as flavones and chromones.
Figure 3. Correlation between insect antifeedant activity and melting point
in active compounds.
To determine the structural requirements that are needed for
the activity of aurones, biological activities were compared to
physicochemical parameters by regression. The biological
activities and physicochemical parameters of the nine active
compounds are summarized in Table 2. While melting points
did not show a good correlation with insect antifeedant activity
against S. litura larvae (r ) 0.62, with 15 excluded from the
data set) (Figure 3), compounds that were nearly inactive had
high melting points. Despite its high melting point, a methyl-
enedioxy derivative (15) showed moderate activity, and we
considered that its potent activity may overcome its disadvanta-
geous physicochemical property. Finally, significant correlations
were found between biological activity (pED50) and a HB
calculated from the Rf value developed with SiOH TLC and a
lipophilicity parameter (log k) calculated from the retention time
in ODS HPLC. The respective correlation coefficients (r) were
-0.83 and -0.70 (Figure 4). There were large differences
between 3′-methoxyaurone (10) and 3′-ethoxy-4′-hydroxy-
aurone (18) with respect to HB and log k. This result sug-
gested that the 3′-position and hydroxyl group in the B ring of
aurones were sensitive to the effects of other molecules, SiOH

Synthesis and Insect Antifeedant Activity of Aurones
J. Agric. Food Chem., Vol. 55, No. 3, 2007 705
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pyridazinones, against armyworm (Pseudaletia separata) (16).
These correlations between physicochemical properties and
insect antifeedant activity were similar to previous results with
2,3-dihydrobenzofurans (7). This suggests that the antifeedant
activity of aurone is strongly dependent on the similarity of the
chemical structure between the benzofuran and the benzofura-
none moiety of aurone.
In conclusion, the introduction of alkoxy and alkyl groups
along with adequate HB seems to contribute to the antifeedant
activity of the compounds tested. This could lead to the
development of a compound that regulates insect behavior from
natural flavonoids.
LITERATURE CITED
Received for review September 6, 2006. Revised manuscript received
November 15, 2006. Accepted November 28, 2006.
(1) Harborne, J. B.; Grayer, R. J. Flavonoids and insects. In The
FlaVonoids; Harborne, J. B., Ed.; Chapman & Hall: London,
1993; pp 589-618.
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