Synthesis and structure-activity relationships and effects of phenylpropanoid amides of octopamine and dopamine on tyrosinase inhibition and antioxidation

Article abstract of DOI:10.1016/j.foodchem.2012.02.152

Phenylpropanoid amides of octopamine (OA) 1a-1e and dopamine (DA) 2a-2e were synthesised and the structure-activity relationships (SARs) for antioxidant and tyrosinase inhibition activities were analysed. Among synthesised compounds, 2c, which contains two catechol moieties, exhibited the most DPPH radical-scavenging activity (EC₅₀ = 16.2 ± 2.4 μM), and 1d exhibited significant tyrosinase inhibitory activity (IC₅₀ = 5.3 ± 1.8 μM). Interestingly, with the same acid moiety, OA derivatives showed more inhibitory effect on tyrosinase than did compounds derived from DA, whereas DA derivatives were found to have higher antioxidant activity than compounds derived from OA. The relationship between their structures and their potencies, demonstrated in the current study, will be useful for the design of optimal agents.

Full text of DOI:10.1016/j.foodchem.2012.02.152

Food Chemistry 134 (2012) 1128–1131
Contents lists available at SciVerse ScienceDirect
Food Chemistry
journal homepage: www.elsevier.com/locate/foodchem
Short communication
Synthesis and structure–activity relationships and effects of phenylpropanoid
amides of octopamine and dopamine on tyrosinase inhibition and antioxidation
Zhengrong Wu a, Lifang Zheng b, Yang Li c, Feng Su c, Xiaoxuan Yue c, Wei Tang b, Xiaoyan Ma b,
Junyu Nie a, Hongyu Li c,
⇑
a College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, People’s Republic of China
b School of Pharmaceutics, Lanzhou University, Lanzhou 730000, People’s Republic of China
c Institute of Microbiology, School of Life Sciences, Lanzhou University, 222 Tian Shui South Road, Lanzhou 730000, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 August 2011
Received in revised form 10 January 2012
Accepted 23 February 2012
Available online 3 March 2012
Phenylpropanoid amides of octopamine (OA) 1a–1e and dopamine (DA) 2a–2e were synthesised and the
structure–activity relationships (SARs) for antioxidant and tyrosinase inhibition activities were analysed.
Among synthesised compounds, 2c, which contains two catechol moieties, exhibited the most DPPH
radical-scavenging activity (EC50 = 16.2 2.4
lM), and 1d exhibited significant tyrosinase inhibitory activ-
ity (IC50 = 5.3 1.8 M). Interestingly, with the same acid moiety, OA derivatives showed more inhibitory
l
effect on tyrosinase than did compounds derived from DA, whereas DA derivatives were found to have
higher antioxidant activity than compounds derived from OA. The relationship between their structures
and their potencies, demonstrated in the current study, will be useful for the design of optimal agents.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Phenylpropanoid amides
Octopamine
Dopamine
Tyrosinase inhibition
Antioxidation
1. Introduction
synthesis and SARs for antioxidant and tyrosinase inhibition activ-
ities of OA derivatives have not yet been fully elucidated; besides,
In the food industry, tyrosinase is responsible for enzymatic
browning reactions in vegetables and fruits; the browning reactions
can produce undesirable changes in colour, flavour, and nutritive va-
lue of the products (Nerya, Musa, Khatib, Tamir, & Vaya, 2004).
Therefore, the unfavourable browning has been of great concern,
and it is necessary to search for potent tyrosinase inhibitors
(Friedman, 1996; Takahashi & Miyazawa, 2011). Great interest has
also been shown in antioxidants, which are used as food additives
to help guard against food deterioration (Capecka, Mareczek, & Leja,
2005). So far, many efforts have been spent in the search for potent
tyrosinase inhibitors and antioxidants in the food industry (Chiari,
Joray, Ruiz, Palacios, & Carpinella, 2010; Cho, Roh, Sun, Kim, & Park,
2006; Kubo, Chen, & Nihei, 2003; Qiu et al., 2009; Um et al., 2003; Yu,
2003). In particular, there is a concerned effort to search for naturally
occurring tyrosinase inhibitors and antioxidants from plants, be-
cause plants constitute a rich source of bioactive chemicals and
manyofthemarefreefromharmfuladverseeffects(Lee&Lee, 1997).
OA derivatives, such as N-trans-coumaroyloctopamine and
N-trans-feruloyloctopamine, belonging to the hydroxycinnamic
acid amides family, were identified as the primary antioxidant con-
stituents of garlic skin (Ichikawa et al., 2003). To our knowledge, the
OA and DA (Fig. 1), each have two hydroxyl groups and the only
difference is the position of the hydroxyl groups. Therefore, in this
study, a series of OA derivatives (1a–1e) and DA derivatives (2a–2e)
was synthesised and the relationship between the chemical struc-
tures and two biological activities was explored.
2. Materials and methods
2.1. Chemicals and reagents
Melting points were determined on a WRS-1B digital instrument
without correction. IR spectra were obtained on a Nicolet NEXUS
670 FT-IR spectrometer. All NMR spectra were recorded on a Varian
Mercury 400 MHz instrument. FAB HRMS spectra were obtained on
an Autostec-3090 mass spectrometer. Tyrosinase, ascorbic acid
(Vc), 1, 1-di-phenyl-2-picrylhydrazyl (DPPHÅ),
L-3, 4-dihydroxy-
phenylalanine ( -DOPA) and tertiary-butyl-hydroquinone (TBHQ)
L
were purchased from Sigma–Aldrich Chemical Co., (St. Louis, MO).
Other chemicals were purchased from commercial suppliers.
2.2. Synthesis
⇑
The synthetic pathways and chemical structures of OA and DA
derivatives are shown in Fig. 2. The substituted cinnamic acids
Corresponding author. Tel.: +86 931 8912560; fax: +86 931 8912561.
E-mail addresses: wuzhrong@163.com, lihy@lzu.edu.cn (H. Li).
0308-8146/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.foodchem.2012.02.152

Z. Wu et al. / Food Chemistry 134 (2012) 1128–1131
1129
OH
5.0 mM L-DOPA was mixed with 0.6 ml of 0.25 M phosphate buffer
(pH 6.8) and 1.9 ml of water, incubated at 37 °C for 10 min. Then,
0.1 ml of the sample solution and 0.1 ml of the aqueous solution
of the tyrosinase (20 lg) were added, and the assay mixture was
incubated at 37 °C for 25 min, the absorbance was measured at
490 nm using a 722s spectrophotometer. The extent of tyrosinase
inhibition was expressed as the percentage necessary for 50% inhi-
bition concentration (IC50).
HO
HO
NH2
NH2
OA
HO
DA
Fig. 1. Chemical structures of OA and DA.
were synthesised using Doebner–Knoevenagel modification
(Vishnoi, Agrawal, & Kasana, 2009). The amides were obtained by
coupling of substituted cinnamic acids with phenylalkylamine
(OA and DA) in DMF in the presence of triethylamine and BOP as
a coupling agent (Okombi et al., 2006). The yields were between
62% and 80%.
The structures of the synthesised compounds were confirmed
by IR, 1H NMR, 13C NMR, and HRMS, The spectroscopic data of
1b, 1d and 2a–2c were consistent with literature values (Ichikawa
et al., 2003; Lee et al., 2004; Rajan et al., 2001). The NMR spectro-
scopic data for 1a, 1c and 1e, which have not previously been re-
ported, are listed in Table 1.
2.4. DPPH radical-scavenging assay
The assay was performed according to the method by Takahashi
and Miyazawa (2011) with slight modifications. 0.63 ml of
100 mM acetate buffer (pH 5.5) and 0.35 ml of an ethanolic solu-
tion of 0.3 mM DPPHÅ were put into a test tube. Then, 0.02 ml of
the sample solution (dissolved in ethanol) was added to the tube
and incubated at 25 °C for 30 min, the absorbance was measured
at 517 nm. The extent of reduction was expressed as the percent-
age necessary for 50% reduction (EC50).
N-trans-Cinnamoyloctopamine (1a): White powder. Melting
point: 187–189 °C. IR (KBr, cmꢀ1): 3365, 3262 (N–H, O–H); 2929
(C–H); 1651 (C@O); 1610 (C@C); 1514 (C–C of benzene); 1117
(C–O). HRMS: m/z 306.1105 (calcd for C17H17NO3+Na, 306.1101).
N-trans-Caffeoyloctopamine (1c): Yellowish powder. Melting
point: 174–176 °C. IR (KBr, cmꢀ1): 3354–3117 (NH, OH); 2935
(C–H); 1655 (C@O); 1604 (C@C), 1512 (C–C of benzene); 1112
(C–O). HRMS: m/z 338.1007 (calcd for C17H17NO5+Na, 338.0999).
N-trans-Sinapoyloctopamine (1e): Yellowish powder. Melting
point: 178–180 °C. IR (KBr, cmꢀ1): 3365–3017 (NH, OH); 2934
(C–H); 1655 (C@O); 1611(C@C); 1514 (C–C of benzene); 1374
(CH3); 1113 (C–O). HRMS: m/z 382.1258 (calcd for C19H21NO6+Na
382.1261).
3. Results and discussion
3.1. Effects of inhibitors on the enzyme activity
As shown in Fig. 3, the tyrosinase inhibition strength decreased
in the following order: 1d > 2d > 1b > 2b > Vc > TBHQ > 1e >
2e > 1a > 2a > 1c > 2c.
When compared with 1a and 1a, compounds (1b and 2b)
substituted in the 4-position with a hydroxyl group were more po-
tent in tyrosinase inhibitory activity; this result further confirmed
that the hydroxyl group was important in raising the inhibitory
activity (Huang et al., 2006; Shi et al., 2005). But increasing the
hydroxyl number on aromatic ring did not necessarily lead to
enhanced inhibitory activity (1c and 2c versus 1b and 2b, respec-
tively). The inhibitory activity toward tyrosinase can be lost or
reduced due to steric hindrance with excessive hydroxyl groups
(Kim et al., 2006), which is why 1c and 2c showed the lowest
2.3. Enzyme activity assay
The assay was performed according to the method by Shi, Chen,
Wang, Song, and Qiu (2005) with slight modifications. 0.3 ml of
O
O
COOH
R1
R1
H
OH
COOH
Pyridine,
Piperidine
R2
R2
R3
R3
OA or DA BOP/DMF
5'
OH
6'
O
4'
7
8'
7'
6
R1
1
9
1'
3'
N
H
5
8
2'
R5
2
R4
4
R2
3
R3
2a R1=H
2b R1=H
2c R1=H
2d R1=H
R2 =H R3 =H
R2=OH R3 =H
R2=OH R3 =OH
R4 =H R5 =OH
R4 =H R5 =OH
R4 =H R5 =OH
1a R1=H
R2=H
R2=OH R3=H
R2=OH R3=OH
R2=OH R3=OMe R4 =OH R5=H
R3=H
R4 =OH R5=H
R4 =OH R5=H
R4 =OH R5=H
1b R1=H
1c R1=H
1d R1=H
R2=OH R3 =OMe R4 =H R5 =OH
2e R1=OMe R2=OH R3=OMe R4 =H R5 =OH
1e R1=OMe R2=OH R3=OMe R4 =OH R5=H
Fig. 2. The synthetic pathways and chemical structures of OA derivatives (1a–1e) and DA derivatives (2a–2e).

1130
Z. Wu et al. / Food Chemistry 134 (2012) 1128–1131
Table 1
1H and 13C NMR data of compounds 1a, 1c and 1e in CD3OD-d4.
Compounds
NMR data
a
1a
dH : 3.43 (1 H, dd, J = 13.6, 8.0 Hz, H-80a), 3.54 (1 H, dd, J = 13.2, 4.8 Hz, H-80b), 4.72 (1 H, dd, J = 7.6, 5.2 Hz, H-70), 6.64 (1 H, d, J = 16.0 Hz, H-8),
6.77 (2 H, d, J = 8.4 Hz, H-30, 50), 7.22 (2 H, d J = 8.4 Hz, H-20, H-60), 7.35–7.54 (5 H, m, H-2, H-3, H-4, H-5, H-6), 7.55 (1 H, d, J = 16.0 Hz, H-7).
a
dC : 168.9 (C-9), 158.1 (C-40), 141.8 (C-7), 136.3 (C-l), 134.7(C-l0), 130.8 (C-3, C-5), 129.9 (C-20, C-60), 128.8 (C-4), 128.5 (C-2, C-6), 121.8 (C-8),
116.1(C-30, C-50), 73.4 (C-70), 48.3 (C-80).
a
1c
1e
dH : 3.40 (1 H, dd, J = 13.6, 8.4 Hz, H-80a), 3.52 (1 H, dd, J = 13.2, 4.4 Hz, H-80b), 4.72 (1 H, dd, J = 8.8, 5.2 Hz, H-70), 6.38 (1 H, d, J = 15.6 Hz, H-8),
6.75 (2 H, d, J = 7.2 Hz, H-30, H-50), 6.77–6.99 (3 H, m, H-2, H-5, H-6), 7.22 (2 H, d, J = 8.4 Hz, H-20, H-60), 7.38 (1 H, d, J = 15.6 Hz, H-7).
a
dC : 169.6 (C-9), 158.0 (C-40), 148.7 (C-3), 146.6 (C-4), 142.4 (C-7), 134.7 (C-l0), 128.4(C-l), 128.3 (C-20, C-60), 122.1 (C-6), 118.3 (C-8), 116.5(C-
5), 116.1 (C-30, C-50), 115.1 (C-2), 73.4 (C-70), 48.3 (C-80).
a
dH : 3.44 (1 H, dd, J = 13.6, 7.6 Hz, H-80a), 3.53 (1 H, dd, J = 13.6, 4.8 Hz, H-80b), 3.87 (6 H, s, 3-OMe; 5-OMe), 4.72 (1 H, dd, J = 8.4, 5.2 Hz, H-70),
6.49 (1 H, d, J = 15.6 Hz, H-8), 6.77 (2 H, d, J = 8.4, H-30, H-50), 6.85 (2 H, s, H-2, H-6), 7.22 (2 H, d, J = 8.4 Hz, H-20, H-60), 7.43 (1 H, d, J = 15.6 Hz,
H-7).
a
dC : 169.4 (C-9), 158.1 (C-40), 149.5 (C-3, C-5), 142.4 (C-7), 138.9 (C-l0), 134.7 (C-4), 128.5 (C-1), 127.2 (C-20, C-60), 119.1 (C-8), 116.1 (C-30, C-
50), 106.5 (C-2, C-6), 73.4 (C-70), 56.8 (2ꢁ OMe), 48.4 (C-80).
a
Recorded at 400 MHz for 1H and 100 MHz for 13C.
50
40
30
20
10
0
200
160
120
80
40
0
1a 1b 1c
1d 1e 2a 2b 2c
Compound
2d 2e Vc TBHQ
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
Vc TBHQ
Compound
Fig. 3. Inhibitory effects and EC50 for Vc, TBHQ and OA and DA derivatives against
tyrosinase. Vc and TBHQ were used as standard references. Values were determined
from logarithmic concentration–effect curves. All data points represent the
mean SD of three independent replicates (n = 3).
Fig. 4. DPPH radical-scavenging and IC50 for Vc, TBHQ and OA and DA derivatives.
Vc and TBHQ were used as standard references. Values were determined from
logarithmic concentration–effect curves. All data points represent the means SD
of three independent replicates (n = 3).
activity. Furthermore, the presence of a catechol entity, and prefer-
ably at the amine moiety, seemed to be more detrimental to the
tyrosinase inhibitory activity, because DA derivatives were less
active than compounds derived from OA.
DPPH radical-scavenging activity among the synthesised com-
pounds. This can be explained by the presence of two catechol
moieties.
Additionally, 1d and 2d showed higher inhibitory activities than
did 1b and 2b; so it was clear that addition of one methoxyl group,
ortho to the 4-hydroxyl group, was very important for the tyrosi-
nase inhibitory activity. But addition of a second methoxyl group,
also ortho to the hydroxyl group, did not necessarily lead to en-
hanced inhibitory activity (1e and 2e versus 1d and 2d,
respectively).
The results indicated that the DPPH radical-scavenging activity
was dependent on the number of hydroxyl groups and on struc-
tural features stabilizing the radical formed; this was in agreement
with earlier findings (Fagerlund, Sunnerheim, & Dimberg, 2009;
Son & Lewis, 2002; Yi, Wu, Cao, Song, & Ma, 2009).
3.3. The relationship between the two bioactivities
3.2. Radical-scavenging activity on DPPHÅ
According to further SAR analyses, the potency of tyrosinase
inhibition and the antioxidant activity of the synthesised com-
pounds both shared similar chemical features and functional
groups, such as the presence of hydroxyl and methoxyl groups,
as shown by Figs. 3 and 4. Introduction of a hydroxyl into 1a and
2a to produce 1b and 2b increases both tyrosinase inhibition and
the antioxidant activities; this indicated that both activities are en-
hanced by the presence of a 4-hydroxyl group. Addition of one
methoxyl group ortho to the hydroxyl group, 1b ? 1d and
2b ? 2d, resulted in enhancing of both activities. Addition of a sec-
ond methoxyl group, ortho to the other hydroxyl group, 1d ? 1e
and 2d ? 2e, or changing the methoxyl group to a hydroxyl group,
1b ? 1c and 2b ? 2c, resulted in even greater increase in antioxi-
dant activity, but a decrease in tyrosinase inhibitory activity.
The radical-scavenging effects of the compounds are shown in
Fig. 4; their scavenging activity on DPPH radicals decreased in
the following order: Vc > TBHQ > 2c > 2e > 1c > 2d > 1e > 1d >
2b > 1b > 2a > 1a. As seen from the sequence 2c > 1c > 2b > 1b >
2a > 1a, the number of hydroxyl groups preferably attached to
the aromatic ring might play an important role in determining
the activity. In addition, it was also noticed that the introduction
of methoxyl groups would increase the activity (1d and 2d versus
1b and 2b, 1e and 2e versus 1d and 2d, respectively). This was due
to the fact that the methoxyl group is an electron-donating group,
which could help to stabilize the phenoxy radicals (Pinedo,
Peñalver, & Morales, 2007). Additionally, 2c exhibited the highest

Z. Wu et al. / Food Chemistry 134 (2012) 1128–1131
1131
Huang, X. H., Chen, Q. X., Wang, Q., Song, K. K., Wang, J., Sha, L., et al. (2006).
Inhibition of the activity of mushroom tyrosinase by alkylbenzoic acids. Food
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Journal of Agriculture and Food Chemistry, 51, 7313–7317.
Kim, D., Park, J., Kim, J., Han, Ch., Yoon, J., Kim, N., et al. (2006). Flavonoids as
mushroom tyrosinase inhibitors: A fluorescence quenching study. Journal of
Agriculture and Food Chemistry, 54, 935–941.
Kubo, I., Chen, Q. X., & Nihei, K. (2003). Molecular design of antibrowning agents:
Antioxidative tyrosinase inhibitors. Food Chemistry, 81, 242–247.
Lee, G. C., & Lee, C. Y. (1997). Inhibitory effect of caramelization products on
enzymic browning. Food Chemistry, 60, 231–235.
Additionally, with the same acid moiety, OA derivatives showed
more inhibitory activity on tyrosinase than did compounds derived
from DA, whereas DA derivatives were found to have higher DPPH
radical-scavenging activity than had compounds derived from OA.
Making this distinction was the number of phenolic hydroxyl
groups attached to the aromatic ring of amines, which we have
discussed above.
4. Conclusions
Lee, D. G., Park, Y., Kim, M. R., Jung, H. J., Seu, Y. B., Hahm, K. S., et al. (2004). Anti-
fungal effects of phenolic amides isolated from the root bark of Lycium chinense.
Biotechnology Letters, 26, 1125–1130.
Nerya, O., Musa, R., Khatib, S., Tamir, S., & Vaya, J. (2004). Chalcones as potent
tyrosinase inhibitors: The effect of hydroxyl positions and numbers.
Phytochemistry, 65, 1389–1395.
Okombi, S., Rival, D., Bonnet, S., Mariotte, A. M., Perrier, E., & Boumendjel, A. (2006).
Analogues of N-hydroxycinnamoylphenalkylamides as inhibitors of human
melanocyte–tyrosinase. Bioorganic & Medicinal Chemistry, 16, 2252–2255.
Pinedo, A. T., Peñalver, P., & Morales, J. C. (2007). Synthesis and evaluation of new
phenolic-based antioxidants: Structure–activity relationship. Food Chemistry,
103, 55–61.
Qiu, L., Chen, Q. H., Zhuang, J. X., Zhong, X., Zhou, J. J., Guo, Y. J., et al. (2009).
Inhibitory effects of a-cyano-4-hydroxycinnamic acid on the activity of
mushroom tyrosinase. Food Chemistry, 112, 609–613.
The relationship between the structures and the biological
activities demonstrated in the current study will contribute to
the design of optimal agents. OA derivatives exhibited potent
tyrosinase inhibitory activity, especially compound 1d, which
seemed to be useful as a good depigmentation agent with inhibi-
tory activity on tyrosinase in addition to its antioxidant property.
Further experiments are in progress in order to know how these
compounds interact with the enzyme on a molecular basis. Addi-
tionally, two of the synthesised OA derivatives (1b and 1d) have
been isolated from garlic skins. Presently, garlic skin is an indus-
trial waste, so this research also offers a pointer to the full use of
garlic skin.
Rajan, P., Vedernikova, I., Cos, P., Berghe, D. V., Augustyns, K., & Haemers, A. (2001).
Synthesis and evaluation of caffeic acid amides as antioxidants. Bioorganic &
Medicinal Chemistry Letters, 11(2), 215–217.
Shi, Y., Chen, Q. X., Wang, Q., Song, K. K., & Qiu, L. (2005). Inhibitory effects of
cinnamic acid and its derivatives on the diphenolase activity of mushroom
(Agaricus bisporus) tyrosinase. Food Chemistry, 92(4), 707–712.
Appendix A. Supplementary data
Son, S., & Lewis, B. A. (2002). Free radical scavenging and antioxidative activity of
caffeic acid amide and ester analogues: Structure–activity relationship. Journal
of Agricultural and Food Chemistry, 50, 468–472.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.foodchem.2012.02.152.
Takahashi, T.,
&
Miyazawa, M. (2011). Synthesis and structure–activity
relationships of phenylpropanoid amides of serotonin on tyrosinase
inhibition. Bioorganic & Medicinal Chemistry Letters, 21, 1983–1986.
Um, S. J., Park, M. S., Park, S. H., Han, H. S., Kwon, Y. J., & Sin, H. S. (2003). Synthesis of
new glycyrrhetinic acid (GA) derivatives and their effects on tyrosinase activity.
Bioorganic & Medicinal Chemistry, 11, 5345–5352.
Vishnoi, S., Agrawal, V., & Kasana, V. K. (2009). Synthesis and structure–activity
relationships of substituted cinnamic acids and amide analogues: A new class of
herbicides. Journal of Agricultural and Food Chemistry, 57, 3261–3265.
Yi, W., Wu, X. Q., Cao, R. H., Song, H. C., & Ma, L. (2009). Biological evaluations of
novel vitamin C esters as mushroom tyrosinase inhibitors and antioxidants.
Food Chemistry, 117, 381–386.
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