Hindawi

Evidence-Based Complementary and Alternative Medicine

Volume 2021, Article ID 5561176, 7 pages
https://doi.org/10.1155/2021/5561176

Research Article
Tyrosinase Inhibitors from the Stems of Streblus Ilicifolius

Nhan T. Nguyen ,1,2,3 Phu H. Dang ,1,2 Hai X. Nguyen ,1,2 Truong N. V. Do ,1,2
Tho H. Le ,1,2 Tuyen Q. H. Le ,1,2 and Mai T. T. Nguyen 1,2,3
1
Faculty of Chemistry, University of Science, 227 Nguyen Van Cu Street, Ward 4, District 5, Ho Chi Minh City, Vietnam
2
Vietnam National University, Quarter 6, Linh Trung Ward, Thu Duc District, Ho Chi Minh City, Vietnam
3
Cancer Research Laboratory, University of Science, 227 Nguyen Van Cu Street, District 5, Ho Chi Minh City, Vietnam

Correspondence should be addressed to Mai T. T. Nguyen; nttmai@hcmus.edu.vn

Received 18 March 2021; Accepted 25 June 2021; Published 1 July 2021

Academic Editor: Hilal Zaid

Copyright © 2021 Nhan T. Nguyen et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
Two new stilbene derivatives, named strebluses C and D, were isolated from the EtOAc-soluble fraction of the stems of Streblus
ilicifolius (Moraceae). Its absolute configuration was elucidated based on NMR spectroscopic data interpretation and optical
rotation calculation. Streblus C possesses strong tyrosinase inhibitory activity with an IC50 value of 0.01 μM. Docking studies of 1
and 2 with oxy-tyrosinase were carried out to analyze their interactions. The analysis of the docked poses confirmed that 1 showed
better binding affinity for oxy-tyrosinase than that of 2.

1. Introduction our study on chemical constituents of the stems of

S. ilicifolius was carried out, leading to the isolation of two
Tyrosinase (EC 1.14.18.1), which is a binuclear copper- undescribed stilbene derivatives, strebluses C (1) and D (2).
containing monooxygenase, is a key enzyme in the oxidation Compound 1 showed a strong tyrosinase inhibitory activity
of phenol to the corresponding o-quinone [1, 2]. It plays a with an IC50 value of 0.01 μM, which makes it 4400 times
main factor causing freckles, brown age spots, and melasma. more potent than that of kojic acid (IC50, 44.6 μM). In
Some commercial compounds, such as hydroquinone, addition, molecular docking studies of 1 and 2 with the oxy-
arbutin, kojic acid, azelaic acid, L-ascorbic acid, ellagic acid, form of the copper-bound Streptomyces castaneoglobisporus
and tranexamic acid, were reported as the well-known ty- tyrosinase were performed.
rosinase inhibitors. These compounds have been used as skin
whitening agents in cosmetic products, but they have certain
drawbacks [3]. Thus, the finding of the new efficient and safe
2. Materials and Methods
tyrosinase inhibitors is necessary for antihyperpigmentation 2.1. General Experimental Procedures. Optical values were
product development. measured on a Shimadzu UV-1800 spectrophotometer
Streblus ilicifolius (Vidal) Corner, which belongs to (Shimadzu Pte., Ltd., Singapore). IR spectra were measured
Moraceae family, was found and cultivated in Vietnam. Its with a Shimadzu IR-408 infrared spectrometer (Shimadzu
barks have been traditionally used as an antipimple medi- Pte., Ltd., Singapore). NMR spectra were acquired on a
cine. In a few published studies, some phenolic compounds Bruker Avance III 500 spectrometer (Bruker BioSpin AG,
have been reported in this plant [4–7]. In our continued Bangkok, Thailand). Chemical shifts are expressed as δ
studies on the screening of medicinal plants for tyrosinase values. HRESIMS data were acquired on Bruker micrOTOF-
inhibitory activity [8–12], it was found that a MeOH-soluble QII mass spectrometer (Bruker Singapore Pte., Ltd., Sin-
extract of the stems of Streblus ilicifolius showed a strong gapore). Column chromatography was carried out using
inhibitory effect, with an IC50 value of 0.63 μg·mL−1. Thus, silica gel 60, 0.06–0.2 mm (Scharlau, Barcelona, Spain), and
2 Evidence-Based Complementary and Alternative Medicine

LiChroprep RP-18, 40−63 μm (Merck KGaA, Darmstadt, 2.3. Tyrosinase Inhibitory Assay. All pure compounds were
Germany). Kieselgel 60 F254 or RP-18 F254 plates for TLC dissolved in DMSO and tested at concentrations ranging
were purchased from Merck (Merck KGaA, Darmstadt, from 0.01 to 100 μM. Assay mixtures in 0.1 M phosphate
Germany). Tyrosinase (EC 1.14.18.1) from mushroom buffer pH 6.8 were prepared immediately before use, con-
(3933 U·mL−1) and L-dihydroxyphenylalanine (L-DOPA) sisting of 100 μL of tyrosinase solution (15 U/mL) and
were obtained from Sigma-Aldrich (Sigma-Aldrich Pte Ltd, 1900 μL of test solution. These mixtures were preincubated
Singapore). Other chemicals were of the highest grade at 32°C for 30 min, followed by addition of 1000 μL of L-
available. DOPA 1.5 mM in pH 6.8 phosphate buffer, and incubated at
32°C for 7 min. The absorbance (A) at 475 nm was acquired
on Shimadzu UV-1800 spectrophotometer. The inhibitory
2.2. Plant Material. The stems of Streblus ilicifolius were percentage (I%) was calculated according to the formula: I
collected at Hoai Nhon District, Binh Dinh Province, % � [(Acontrol − Asample)/Acontrol] × 100%. Data were repre-
Vietnam, in October 2017. The plant was identified by Dr. sented as means ± standard error (n � 3). The IC50 values
rer. nat. Anh Tuan Dang-Le, Faculty of Biology and Bio- were determined by using GraphPad Prism software with
technology, University of Science, Ho Chi Minh City, multivariate nonlinear regression and R2 > 0.9. Kojic acid
Vietnam. A voucher sample (MCE0052) has been deposited was used as positive control.
at the Department of Medicinal Chemistry, Faculty of
Chemistry, University of Science, Ho Chi Minh City,
Vietnam. 2.4. HPLC Data of the EtOAc-Soluble Fraction from
S. ilicifolius. The concentrations of the EtOAc-soluble
fraction and streblus C (1) were approximately 12,000 ppm
2.2.1. Extraction and Isolation. The dried powdered stems of and 200 ppm, respectively. The detection wavelength was set
S. ilicifolius (7.0 kg) were exhaustively extracted in a Soxhlet at 385 nm. An Agilent Zorbax SB-C18 column
extractor with n-hexane, EtOAc, and MeOH to yield n- (150 × 4.6 × 5 mm) was used with a flow rate of 1 mL/min.
hexane-(64.8 g), EtOAc-(117.2 g), and MeOH-(378.0 g) The injection volume was 10 Μl, and the column temper-
soluble fractions, respectively. The EtOAc-soluble fraction ature was maintained at 30°C. The mixtures of water and
was chromatographed by silica gel column chromatography ACN were used as the mobile phase with gradient elution
(15 × 150 cm) and eluted with MeOH–CHCl3 (v/v, 0 : (20 ⟶ 40% ACN for 30 min).
100 ⟶ 100 : 0) mixtures to afford 18 fractions (Fr.1−Fr.18).
Fraction Fr.8 (0.8 g) was separated by silica gel column
chromatography with MeOH–CHCl3 (v/v, 0 : 100 ⟶ 30 : 2.5. Optical Rotation Calculation. The conformational
70) mixtures to obtain six subfractions (Fr.8.1−Fr.8.6). searches were performed on Spartan’18 (Wave function,
Subfraction Fr.8.1 (34.8 mg) was loaded onto a silica gel Inc., Irvine, USA) by using Merck molecular force field
column and eluted with EtOAc−CHCl3 mixtures (v/v, 0 : (MMFF). All conformers with Boltzmann weight ˃10% were
100 ⟶ 100 : 0) and then purified by preparative TLC with optimized using DFT method at the B3LYP/6-31G∗ level in
an EtOAc−CHCl3 mixture (v/v, 15 : 85) to afford compound the gas phase, to give the preferred conformers with the
2 (2.0 mg). Fraction Fr.14 (19.6 g) was subjected to further Boltzmann weight >90%. The optical rotation calculations at
silica gel column chromatography and was eluted with sodium D line frequency were carried out using the B3LYP
CHCl3–n-hexane (v/v, 0 : 100 ⟶ 100 : 0) mixtures to yield functional and the 6-311++G(2d, 2p) basis set in IEFPCM
11 subfractions (Fr.14.1−Fr.14.11). Subfraction Fr.14.2 solvation model for methanol. These calculations were
(69.0 mg) was chromatographed over a silica gel column performed on Gaussian 09 (Gaussian, Inc., Wallingford,
with CHCl3–n-hexane (v/v, 0 : 100 ⟶ 100 : 0) mixtures to USA). The calculated optical rotation values were expressed
obtain two subfractions (Fr.14.2.1 and Fr.14.2.2). Subfraction as Boltzmann-weighted average of all output data.
Fr.14.2.2 (28.1 mg) was again chromatographed with
CHCl3–n-hexane (v/v, 0 : 100 ⟶ 100 : 0) mixtures to give
2.6. Molecular Docking. Docking studies of 1 and 2, positive
four subfractions (Fr.14.2.2.1−Fr.14.2.2.4). Subfraction
reference (kojic acid), and decoy (hypoxanthine) were
Fr.14.2.2.3 (8.5 mg) was purified by preparative TLC with
performed with Molecular Operating Environment 2019
EtOAc−n-hexane (v/v, 20 : 80) mixture to afford 1 (3.9 mg).
(MOE 2019.0102) suite (Chemical Computing Group ULC,
Montreal, Canada). The structures of these compounds were
2.2.2. Streblus C (1). Yellow, amorphous powder; 1H and constructed by using the Builder module. Subsequently, all
13
C NMR (500 MHz, acetone-d6, see Table 1 and compounds were minimized up to 0.0001 gradients using
Figures S2–S7); HRESIMS m/z 393.1704 [M + Na]+ the Amber12: EHT force field. The crystal structure of the
(Figure S8) (calcd for C22H26O5Na, 393.1678). oxy-tyrosinase was taken from the Protein Data Bank (PDB
ID : 1WX2). The caddie protein (ORF378) and water mol-
ecules were removed. The enzyme structure was prepared
2.2.3. Streblus D (2) (Figures S9–S15). Yellow, amorphous using the QuickPrep module. The binding site was deter-
powder; 1H and 13C NMR (500 MHz, acetone-d6, see Table 1 mined based on the Propensity for Ligand Binding (PLB)
and Figures S8–S14); HRESIMS m/z 351.1224 [M + Na]+ score in the Site Finder module. The molecular docking was
(Figure S15) (calcd for C19H20O5Na, 351.1208). performed by Dock Module, using Triangle Matcher
Evidence-Based Complementary and Alternative Medicine 3

Table 1: 1H (500 MHz) and 13

C (125 MHz) NMR data (acetone-d6) for compounds 1 and 2.
1 2
Position
δC, type C δH (J, Hz) δC, type C δH (J, Hz)
1 116.3, C 122.0, C
2 158.3, C 158.0, C
3 103.6, CH 6.46, d (2.4) 98.3, CH 7.00, d (2.1)
4 160.8, C 158.9, C
5 108.9, CH 6.42, dd (8.5, 2.4) 114.3, CH 6.87, dd (8.5, 2.1)
6 129.6, CH 7.48, d (8.5) 123.4, CH 7.52, d (8.5)
1′ 153.9, C 143.6, C
2′ 125.0, CH 5.97, d (2.0) 118.7, CH 6.48, d (2.1)
3′ 199.2, C�O 200.6, C�O
4′ 82.8, C 79.6, C
5′ 77.3, CH 4.48, dd (4.3, 1.6) 73.0, CH 4.27, dd (5.9, 2.7)
3.19, dd (18.8, 1.6) 3.15, ddd (18.5, 5.9, 2.1)
6′ 27.4, CH2 32.0, CH2
2.82, ddd (18.8, 4.3, 2.0) 3.08, dd (18.5, 2.7)
α 132.3, CH 7.40, d (16.4) 110.7, CH 7.31, s
β 126.4, CH 7.01, d (16.4) 153.2, C
2.54, dd (14.4, 8.0) 2.47, dd (14.9, 7.7)
1″ 33.0, CH2 35.3, CH2
2.39, dd (14.4, 7.2) 2.40, dd (14.9, 7.0)
2″ 118.1, CH 5.18, brs 118.8, CH 5.22, brt (7.3)
3″ 136.0, C 135.0, C
4″ 26.0, CH3 1.68, s 26.1, CH3 1.67, s
5″ 18.1, CH3 1.63, s 18.1, CH3 1.58, s
1‴ 108.0, C
2‴ 27.8, CH3 1.32, s
3‴ 26.8, CH3 1.18, s
4-OH 8.88, s
4′-OH 4.18, s
5′-OH 3.83, s

Placement, Induced Fit Refinement, London Dg, and GBVI/ J � 4.3, 1.6 Hz, H-5′)], a prenyl group [δH 2.54 (dd, J � 14.4,
WSA dG scoring methods. Five top poses showed up based 8.0 Hz, H-1″a), 2.39 (dd, J � 14.4, 7.2 Hz, H-1″b), 5.18 (brs,
on the negative binding free energy value (S value). The best H-2″), 1.68 (s, H3-4″), 1.63 (s, H3-5″)], two methyl groups
pose was selected to analyze the receptor–ligand interactions [δH 1.32 (s, H3-2‴), 1.18 (s, H3-3‴)], and a methylene group
by using BIOVIA Discovery Studio Visualizer 2016 (Das- [δH 3.19 (dd, J � 18.8, 1.6 Hz, H2-6′a), 2.82 (ddd, J � 18.8, 4.3,
sault Systèmes Americas Corp., Waltham, USA). 2.0 Hz, H2-6′b)]. The 13C NMR data (Table 1) exhibited
resonances for a keto-carbonyl (δC 199.2), six aromatic
carbons and six olefinic carbons [δC 103.6–160.8], an ace-
3. Results and Discussion
tonide group [δC 108.0, 27.8, 26.8], two oxygenated carbons
3.1. Extraction and Isolation. The dried powdered stems of [δC 82.8, 77.3], two methylene carbons [δC 33.0, 27.4], and
S. ilicifolius were exhaustively extracted in a Soxhlet ex- two methyl carbons [δC 26.0, 18.1]. The HMBC correlations
tractor with n-hexane, EtOAc, and MeOH to yield the (Figure 2) from H-3 to C-1, C-2, and C-4, from H-5 to C-1
corresponding fractions. The EtOAc-soluble fraction was and C-4, from H-6 to C-2 and C-4, from H-α to C-2 and C-6,
repeatedly chromatographed using silica gel CC and pre- and from H-β to C-1, indicated that two hydroxy groups and
parative TLC to obtain two undescribed stilbene derivatives, Cα-Cβ double bond located at C-2, C-4, and C-1, respec-
strebluses C (1) and D (2) (Figure 1). tively, of the 1,2,4-trisubstituted aromatic ring. The presence
of the cyclohex-2-en-1-one 5,6-acetonide moiety in 1 was
established based on the observed HMBC correlations. The
3.2. Structural Elucidation of Two New Isolated Compounds HMBC correlations from H-α to C-1′ and from H-β to C-1′
from S. ilicifolius. Compound 1, streblus C, showed a mo- and C-2′ were supportive of the Cβ-C1′ linkage. In addition,
lecular formula to be C22H26O5 based on the HRESIMS the prenyl group was determined to be located at C-4′ by the
sodium adduct ion at m/z 393.1704 [M + Na]+ (calcd for HMBC correlations from H-1″ to C�O, C-4′, and C-5′ and
C22H26O5Na, 393.1678). The 1H NMR spectrum showed from H-5′ to C-1″. Therefore, 1 was suggested to be a
signals for a 1,2,4-trisubstituted aromatic ring [δH 7.48 (d, prenylated stilbene-like compound. The difference in
J � 8.5 Hz, H-6), 6.46 (d, J � 2.4 Hz, H-3), 6.42 (dd, J � 8.5, chemical shifts of the methyl groups of the dimethylace-
2.4 Hz, H-5), two trans-coupling olefinic protons [δH 7.40 (d, tonide moiety in 1 is 0.14 ppm, which established the
J � 16.4 Hz, H-α), 7.01 (d, J � 16.4 Hz, H-β)], an α-olefinic presence of the cis-acetonide [13]. Moreover, it was un-
proton of α, β-unsaturated carbonyl group [δH 5.97 (d, ambiguously confirmed based on the NOESY correlation
J � 2.0 Hz, H-2′)], an oxymethine proton [δH 4.48 (dd, between H-5′ and H2-1″ (Figure 2). The preferred
4 Evidence-Based Complementary and Alternative Medicine

5 O
HO 6 3′
4 6 α 2′
5 OH 5′′
β 1 1′′ CH3
2′
3 3′ O β 1′ 4′
1 5′′ 3′′
2 α 1′ 1′′ 4 2 O 5′
CH3 HO 2′′
3′′ 3 6′ CH3
OH OH
6′ 4′
2′′ 4′′ 4′′
5′ O CH3
O 1′′′ 3′′′
CH3
CH3
2′′′
(a) (b)

Figure 1: Structure of compounds 1 and 2.

5
HO 4 6
β 2′ O
3 3′ O 6 α 2′ 3′
1 5′′ OH
α 1′′ 5 5′′
2 1′ CH3 4′ 1′′
3′′ 1 CH3
OH 6′ β 1′
4′ 2′′ 4′′ 4 O 5′ 3′′
O 2 2′′
5′ CH3 HO 6′
1′′′ 3 CH3
O 3′′′ OH 4′′
CH3
CH3
2′′′
1 2

5′ 1′′

1′′ 5′

1 2
Figure 2: Significant HMBC (solid arrows) and NOESY (blue, dashed arrows) correlations observed for 1 and 2.

conformations of the cis-(R, R)-acetonide 1 were generated A careful HPLC analysis of the EtOAc-soluble fraction
by the MM2 calculation using MMFF94 force field [14]. was accomplished, which revealed a peak at tR 20.766 min in
These conformers were reoptimized by DFT-B3LYP the chromatogram in accord with that of 1 (tR 20.800 min)
method using basis set 6-31G∗, to obtain the most pre- (Figure S1). Thus, the presence of 1 in the EtOAc-soluble
ferred conformer with 92.8% Boltzmann distribution fraction from S. ilicifolius was confirmed, and the possibility
(Table S1). The optical rotation value at sodium D line of 1 being artifact could be ignored.
frequency was computed using B3LYP/6-311++G(2d, 2p) Compound 2, streblus D, showed a molecular formula
level with IEFPCM solvent model for methanol. The large to be C19H20O5 based on the HRESIMS sodium adduct ion
basis set with diffuse functions such as 6-311++G(2d, 2p) at m/z 351.1224 [M + Na]+ (calcd for C19H20O5Na,
was applied to give very consistent results [15, 16]. The 351.1208). The 1H and 13C NMR data of 2 (Table 1) re-
calculated [α]D value of (R,R)-acetonide 1 was −102.36, sembled those of 1, except for the presence of the singlet
compared with its experimental value [α]D: −101.7 (c 0.023, olefinic proton at δH 7.31 instead of two trans-coupling
MeOH). Thus, a (R, R) absolute configuration was con- olefinic protons in 1 and disappearance of the acetonide
cluded for streblus C (1). group. Based on the 13C NMR data and observed HMBC
Evidence-Based Complementary and Alternative Medicine 5

(a) (b)

Figure 3: Docked pose of best ranked docking score of compounds 1 (a) and 2 (b).

correlations for 2 (Figure 2), the structure of 2 was o-quinones. Herein, mushroom tyrosinase (EC 1.14.18.1)
assigned as a benzofuran-type stilbene. The NOESY plays the same role with respect to oxy-tyrosinase form.
correlations between H-5′ and H2-1″ indicated the Two bound Cu 2+ ions bind to six histidine residues, and
presence of the cis-diol configuration. The 3JH-5′/H-6′ the peroxide group is in the binding site of oxy-tyrosi-
coupling constants were 5.9 and 2.7 Hz, to suggest the nase, which has a role in the catalytic oxidation [22]. To
equatorial configuration of H-5′ [17], which was sup- explore the strong inhibitory activity of 1 against ty-
portive of the (R,R) or (S,S) absolute configurations for 2. rosinase, the molecular docking studies of 1 and 2, re-
The conformational search for (R,R)-2 was generated and spectively, with oxy-tyrosinase (PDB ID : 1WX2) were
optimized to obtain six conformers with total Boltzmann carried out [23].
weight >90% (Table S1). The Boltzmann-weighted cal- The docking studies were performed with MOE. The top-
culated [α]D value of (R,R)-2 was +301.74, compared with ranked pose with the highest negative binding free energy
its experimental value [α]D: −228.9 (c 0.002, MeOH). value (S value) was selected for further interaction analysis
Thus, a (S, S) absolute configuration was concluded for with Discovery Studio Visualizer. Following our previous in
streblus D (2). silico study on tyrosinase inhibition, this docking procedure
was already validated based on the docking results of the
positive control (kojic acid) and the decoy (hypoxanthine)
3.3. Tyrosinase Inhibitory Activity of Isolated Compounds from
[12].
S. ilicifolius. Compounds 1 and 2 were tested for their ty-
In the binding site, compound 1 showed the H-donor
rosinase inhibitory activities [18]. Kojic acid, a purported
interaction between the C-4 hydroxy group and peroxide
skin lightening agent, was used as a positive control. Streblus
bridge PER404, presenting the distances of 1.85 Å. The
C (1) exhibited remarkable inhibitory effect with an IC50
C-3′ carbonyl group formed the H-acceptor interaction
value of 0.01 μM, which was 4400 times more potent than
with ASN188 residue (Figure 3). The aromatic ring
that of kojic acid (IC50, 44.6 μM). Meanwhile, streblus D (2)
exhibited the π-π stacking interaction with HIS194 resi-
was inactive with an IC50 value > 100 μM. These results were
due localized in the active pocket. In addition, two
consistent with a previous report on the structure–activity
methyls of the acetonide group showed the π-σ interac-
relationships of stilbene derivatives. Compound 1 having
tions with TRP184 residue. Compound 2 did not show any
2,4-resorcinol subunit contributed the most to inhibitory
interaction with the catalytic site (i.e., Cu2+ ions and
activity [19]. In addition, the 2-arylbenzofuran derivatives
peroxide bridge), whereas kojic acid showed the inter-
showed lower tyrosinase inhibitory activities than the cor-
actions with a Cu2+ ion, HIS194, and THR203 residues in
responding stilbene derivatives, suggesting that the forma-
the binding site. Three hydroxy groups of 2 interacted
tion of the five-membered ring led to the loss of inhibitory
with ASP45, ALA202, and MET201 residues via the
activity [20].
H-donor bonding. The furan ring formed the π-π and π-σ
interactions with TRP184 and ILE42 residues, respec-
3.4. Docking Studies of Compounds 1 and 2. Tyrosinase is an tively. The S values and these interactions suggested that 1
oxidase, which is represented as one of four possible showed high binding affinity for oxy-tyrosinase than that
forms (deoxy-, oxy-, met-, and deact- forms) [21]. Oxy- of 2 (Table 2). This result confirmed that the formation of
tyrosinase form oxidizes both phenols and catechols to furan ring in 2 led to the loss of inhibitory activity.
6 Evidence-Based Complementary and Alternative Medicine

Table 2: Docking results of 1 and 2 with oxy-tyrosinase. References

oxy-tyrosinase (1 WX2) [1] J. N. Rodrı́guez-López, J. Tudela, R. Varón, F. Garcı́a-Car-
Compound S Targeting Distance mona, and F. Garcı́a-Cánovas, “Analysis of a kinetic model for
Interactions
values residues (Å) melanin biosynthesis pathway,” Journal of Biological Chem-
–6.56 H-donor PER404 1.85 istry, vol. 267, no. 6, pp. 3801–3810, 1992.
H-acceptor ASN188 2.44 [2] H. Decker and F. Tuczek, “Tyrosinase/catecholoxidase activity
π-π HIS194 4.19 of hemocyanins: structural basis and molecular mechanism,”
1 π-σ TRP184 5.15 Trends in Biochemical Sciences, vol. 25, no. 8, pp. 392–397,
5.06 2000.
5.47 [3] T. Pillaiyar, M. Manickam, and V. Namasivayam, “Skin
σ-σ VAL195 4.09 whitening agents: medicinal chemistry perspective of tyros-
–6.17 H-donor ASP45 1.71 inase inhibitors,” Journal of Enzyme Inhibition and Medicinal
ALA202 2.54 Chemistry, vol. 32, no. 1, pp. 403–425, 2017.
MET201 2.97 [4] S. Dej-adisai, K. Parndaeng, and C. Wattanapiromsakul,
2 π-π TRP184 4.98 “Determination of phytochemical compounds, and tyrosinase
π-σ ILE42 4.66 inhibitory and antimicrobial activities of bioactive com-
4.61 pounds from Streblus ilicifolius (S Vidal) Corner,” Tropical
σ-σ VAL195 4.73 Journal of Pharmaceutical Research, vol. 15, no. 3, pp. 497–
506, 2016.
–4.50 H-donor THR203 2.04
[5] G. Zhang, L. Hao, D. Zhou et al., “A new phenylpropanoid
Metal-
Kojic acida CU401 2.92 glycoside from the bark of Streblus ilicifolius (Vidal) Corner,”
acceptor
Biochemical Systematics and Ecology, vol. 87, Article ID
π-π HIS194 4.30
a
103962, 2019.
Positive control. [6] Y. Huang, X. Huang, G. Tian et al., “Two new amide gly-
cosides with anti-inflammatory activity from the leaves of
Streblus ilicifolius (Vidal) corner,” Natural Product Research,
4. Conclusions pp. 1–9, 2021.
[7] N. T. Nguyen, H. X. Nguyen, T. H. Le et al., “Two new de-
Two new stilbene derivatives were isolated from the stems of rivatives of 8-prenyl-5,7-dihydroxycoumarin from the stems
S. ilicifolius. Their structures were elucidated based on the of Streblus ilicifolius (S.Vidal) Corn,” Natural Product Re-
NMR spectroscopic interpretation and optical rotation cal- search, pp. 1–6, 2021.
culation. Compound 1 was found to possess strong tyrosinase [8] N. T. Nguyen, M. H. K. Nguyen, H. X. Nguyen, N. K. N. Bui,
inhibitory activity with an IC50 value of 0.01 μM. Binding and M. T. T. Nguyen, “Tyrosinase inhibitors from the wood of
interaction analyses between the isolated compounds (1 and Artocarpus heterophyllus,” Journal of Natural Products,
2) and oxy-tyrosinase active site have been performed. vol. 75, no. 11, pp. 1951–1955, 2012.
[9] H. X. Nguyen, N. T. Nguyen, M. H. K. Nguyen et al., “Ty-
rosinase inhibitory activity of flavonoids from Artocarpus
Data Availability heterophyllous,” Chemistry Central Journal, vol. 10, no. 1, p. 2,
2016.
The NMR data used to support the findings of this study are [10] P. H. Dang, T. T. Nguyen, T. H. Le, H. X. Nguyen,
included within the supplementary information file. M. T. T. Nguyen, and N. T. Nguyen, “A new bischromanone
from the stems of Semecarpus caudata,” Natural Product
Research, vol. 32, no. 15, pp. 1745–1750, 2018.
Conflicts of Interest [11] P. H. Dang, L. T. T. Nguyen, H. T. T. Nguyen et al., “A new
dimeric alkylresorcinol from the stem barks of Swintonia
The authors declare that there are no conflicts of interest floribunda (Anacardiaceae),” Natural Product Research,
regarding the publication of this paper. vol. 33, no. 20, pp. 2883–2889, 2019.
[12] P. H. Dang, T. H. Le, T. N. V. Do, H. X. Nguyen,
M. T. T. Nguyen, and N. T. Nguyen, “Diarylalkanoids as
Acknowledgments potent tyrosinase inhibitors from the stems of Semecarpus
caudata,” Evidence-Based Complementary and Alternative
This research was funded by Vietnam National University Medicine, vol. 2021, Article ID 8872920, 8 pages, 2021.
Ho Chi Minh City (VNU-HCM) under grant number [13] L. C. Dias, T. Augusto, C. C. Perez, and L. J. Steil, “Addition of
NCM2020-18-01. chiral and achiral allyltrichlorostannanes to chiral±-alkoxy
aldehydes,” Journal of the Brazilian Chemical Society, vol. 20,
no. 4, pp. 802–812, 2009.
Supplementary Materials [14] T. Lewis-Atwell, P. A. Townsend, and M. N. Grayson,
“Comparisons of different force fields in conformational
Figure S1: HPLC chromatogram of 1 from the stems of analysis and searching of organic molecules: a review,” Tet-
S. ilicifolius. Table S1: conformational data. Figures S2–S15: rahedron, vol. 79, Article ID 131865, 2021.
copies of spectroscopic data for 1 and 2. (Supplementary [15] P. J. Stephens, F. J. Devlin, J. R. Cheeseman, and M. J. Frisch,
Materials) “Calculation of optical rotation using density functional
Evidence-Based Complementary and Alternative Medicine 7

theory,” The Journal of Physical Chemistry A, vol. 105, no. 22,

pp. 5356–5371, 2001.
[16] T. Aharon and M. Caricato, “Compact basis sets for optical
rotation calculations,” Journal of Chemical Theory and
Computation, vol. 16, no. 7, pp. 4408–4415, 2020.
[17] Z. Lin, T. Zhu, Y. Fang, Q. Gu, and W. Zhu, “Polyketides from
Penicillium sp. JP-1, an endophytic fungus associated with the
mangrove plant Aegiceras corniculatum,” Phytochemistry,
vol. 69, no. 5, pp. 1273–1278, 2008.
[18] E. T. Arung, I. W. Kusuma, Y. M. Iskandar, S. Yasutake,
K. Shimizu, and R. Kondo, “Screening of Indonesian plants
for tyrosinase inhibitory activity,” Journal of Wood Science,
vol. 51, no. 5, pp. 520–525, 2005.
[19] S. Khatib, O. Nerya, R. Musa, M. Shmuel, S. Tamir, and
J. Vaya, “Chalcones as potent tyrosinase inhibitors: the im-
portance of a 2,4-substituted resorcinol moiety,” Bioorganic &
Medicinal Chemistry, vol. 13, no. 2, pp. 433–441, 2005.
[20] Z.-P. Zheng, K.-W. Cheng, Q. Zhu, X.-C. Wang, Z.-X. Lin,
and M. Wang, “Tyrosinase inhibitory constituents from the
roots of morus nigra: a structure−activity relationship study,”
Journal of Agricultural and Food Chemistry, vol. 58, no. 9,
pp. 5368–5373, 2010.
[21] C. A. Ramsden and P. A. Riley, “Tyrosinase: the four oxidation
states of the active site and their relevance to enzymatic ac-
tivation, oxidation and inactivation,” Bioorganic & Medicinal
Chemistry, vol. 22, no. 8, pp. 2388–2395, 2014.
[22] M. Kanteev, M. Goldfeder, and A. Fishman, “Structure-
function correlations in tyrosinases,” Protein Science, vol. 24,
no. 9, pp. 1360–1369, 2015.
[23] Y. Matoba, T. Kumagai, A. Yamamoto, H. Yoshitsu, and
M. Sugiyama, “Crystallographic evidence that the dinuclear
copper center of tyrosinase is flexible during catalysis,”
Journal of Biological Chemistry, vol. 281, no. 13, pp. 8981–
8990, 2006.