Preparation of novel 1,2,3-triazole furocoumarin derivatives via click chemistry and their anti-vitiligo activity

Article abstract of DOI:10.1039/C8RA09755K

The extracts of Psoralea corylifolia?L. were often used for the repigmentation of leukoderma (vitiligo) in traditional Uygur medicine thousands years ago. Nowadays, its active ingredient, furocoumarins, has been clinically applied since it exhibited stron

Full text of DOI:10.1039/C8RA09755K

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Preparation of novel 1,2,3-triazole furocoumarin
derivatives via click chemistry and their anti-vitiligo
Cite this: RSC Adv., 2019, 9, 1671
activity
ab
Chao Niu,ab Xueying Luab and Haji Akber Aisa
*
The extracts of Psoralea corylifolia L. were often used for the repigmentation of leukoderma (vitiligo) in
traditional Uygur medicine thousands years ago. Nowadays, its active ingredient, furocoumarins, has
been clinically applied since it exhibited strong photosensitivity. Thus, a new series of furocoumarin
derivatives (8a–8o) containing 1,2,3-triazole were designed and synthesized based on our previous work.
After biological evaluation for melanin contents and tyrosinase activity in B16 murine cells, the SAR was
summarized. The results indicated that five compounds (8a, 8j, 8m–8o) were more potent than the
positive control (8-MOP) on melanogenesis. Among them, 8a and 8o showed the best stimulating effect
on tyrosinase activity as well, and were submitted for further pharmacological study of anti-vitiligo.
Received 27th November 2018
Accepted 26th December 2018
DOI: 10.1039/c8ra09755k
rsc.li/rsc-advances
(ruxolitinib, baricitinib, tofacitinib) (Fig. 2), which are oen
used for myelodysplastic disorders, were recently proven to be
1 Introduction
efficacious for vitiligo based on a large number of clinical
cases.12,13
Vitiligo is an acquired pigmentary disorder of the skin charac-
terized by circumscribed depigmented macules due to the
destruction of the melanocyte and subsequent obstruction of
melanin synthesis (Fig. 1).1,2 The prevalence of vitiligo is oen
referred to as 0.5–2% of the world's population.3 The origin of
vitiligo is thought to be a complex interplay of genetics, envi-
ronment, oxidative stress, and autoimmunity.4,5 And the auto-
immune theory is the leading hypothesis that is supported by
strong evidence.6
Traditional Chinese medicine is an important source of
modern drugs. In Uygur medicine, the extract of Psoralea
corylifolia L. (Fig. 3) was oen used for repigmentation of viti-
ligo with natural sunlight and initially recorded in ‘Yao Yong
Zong Ku’ around 300 years ago. Its active ingredient,
In humans, melanin is the primary determinant of skin color
and thought to protect skin cells from UVB radiation damage,
reducing the risk of cancer.7 It is produced by melanocytes
which are found in the basal layer of the epidermis and regu-
lated by enzymatic cascade, including tyrosinase (TYR),
tyrosinase-related protein 1 (TRP-1) and tyrosinase-related
protein 2 (TRP-2).8 Among them, TYR is the rate-limiting
enzyme and is mainly involved in two distinct reactions of
melanin synthesis: rstly, the hydroxylation of a monophenol
and secondly, the conversion of an o-diphenol to the corre-
sponding o-quinone.9,10
Fig. 1 Vitiligo with typical lesions of the face and trunk.
Presently, there are several drugs used for the treatment of
vitiligo including photosensitizer (8-MOP, khellin), topical
corticosteroids (dexamethasone), calcineurin inhibitors (tacro-
limus), vitamin D3 analogs (tacalcitol),11 and JAK inhibitors
aKey Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical
Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011,
China. E-mail: haji@ms.xjb.ac.cn
bState Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource
Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy
of Sciences, Urumqi 830011, China
Fig. 2 Structures of commonly used drugs for vitiligo.
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As depicted in Fig. 5, it is quite clear that more structure
modication should be proceed on C-5 position of the furo-
coumarin to improve this efficiency. Thus, a new series of
derivatives containing 1,2,3-triazole group was synthesized,
which may be developed as better candidates for the vitiligo.
2 Results and discussion
2.1 Chemistry
The synthetic route for the target compounds is outlined in
Scheme 1. First, the commercially available material resorcine
was converted to the desired intermediate 4-methylumbellifer-
one 1 at a 92% yield via Pechmann reaction.30,31 Then, Wil-
liamson reaction between 1 and 2-bromoacetophenone in the
presence of potassium carbonate afforded intermediate 2,
which was cyclized in 4% KOH ethanolic solution to form 3.32
Selenium dioxide was applied in selective oxidation of
compound 3 to produce 5-carbaldehyde 4. Aer that, it was
further reduced with NaBH4 to achieve alcohol 5 in 76%
yield.33,34 Bromination and azidation of hydroxy with PBr3 and
NaN3 successively gave the key intermediate 7. Finally,
compound 7 was converted to the target 8a–8o through click
chemistry with different alkyne a–o.35
Fig. 3 The plant of the Psoralea corylifolia L.
Fig. 4 The structures of the furocoumarins used for vitiligo.
furocoumarins, has been clinically applied, including 8-
methoxypsoralen (8-MOP), 5-methoxypsoralen (5-MOP) and
4,5,8-trimethylpsoralen (TMP) (Fig. 4). Further research proved
that these compounds exhibited strong photosensitivity,14
which may be benecial for the repigmentation of skin with
subsequent exposure to long-waved ultraviolet radiation.15 In
spite of some undesired side effects,16,17 the therapy is still the
most effective way to treat the disease today.
Unfortunately, the targets of furocoumarin for the therapies
was still unknown due to the complexity of pathogenesis, and
few derivatives with anti-vitiligo activity were reported.18–20
During past few years, many molecules with superior effect on
melanogenesis and tyrosinase activity were isolated or synthe-
sized by our group.21–24 The preliminary SAR of furocoumarins
on vitiligo was outlined in Fig. 5 based on these studies.
1,2,3-Triazole and its derivatives showed particular promise
as amide bond isosteres, given their diverse biological proper-
ties and facile synthesis from readily available azide and
alkyne.25–28 The moiety is stable to metabolic degradation and
capable of hydrogen bonding, which could be favorable in
binding of biomolecular targets and increasing water
solubility.29
2.2 Biological evaluation
Compounds 8a–8o were evaluated for their activity on melanin
synthesis in murine B16 cells, with a known method.36
According to the results in Fig. 6, the reference drug 8-MOP
enhanced the melanin synthesis by 126.03 ꢀ 2.97% at 50 mm as
compared to the blank control. Most of synthesized compounds
could increase the melanin content, especially for 8a, 8j, 8m–8o,
which were more potent than the positive control (8-MOP) with
a value from 134% to 211%. For example, derivatives bearing
EDG (8l–8o) on benzene exhibited a stronger effect than
unsubstituted 8k. The OCH3 group contributed more than CH3
to the activity, such as 8o > 8m, 8n > 8l. And it seemed that the
para-position may be superior for the substituent to improve
melanin synthesis (8m > 8l, 8o > 8n). Among these halogenated
derivatives (8a–8j), ones with –Cl and –Br showed higher activity
compared with –F (8a, 8j > 8g, 8b > 8h). The position of the
halogen on benzene also played an important role for their
efficacy, the shi of –Cl substituent from the para- (8a, 166%)
into the ortho- or meta-position led to 8b (118%) or 8c (106%)
separately, which induced a decreased value in melanin
content. The similar result was observed in compounds 8g and
8h, substituted with –F group as well. However, introduction of
a second –F or –Cl to the benzene may not strengthen this
ability (8a > 8d–8f, 8g > 8i), and it is apparent that the presence
of a halogen group in the para-position of the phenyl ring was
crucial for melanogenesis (8d > 8f > 8e).
Aer that, all these derivatives were further studied for their
stimulating effect on tyrosinase.37 As shown in Fig. 7, only two
compounds (8a, 8o) showed a higher value than 8-MOP. And it
can be noticed that the –Cl, and –OCH3 groups might be
favorable to enhance the activity among these monosubstituted
compounds, since the value of them were all over 110% (8a–8c,
Fig. 5 The SAR of furocoumarins on vitiligo.
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Scheme 1 Synthesis of furocoumarin derivatives containing 1,2,3-triazole (8a–8o). Reagents and conditions: (i) DMF, K2CO3, 70 ꢁC (ii) ethyl
acetoacetate, H2SO4, 60 ꢁC (iii) 2-bromoacetophenone, K2CO3, acetone, reflux (iv) 4% KOH ethanolic solution, reflux (v) SeO2, xylene, reflux (vi):
NaBH4, methanol, rt (vii): PBr3, THF, 0 ꢁC-rt (viii): NaN3, CH3CN, reflux (ix) a–o, CuSO4$5H2O, Cu, t-BuOH : H2O ¼ 1 : 3, 80 ꢁC.
Fig. 6 Stimulation of melanin content of B16 cells by 8a–8o. N means
Fig. 7 Stimulation of tyrosinase activity of B16 cells by 8a–8o. N
means negative control; P means positive control (8-MOP). B16 cells
was treated with 50 mM different furocoumarin derivatives for 48 h.
After that, tyrosinase activity was measured directly. The data are the
mean ꢀ SD of three experiments, P < 0.05.
negative control; P means positive control (8-MOP); the B16 cells was
treated with 50 mM different furocoumarin derivatives for 48 h. After
that, melanin content was measured directly. Values are expressed as
the mean ꢀ SD of three separate experiments, P < 0.05.
8n–8o > 110%). Changing the position of –Cl on benzene ring
weakened stimulatory efficiency (8a > 8b or 8c), indicating that
the presence of a substituent in the para-position may be
benecial for the enzyme activation, and it was also applicable
for the OCH3 group (8o > 8n). Nevertheless, dihalide derivatives
possessed a lower activity than mono- ones. Additionally, the
effect of most potential 8a, 8n, on both melanin synthesis and
tyrosinase activity, were positively in a concentration dependent
manner as depicted in Fig. 8.
3 Experimental
3.1 Chemistry
Fig. 8 The concentration dependent manner of 8a, 8o on melanin
synthesis and tyrosinase activity. “A”, “-” and “ꢂ”, “:” means the
effect of 8a, 8o on melanin synthesis (in blue) and tyrosinase activity (in
Reagents and solvents were purchased from Sigma, and used
without further purication. Thin-layer chromatography (TLC) red) separately at different concentration in B16 cells.
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was carried out on glass plates coated with silica gel (Qingdao 7.48, 3H), 6.94 (dd, J ¼ 8.8, 2.6 Hz, 1H), 6.79 (d, J ¼ 2.5 Hz, 1H),
Haiyang Chemical Co., G60F-254) and visualized by UV light 6.13 (d, J ¼ 1.1 Hz, 1H), 5.38 (s, 2H), 2.38 (d, J ¼ 1.1 Hz, 3H).
(254 nm). The products were puried by column chromatog-
3.1.4 Preparation
of
5-methyl-3-phenyl-7H-furo[3,2-g]
raphy over silica gel (Qingdao Haiyang Chemical Co., 200–300 chromen-7-one (3). To an ethanolic solution (100 mL) of inter-
mesh). Melting points were determined on a Buchi B-540 mediate 2 (2.94 g, 10 mmol) was added a 4% ethanol potassium
apparatus and uncorrected. All the NMR spectra were recor- hydroxide solution (20 mL) and the mixture was reuxed for 4 h.
ded with a Varian 400 MHz NMR spectrometer in CDCl3 or Aer cooling, the solution was acidied with 1 M hydrochloric
acetone-d6, using TMS as an internal standard. High-resolution acid and extracted with ethyl acetate three times. The organic
mass spectra (HRMS) were recorded on AB SCIEX QSTAR Elite phase was dried over night and evaporated under reduced
quadrupole time-of-ight mass spectrometry. The IR data were pressure. The resulting residue was puried by silica gel chro-
recorded on a Thermo Fisher Scientic Nicolet 6700 FT-IR matography with petroleum ether/ethyl acetate to give
1
ꢁ
infrared spectrometer (KBr).
compound 3. Yield 95%, white solid, mp 171–173 C; H NMR
3.1.1 General procedure of preparation of alkyne a–o. To (400 MHz, CDCl3) d 7.98 (s, 1H), 7.83 (s, 1H), 7.64 (dd, J ¼ 8.2,
substituted phenol (3.50 mmol) and potassium carbonate 1.1 Hz, 2H), 7.50–7.56 (m, 3H), 7.44 (td, J ¼ 7.4, 1.1 Hz, 1H), 6.29
(10.5 mmol, 1.45 g) in DMF was aꢁdded 3-bromopropyne (s, 1H), 2.52 (s, 3H).
(4.20 mmol, 500 mg) and stirred at 70 C overnight. Then the
3.1.5 Preparation
of
7-oxo-3-phenyl-7H-furo[3,2-g]
mixture was quenched with water, extraction was with DCM chromene-5-carbaldehyde (4). Powdered SeO2 (3.33 g, 30
(20 mL ꢂ 3) and the combined organic layer was washed by mmol) was added to a solution of 3 (5.52 g, 20 mmol) in 20 mL
saturated sodium chloride solution for three times, dried by of hot dry xylene and the mixture were reuxed for 24 h with
anhydrous Na2SO4 and concentrated under reduced pressure to vigorous stirring under the nitrogen. The reaction mixture was
give
a oil or solid, which was puried by silica gel ltered to remove black Se, and the deep orange ltrate was
chromatography.
allowed to stand overnight. Almost pure crystals of 4 could be
a: 1H NMR (400 MHz, CDCl3) d 7.26 (d, J ¼ 8.9 Hz, 2H), 6.92 separated from the solution. Yield 63%, yellow solid, mp 148–
(d, J ¼ 8.9 Hz, 2H), 4.67 (d, J ¼ 2.4 Hz, 2H), 2.52 (t, J ¼ 2.4 Hz, 150 ꢁC; 1H NMR (400 MHz, CDCl3) d 10.14 (s, 1H), 9.10 (s, 1H),
1H).
7.87 (s, 1H), 7.66 (d, J ¼ 7.4 Hz, 2H), 7.59–7.49 (m, 3H), 7.44 (t, J
d: 1H NMR (400 MHz, CDCl3) d 7.38 (d, J ¼ 2.5 Hz, 1H), 7.20 ¼ 7.2 Hz, 1H), 6.86 (s, 1H).
(dd, J ¼ 8.8, 2.5 Hz, 1H), 7.02 (d, J ¼ 8.8 Hz, 1H), 4.76 (d, J ¼
2.4 Hz, 2H), 2.55 (t, J ¼ 2.3 Hz, 1H).
3.1.6 Preparation of 5-(hydroxymethyl)-3-phenyl-7H-furo
[3,2-g]chromen-7-one (5). Compound 4 (5.80 g, 20 mmol) was
e: 1H NMR (400 MHz, CDCl3) d 7.01 (t, J ¼ 1.7 Hz, 1H), 6.88 (d, dissolved in ethanol (130 mL), sodium borohydride (380 mg,
J ¼ 1.7 Hz, 2H), 4.67 (d, J ¼ 2.4 Hz, 2H), 2.57 (t, J ¼ 2.4 Hz, 1H). 10.0 mmol) was added, and the solution was stirred for 2 h at
k: 1H NMR (400 MHz, CDCl3) d 7.37–7.29 (m, 2H), 7.05–6.97 room temperature. Thereaer the suspension was carefully
(m, 3H), 4.71 (d, J ¼ 2.4 Hz, 2H), 2.53 (t, J ¼ 2.4 Hz, 1H).
hydrolyzed with 1 M HCl (20 mL), diluted with H2O and
l: 1H NMR (400 MHz, CDCl3) d 7.26–7.21, (m, 2H), 7.06–6.95 extracted three times with DCM. The organic phase was washed
(m, 2H), 4.76 (d, J ¼ 2.4 Hz, 2H), 2.56 (t, J ¼ 2.4 Hz, 1H), 2.34 (s, with brine, dried over Na2SO4 and evaporated under reduced
3H).
pressure. The residue was puried by ash chromatography on
o: 1H NMR (400 MHz, CDCl3) d 6.93 (d, J ¼ 9.1 Hz, 2H), 6.85 silica gel to afford alcohol 5. Yield 76%, white solid, mp 99–
1
ꢁ
(d, J ¼ 9.1 Hz, 2H), 4.64 (d, J ¼ 2.4 Hz, 2H), 3.77 (s, 3H), 2.51 (t, J 100 C; H NMR (400 MHz, CDCl3) d 7.85 (s, 1H), 7.79 (s, 1H),
¼ 2.3 Hz, 1H).
7.59 (d, J ¼ 7.3 Hz, 2H), 7.55–7.47 (m, 2H), 7.46–7.38 (m, 2H),
3.1.2 Preparation of 7-hydroxy-4-methyl-2H-chromen-2- 6.62 (s, 1H), 4.97 (s, 2H).
one (1). To an ice-cold solution of resorcinol (2.0 g, 18.2 mol)
3.1.7. Preparation of 5-(bromomethyl)-3-phenyl-7H-furo
in dioxane, conc. H2SO4 (0.5 mL) was added dropwise under [3,2-g]chromen-7-one (6). A mixture of 5ꢁ(2.92 g, 10 mmol) in
20 ꢁC. Aer that, ethyl acetoacetate (2.8 g, 21.8 mmol) was anhydrous THF (25 mL) was cooled to 0 C, a solution of PBr3
added, and the mixture was heated to 60 ꢁC for 4 h. Then, the (0.95 mL, 10 mmol) in THF (2 mL) was added dropwise in ice-
mixture was poured into cold water, and the precipitate was bath and stirred at room temperature. Aer the raw material
ltered and dried under reduced pressure. The resulting consumed, the mixture was neutralized with NaHCO3 and
mixture was recrystallized from methanol to give 1 as white extracted with DCM two times. The organic phase was evapo-
ꢁ
needle crystals. Yield 92%, mp 202–204 C.
rated under reduced pressure and puried by silica gel chro-
3.1.3 Preparation of 4-methyl-7-(2-oxo-2-phenylethoxy)-2H- matography with petroleum ether/ethyl acetate to give 6. Yield
chromen-2-one (2). A mixture of 1 (0.88 g, 5.0 mmol) with 2- 88%, light yellow solid, mp 175–177 ꢁC; 1H NMR (400 MHz,
bromoacetophenone (1.49 g, 7.5 mmol) and anhydrous K2CO3 CDCl3) d 8.13 (s, 1H), 7.86 (s, 1H), 7.68–7.61 (m, 3H), 7.58–7.53
(1.4 g, 10 mmol) in acetone (50 mL) was reuxed under stirring (m, 3H), 6.53 (s, 1H), 4.57 (s, 2H).
for 4 h. Aer cooling, the reaction mixture was ltered, and the
3.1.8 Preparation of 5-(azidomethyl)-3-phenyl-7H-furo[3,2-
ltrate was evaporated under reduced pressure. The obtained g]chromen-7-one (7). To 6 (3.55 g, 10 mmol) in acetonitrile was
residue was puried by silica gel chromatography with petro- added sodium azide (0.96 g, 14.8 mmol) and stirred at reux for
leum ether/ethyl acetate to give intermediate 2. Yield 90%, 12 h. The resulting mixture was evaporated under reduced
1
ꢁ
white solid, mp 162–164 C; H NMR (400 MHz, CDCl3) d 7.98 pressure and puried by silica gel chromatography with petro-
(dd, J ¼ 8.2, 1.0 Hz, 2H), 7.64 (t, J ¼ 7.4 Hz, 1H), 7.51 (m, 7.55– leum ether/ethyl acetate to give compound 7. Yield 81%, yellow
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solid, mp 188–190 ꢁC; 1H NMR (400 MHz, CDCl3) d 7.91 (s, 1H), 115.14, 113.98, 110.98, 101.09, 63.68, 50.95; IR (KBr) n: 2925,
7.85 (s, 1H), 7.62 (d, J ¼ 7.3, 2H), 7.58–7.53 (m, 3H), 7.45 (t, J ¼ 1733, 1635, 1576, 1473, 1271 cmꢃ1; HRMS (ESI) calcd for C27-
7.4, 1H), 6.53 (s, 1H), 4.64 (s, 2H).
H18Cl2N3O4[M + H]+ 518.0669, found 518.0680.
3.1.9 General procedure of preparation of 8a–8o. To
3.1.9.5 5-((4-((3,5-Dichlorophenoxy)methyl)-1H-1,2,3-triazol-
compound 7 (0.32 g, 1.0 mmol) and alkyne a–o (1.2 mmol) in 1-yl)methyl)-3-phenyl-7H-furo[3,2-g]chromen-7-one (8e). Yield
20 mL mixture (vtert-butanol/vH O ¼ 3 : 1) were added copper 88%, light yellow solid, mp 223–224 ꢁC; 1H NMR (400 MHz,
2
sulfate pentahydrate (0.44 mg, 1.75 mmol) and copper (0.06 g, CDCl3) d 8.04 (s, 1H), 7.86 (s, 1H), 7.70 (s, 1H), 7.57–7.51 (m, 5H),
1.0 mmol). The reaction was stirred at 80 ꢁC overnight. Then the 7.48–7.41 (m, 1H), 6.97 (t, J ¼ 1.8 Hz, 1H), 6.87 (d, J ¼ 1.7 Hz,
suspension was extracted with DCM (10 mL ꢂ 2), the combined 2H), 6.07 (s, 1H), 5.82 (s, 2H), 5.20 (s, 2H). 13C NMR (101 MHz,
organic layer was dried over anhydrous Na2SO4 and concen- CDCl3) d 160.04, 157.32, 156.52, 152.79, 148.11, 143.48, 131.06,
trated under reduced pressure to give a residue, which was 129.54, 129.41, 128.99, 128.49, 127.66, 124.73, 123.47, 121.98,
puried by silica gel chromatography to afford nal compounds 115.20, 114.06, 113.77, 109.69, 101.10, 62.44, 50.98; IR (KBr) n:
8a–8o.
3.1.9.1 5-((4-((4-Chlorophenoxy)methyl)-1H-1,2,3-triazol-1-yl)
2926, 1732, 1634, 1571, 1457, 1273, 1150, 1074 cmꢃ1; HRMS
(ESI) calcd for 27H18Cl2N3O4[M
H]+ 518.0669, found
C
+
methyl)-3-phenyl-7H-furo[3,2-g]chromen-7-one (8a). Yield 84%, 518.0651.
1
ꢁ
light yellow solid, mp 180–182 C; H NMR (400 MHz, CDCl3)
3.1.9.6 5-((4-((3,4-Dichlorophenoxy)methyl)-1H-1,2,3-triazol-
d 8.04 (s, 1H), 7.86 (s, 1H), 7.70 (s, 1H), 7.58–7.53 (m, 5H), 7.48– 1-yl)methyl)-3-phenyl-7H-furo[3,2-g]chromen-7-one (8f). Yield
7.41 (m, 1H), 7.21 (d, J ¼ 9.0 Hz, 2H), 6.88 (d, J ¼ 9.0 Hz, 2H), 80%, light yellow solid, mp 159–161 ꢁC; 1H NMR (400 MHz,
6.05 (s, 1H), 5.80 (s, 2H), 5.21 (s, 2H). 13C NMR (101 MHz, CDCl3) CDCl3) d 8.04 (s, 1H), 7.86 (s, 1H), 7.71 (s, 1H), 7.59–7.52 (m, 5H),
d 160.06, 157.52, 156.70, 152.07, 148.18, 143.47, 130.56, 129.60, 7.49–7.41 (m, 1H), 7.30 (d, J ¼ 8.9 Hz, 1H), 7.07 (d, J ¼ 2.9 Hz,
129.54, 128.48, 127.65, 124.70, 123.40, 122.48, 116.24, 115.20, 1H), 6.82 (dd, J ¼ 9.0, 2.9 Hz, 1H), 6.06 (s, 1H), 5.81 (s, 2H), 5.20
114.02, 113.62, 101.06, 62.33, 50.95; IR (KBr) n: 2925, 1732, 1635, (s, 2H). 13C NMR (101 MHz, CDCl3) d 160.05, 157.54, 157.10,
1576, 1489, 1240, 1151, 823 cmꢃ1; HRMS (ESI) calcd for C27- 156.31, 152.08, 148.13, 143.49, 130.95, 129.53, 128.48, 127.65,
H19ClN3O4[M + H]+ 484.0986, found 484.0993.
124.72, 123.47, 122.49, 117.05, 115.19, 114.77, 114.05, 113.60,
3.1.9.2 5-((4-((2-Chlorophenoxy)methyl)-1H-1,2,3-triazol-1-yl)
110.15, 101.09, 62.46, 50.98; IR (KBr) n: 2924, 1733, 1653, 1576,
methyl)-3-phenyl-7H-furo[3,2-g]chromen-7-one (8b). Yield 86%, 1473, 1274, 1048 cmꢃ1; HRMS (ESI) calcd for C27H18Cl2N3O4[M
1
light yellow solid, mp 198–201 C; H NMR (400 MHz, CDCl3) + H]+ 518.0669, found 518.0682.
ꢁ
d 8.04 (s, 1H), 7.86 (s, 1H), 7.77 (s, 1H), 7.59–7.50 (m, 5H), 7.48–
3.1.9.7 5-((4-((4-Fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl)
7.40 (m, 1H), 7.33 (d, J ¼ 8.0 Hz, 1H), 7.22–7.15 (m, 1H), 7.06 (d, J methyl)-3-phenyl-7H-furo[3,2-g]chromen-7-one (8g). Yield 82%,
1
ꢁ
¼ 8.2 Hz, 1H), 6.94–6.87 (m, 1H), 6.02 (s, 1H), 5.81 (s, 2H), 5.33 light yellow solid, mp 184–185 C; H NMR (400 MHz, CDCl3)
(s, 2H). 13C NMR (101 MHz, CDCl3) d 160.05, 157.51, 153.66, d 8.04 (s, 1H), 7.86 (s, 1H), 7.71 (s, 1H), 7.59–7.50 (m, 6H), 7.48–
152.08, 148.24, 145.51, 143.42, 132.60, 131.02, 130.57, 129.53, 7.41(m, 1H), 6.99–6.85 (m, 4H), 6.04 (s, 1H), 5.80 (s, 2H), 5.19 (s,
128.95, 128.46, 127.98, 127.67, 124.68, 123.49, 122.51, 115.16, 2H). 13C NMR (101 MHz, CDCl3) d 160.06, 157.50, 156.54,
114.57, 113.92, 101.05, 63.52, 50.90; IR (KBr) n: 2926, 1719, 1634, 154.20, 152.05, 148.24, 143.45, 131.02, 129.53, 128.93, 128.46,
1484, 1273, 1152, 1067, 754 cmꢃ1; HRMS (ESI) calcd for C27- 127.65, 124.67, 123.40, 122.48, 116.21, 115.98, 115.20, 113.95,
H19ClN3O4[M + H]+ 484.0986, found 484.0977.
113.63, 101.03, 62.71, 50.90; IR (KBr) n: 2926, 1732, 1634, 1576,
3.1.9.3 5-((4-((3-Chlorophenoxy)methyl)-1H-1,2,3-triazol-1-yl)
methyl)-3-phenyl-7H-furo[3,2-g]chromen-7-one (8c). Yield 82%,
1506, 1389, 1202, 1152, 1040 cmꢃ1; HRMS (ESI) calcd for
C
27H19FN3O4[M + H]+ 468.1354, found 468.1367.
1
ꢁ
light yellow solid, mp 110–111 C; H NMR (400 MHz, CDCl3)
3.1.9.8 5-((4-((2-Fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl)
d 8.04 (s, 1H), 7.86 (s, 1H), 7.71 (s, 1H), 7.59–7.52 (m, 5H), 7.48– methyl)-3-phenyl-7H-furo[3,2-g]chromen-7-one (8h). Yield 85%,
1
ꢁ
7.41 (m, 1H), 7.22–7.15 (m, 1H), 6.99–6.92 (m, 2H), 6.85 (d, J ¼ light yellow solid, mp 166–167 C; H NMR (400 MHz, CDCl3)
8.6 Hz, 1H), 6.06 (s, 1H), 5.81 (s, 2H), 5.22 (s, 2H). 13C NMR (101 d 8.03 (s, 1H), 7.85 (s, 1H), 7.71 (s, 1H), 7.61–7.49 (m, 5H), 7.47–
MHz, CDCl3) d 160.06, 158.84, 157.53, 152.09, 148.17, 143.45, 7.40 (m, 1H), 7.12–6.96 (m, 3H), 6.96–6.85 (m, 1H), 6.01 (s, 1H),
135.14, 131.06, 130.56, 130.50, 129.54, 128.48, 127.67, 123.36, 5.80 (s, 2H), 5.30 (s, 2H). 13C NMR (101 MHz, CDCl3) d 160.03,
121.83, 115.56, 115.21, 114.04, 113.64, 113.22, 110.17, 108.07, 157.50, 154.29, 152.06, 148.21, 146.00, 143.42, 132.45, 131.05,
101.08, 62.27, 50.96; IR (KBr) n: 2924, 1733, 1635, 1457, 1274, 130.56, 129.52, 128.97, 128.45, 127.66, 124.58, 122.41, 116.46,
1152 cmꢃ1; HRMS (ESI) calcd for C27H19ClN3O4[M + H]+ 115.19, 113.94, 113.66, 101.03, 63.65, 50.94; IR (KBr) n: 2925,
484.0986, found 484.1004.
3.1.9.4 5-((4-((2,4-Dichlorophenoxy)methyl)-1H-1,2,3-triazol-
1-yl)methyl)-3-phenyl-7H-furo[3,2-g]chromen-7-one (8d). Yield
1733, 1634, 1506, 1457, 1257, 1152, 1047 cmꢃ1; HRMS (ESI)
calcd for C27H19FN3O4[M + H]+ 468.1354, found 468.1371.
3.1.9.9 5-((4-((3,5-Diuorophenoxy)methyl)-1H-1,2,3-triazol-
86%, light yellow solid, mp 121–123 ꢁC; 1H NMR (400 MHz, 1-yl)methyl)-3-phenyl-7H-furo[3,2-g]chromen-7-one (8i). Yield
CDCl3) d 8.03 (s, 1H), 7.86 (s, 1H), 7.75 (s, 1H), 7.59–7.50 (m, 5H), 83%, light yellow solid, mp 210–212 ꢁC; 1H NMR (400 MHz,
7.48–7.41 (m, 1H), 7.32 (d, J ¼ 2.4 Hz, 1H), 7.14 (dd, J ¼ 8.8, CDCl3) d 8.05 (s, 1H), 7.86 (s, 1H), 7.72 (s, 1H), 7.59–7.52 (m, 5H),
2.5 Hz, 1H), 7.00 (d, J ¼ 8.8 Hz, 1H), 6.03 (s, 1H), 5.81 (s, 2H), 7.47–7.43 (m, 1H), 6.50 (d, J ¼ 8.8 Hz, 2H), 6.43 (t, J ¼ 8.9 Hz,
5.30 (s, 2H). 13C NMR (101 MHz, CDCl3) d 161.13, 157.53, 1H), 6.06 (s, 1H), 5.82 (s, 2H), 5.19 (s, 2H). 13C NMR (101 MHz,
155.69, 152.48, 148.16, 143.47, 142.31, 131.06, 130.29, 129.53, CDCl3) d 160.04, 157.54, 155.60, 152.09, 148.12, 143.48, 131.06,
128.99, 128.47, 127.87, 127.65, 125.78, 124.70, 123.58, 115.35, 129.54, 128.99, 128.49, 127.66, 124.74, 123.02, 122.53, 115.20,
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114.05, 113.58, 109.19, 101.09, 62.49, 50.98; IR (KBr) n: 2923, 101.02, 63.48, 55.96, 50.90; IR (KBr) n: 2926, 1733, 1635, 1505,
1732, 1599, 1465, 1275, 1152, 1042, 996 cmꢃ1; HRMS (ESI) calcd 1457, 1388, 1253, 1150, 1074, 1026 cmꢃ1; HRMS (ESI) calcd for
for C27H18F2N3O4[M + H]+ 486.1260, found 486.1248.
C
28H22N3O5[M + H]+ 480.1554, found 480.1539.
3.1.9.10 5-((4-((4-Bromophenoxy)methyl)-1H-1,2,3-triazol-1-
3.1.9.15 5-((4-((4-Methoxyphenoxy)methyl)-1H-1,2,3-triazol-1-
yl)methyl)-3-phenyl-7H-furo[3,2-g]chromen-7-one (8j). Yield 84%, yl)methyl)-3-phenyl-7H-furo[3,2-g]chromen-7-one (8o). Yield 88%,
1
1
ꢁ
ꢁ
light yellow solid, mp 104–105 C; H NMR (400 MHz, CDCl3) light yellow solid, mp 195–197 C; H NMR (400 MHz, CDCl3)
d 8.04 (s, 1H), 7.86 (s, 1H), 7.71 (s, 1H), 7.59–7.51 (m, 5H), 7.48– d 8.04 (s, 1H), 7.86 (s, 1H), 7.71 (s, 1H), 7.60–7.50 (m, 5H), 7.48–
7.41 (m, 1H), 7.35 (d, J ¼ 8.9 Hz, 2H), 6.84 (d, J ¼ 8.9 Hz, 2H), 7.41 (m, 1H), 6.93 (d, J ¼ 9.1 Hz, 2H), 6.84 (d, J ¼ 9.1 Hz, 2H),
6.05 (s, 1H), 5.80 (s, 2H), 5.20 (s, 2H). 13C NMR (101 MHz, CDCl3) 6.03 (s, 1H), 5.79 (s, 2H), 5.19 (s, 2H), 3.77 (s, 3H). 13C NMR (101
d 160.06, 157.52, 157.21, 153.19, 152.07, 148.17, 143.47, 132.54, MHz, CDCl3) d 160.07, 157.50, 154.47, 152.19, 151.82, 148.25,
129.54, 128.48, 127.65, 124.69, 123.41, 122.49, 116.75, 115.20, 143.46, 130.57, 129.54, 128.46, 127.67, 124.67, 122.51, 116.29,
114.03, 113.85, 113.62, 101.07, 62.25, 50.95; IR (KBr) n: 2926, 116.08, 115.20, 114.84, 114.00, 113.67, 101.06, 62.88, 55.79,
1733, 1635, 1576, 1489, 1457, 1276, 1150 cmꢃ1; HRMS (ESI) 50.98; IR (KBr) n: 2927, 1717, 1631, 1574, 1439, 1388, 1257, 1151,
calcd for C27H19BrN3O4[M + H]+ 528.0553, found 528.0571.
3.1.9.11 5-((4-(Phenoxymethyl)-1H-1,2,3-triazol-1-yl)methyl)-
3-phenyl-7H-furo[3,2-g]chromen-7-one (8k). Yield 85%, light
yellow solid, mp 152–154 ꢁC; 1H NMR (400 MHz, CDCl3) d 8.05
(s, 1H), 7.86 (s, 1H), 7.72 (s, 1H), 7.61–7.50 (m, 5H), 7.48–7.41
(m, 1H), 7.30–7.24 (m, 2H), 7.00–6.92 (m, 3H), 6.05 (s, 1H), 5.80
1082, 1109 cmꢃ1; HRMS (ESI) calcd for C28H22N3O5[M + H]+
480.1554, found 480.1570.
3.2 Biological activity
3.2.1 Cell cultures. The murine B16 melanoma cell line was
(s, 2H), 5.24 (s, 2H). 13C NMR (101 MHz, CDCl3) d 160.07, 158.12, purchased from Chinese Academy of Sciences (Beijing, China).
157.51, 152.08, 148.24, 143.42, 130.57, 129.72, 129.53, 128.46, The cells were maintained in Dulbecco's Modied Eagle's
127.67, 124.68, 123.32, 122.52, 121.59, 115.23, 114.91, 114.00, Medium (DMEM, Gibco Life Technologies, France) supple-
113.67, 101.03, 62.09, 50.90; IR (KBr) n: 2925, 1732, 1634, 1490, mented with 10% (v/v) FBS, penicillin G (100 U mLꢃ1) and
1274, 1150, 1047 cmꢃ1; HRMS (ESI) calcd for C27H20N3O4[M + streptomycin (100 mg mLꢃ1) (Gibco-BRL, Grand Island, NY,
H]+ 450.1448, found 450.1433.
USA) in 5% CO2 at 37 C.
ꢁ
3.1.9.12 5-((4-((o-Tolyloxy)methyl)-1H-1,2,3-triazol-1-yl)
3.2.2 Cell viability measurement. The cell viability was
methyl)3-phenyl-7H-furo[3,2-g]chromen-7-one (8l). Yield 89%, assayed by adding CCK-8 solution. Generally speaking, the B16
1
light yellow solid, mp 160–161 C; H NMR (400 MHz, CDCl3) cells were seeded in 96-well plates at a density of 8 ꢂ 103 cells
ꢁ
d 8.05 (s, 1H), 7.86 (s, 1H), 7.68 (s, 1H), 7.61–7.50 (m, 5H), 7.48– per well and allowed to adhere for 24 h. The medium was
7.41 (m, 1H), 7.08–7.17 (m, 2H), 6.96–6.83 (m, 2H), 6.04 (s, 1H), replaced with medium containing samples diluted to the
5.81 (s, 2H), 5.25 (s, 2H), 2.19 (s, 3H).13C NMR (101 MHz, CDCl3) appropriate concentrations. The control cells were treated with
d 160.09, 157.51, 156.28, 152.08, 148.31, 143.39, 131.02, 130.57, DMSO at a nal concentration of 0.1%. Aer 24 h, the culture
129.53, 128.46, 127.67, 127.01, 124.68, 122.52, 121.31, 115.19, medium of the cells was discarded, 10 mL of CCK-8 solution was
113.89, 113.69, 111.70, 101.07, 62.41, 50.92, 29.86; IR (KBr) n: added into each well and cells were incubated at 37 ꢁC for
2925, 1733, 1635, 1460, 1273, 1152, 1046 cmꢃ1; HRMS (ESI) another 2 h. The absorbance was measured at 450 nm using
calcd for C28H22N3O4[M + H]+ 464.1605, found 464.1616.
3.1.9.13 5-((4-((p-Tolyloxy)methyl)-1H-1,2,3-triazol-1-yl)
a Spectra Max M5 (Molecular Devices, USA). All assays were
performed in triplicate. Absorbance of cells without treatment
methyl)-3-phenyl-7H-furo[3,2-g]chromen-7-one (8m). Yield 91%, was regarded as 100% of cell survival. Cell viability was calcu-
1
ꢁ
light yellow solid, mp 218–220 C; H NMR (400 MHz, CDCl3) lated using the following formula: cell viability (%) ¼ (Asample
d 8.04 (s, 1H), 7.86 (s, 1H), 7.72 (s, 1H), 7.60–7.51 (m, 5H), 7.48– Acontrol) ꢂ 100%.
/
7.41 (m, 1H), 7.06 (d, J ¼ 8.1 Hz, 2H), 6.85 (d, J ¼ 8.4 Hz, 2H),
3.2.3 Melanin measurement. B16 cells were seeded at
6.05 (s, 1H), 5.79 (s, 2H), 5.20 (s, 2H), 2.27 (s, 3H). 13C NMR (101 a density of 2 ꢂ 105 cells per well in a 6-well plate. Aer over-
MHz, CDCl3) d 160.07, 157.50, 156.00, 152.08, 148.23, 143.45, night incubation, test samples were added to individual wells,
143.37, 130.89, 130.57, 130.15, 129.54, 128.46, 127.67, 124.67, cells were incubated for 48 h and washed twice with ice-cold
122.52, 115.28, 115.23, 114.81, 114.06, 113.99, 113.68, 101.05, PBS. Aer cells lysed, the harvested cells were centrifuged,
62.26, 50.98, 29.85; IR (KBr) n: 2925, 1733, 1647, 1508, 1457, and the pellet was dissolved by adding 1 N NaOH, followed by
1388, 1228, 1151, 1050 cmꢃ1
28H22N3O4[M + H]+ 464.1605, found 464.1589.
3.1.9.14 5-((4-((2-Methoxyphenoxy)methyl)-1H-1,2,3-triazol-1- 405 nm by a multi-plate reader. Protein concentration of each
;
HRMS (ESI) calcd for incubation at 80 ꢁC for 1 h. Each lysate (150 mL) was put in a 96-
C
well microplate, and measured spectro-photometrically at
yl)methyl)-3-phenyl-7H-furo[3,2-g]chromen-7-one (8n). Yield 90%, sample was determined by BCA Protein Assay Kit (Biomed,
1
ꢁ
light yellow solid, mp 172–173 C; H NMR (600 MHz, CDCl3) Beijing). Intracellular melanin amount expressed as abs per mg
d 8.04 (s, 1H), 7.86 (s, 1H), 7.71 (s, 1H), 7.59–7.51 (m, 5H), 7.48– protein was shown as a percentage value. The percentage value
7.41 (m, 1H), 6.99 (d, J ¼ 8.0 Hz, 1H), 6.95–6.90 (m, 1H), 6.89– of the samples treated cells was calculated with respect to the
6.81 (m, 2H), 6.05 (s, 1H), 5.78 (s, 2H), 5.32 (s, 2H). 13C NMR (101 untreated cells.
MHz, CDCl3) d 160.06, 157.52, 156.69, 152.11, 148.21, 147.44,
3.2.4 Tyrosinase activity assay. The assay for tyrosinase
145.97, 143.39, 130.57, 130.18, 129.54, 128.45, 127.68, 124.67, activity was carried out as previously described, with a slight
123.44, 122.39, 121.02, 115.30, 114.94, 114.09, 113.70, 112.08, modication.37 B16 cells were seeded in a 6-well plate at
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a density of 2 ꢂ 105 cells per well and allowed to attach for 24 h.
Test samples were then added to individual wells. Aer a 24 h
incubation, cells were washed with ice-cold PBS twice, lysed
with 1% Triton X-100 solution containing 1% sodium deoxy-
cholate for 30 min at ꢃ80 ꢁC, each lysate was centrifuged at
12 000g for 15 min to obtain the supernatant. Aer protein
quantication and adjustment, 90 mL of the supernatant was
incubated in duplicate with 10 mL of freshly prepared substrate
solution (10 mM L-DOPA) in a well of a 96-well plate. Then the
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In summary, a novel series of furocoumarin derivatives bearing
1,2,3-triazole had been prepared via click chemistry. Two of
them (8a, 8o) could not only promote the melanin synthesis, but
also the tyrosinase activity in vitro than positive control (8-MOP)
in a concentration dependent manner, and the SAR was
summarized. In light of our ndings, it may provide scientic
guidance for further structural modication of the furo-
coumarin, even if without knowing the specic targets of the
disease. Further studies on action mechanism and animal
experiment on transgenic mouse is under way.
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Conflicts of interest
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There are no conicts to declare.
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This research was nancially supported by the Xinjiang Key
Laboratory of Xinjiang Indigenous Medicinal Plants Resource
Utilization (No. 2018D04020); Funds for the Foundation of
Director of XTIPC, CAS (2016TP001); Natural Science Founda-
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