Synthesis of scutellarein derivatives with a long aliphatic chain and their biological evaluation against human cancer cells

Article abstract of DOI:10.3390/molecules23020310

Scutellarin is the major active flavonoid extracted from the traditional Chinese herbal medicine Erigeron breviscapus (Vant.) Hand-Mazz., which is widely used in China. Recently, accumulating evidence has highlighted the potential role of scutellarin and its main metabolite scutellarein in the treatment of cancer. To explore novel anticancer agents with high efficiency, a series of new scutellarein derivatives with a long aliphatic chain were synthesized, and the antiproliferative activities against Jurkat, HCT-116 and MDA-MB-231 cancer cell lines were assessed. Among them, compound 6a exhibited the strongest antiproliferative effects on Jurkat (IC₅₀ = 1.80 μM), HCT-116 (IC₅₀ = 11.50 μM) and MDA-MB-231 (IC₅₀ = 53.91 μM). In particular, 6a even showed stronger antiproliferative effects than the positive control NaAsO2 on Jurkat and HCT-116 cell lines. The results showed that a proper long aliphatic chain enhanced the antiproliferative activity of scutellarein.

Full text of DOI:10.3390/molecules23020310

molecules
Article
Synthesis of Scutellarein Derivatives with a Long
Aliphatic Chain and Their Biological Evaluation
against Human Cancer Cells
Guanghui Ni 1,2, Yanling Tang 1, Minxin Li 1, Yuefeng He 3,* and Gaoxiong Rao 1,2,
*
1
College of Pharmaceutic Science, Yunnan University of Traditional Chinese Medicine, Kunming 650500,
China; niguanghui@ynutcm.edu.cn (G.N.); m18487302692@163.com (Y.T.); lmx04087@163.com (M.L.)
Engineering Laboratory for National Healthcare Theories and Products of Yunnan Province,
Yunnan University of Traditional Chinese Medicine, Kunming 650500, China
School of Public Health, Kunming Medical University, Kunming 650500, China
Correspondence: heyuefeng@kmmu.edu.cn (Y.H.); Rao_gx@163.com (G.R.);
Tel.: +86-871-65922903 (Y.H.); +86-871-65919635 (G.R.)
2
3
*
Received: 14 January 2018; Accepted: 30 January 2018; Published: 1 February 2018
Abstract: Scutellarin is the major active flavonoid extracted from the traditional Chinese herbal
medicine Erigeron breviscapus (Vant.) Hand-Mazz., which is widely used in China. Recently,
accumulating evidence has highlighted the potential role of scutellarin and its main metabolite
scutellarein in the treatment of cancer. To explore novel anticancer agents with high efficiency, a series
of new scutellarein derivatives with a long aliphatic chain were synthesized, and the antiproliferative
activities against Jurkat, HCT-116 and MDA-MB-231 cancer cell lines were assessed. Among them,
compound 6a exhibited the strongest antiproliferative effects on Jurkat (IC50 = 1.80
µM), HCT-116
(IC50 = 11.50 M) and MDA-MB-231 (IC50 = 53.91 M). In particular, 6a even showed stronger
µ
µ
antiproliferative effects than the positive control NaAsO2 on Jurkat and HCT-116 cell lines. The results
showed that a proper long aliphatic chain enhanced the antiproliferative activity of scutellarein.
Keywords: scutellarein; scutellarin; flavonoid; cancer; anti-proliferation; long aliphatic chain
1. Introduction
Cancer is the most threatening and difficult-to-treat disease. Traditional Chinese herbal medicines
have been applied for the treatment of cancers for many years [
Chinese herbs exhibit pharmacological activities [ ] and have been recognized as valuable resources for
the development of novel anti-cancer drugs [ ]. Scutellarin ( , Figure 1) is the major active flavonoid
extracted from the traditional Chinese herbal medicine Erigeron breviscapus (Vant.) Hand-Mazz.,
which is used clinically in cardiovascular diseases [ ]. Recently, accumulating evidence has highlighted
the potential role of scutellarin and its main metabolite scutellarein ( , Figure 1) [ ] in the treatment of
cancer [ ]. Nevertheless, low stability and poor lipophilicity of scutellarin and scutellarein limited
their further application [ ]. Derivatives have been synthesized to overcome these disadvantages and
increase biological activity [10 12]. We report herein the synthesis of a series of scutellarein derivatives
1]. Compounds isolated from traditional
2
3
1
4
2
5
6–8
9
–
with a long aliphatic chain and their evaluation as anti-cancer agents.
Molecules 2018, 23, 310; doi:10.3390/molecules23020310
www.mdpi.com/journal/molecules

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Figure 1. Structures of scutellarin (1) and scutellarein (2).
2. Results and Discussion
The methodologies for preparing the target scutellarein derivatives are outlined in Scheme 1.
Scutellarin ( ) was reacted with acetic anhydride and catalytic 4-N,N-dimethylaminopyridine
(DMAP) in pyridine under reflux to afford 5,6,7,40-O-tetraacetyl scutellarein (
) in 54% yield and
) is assigned its structure
14], the assignment of the single free
1
3
0
0
4) in 23% yield. 6,7,4 -O-triacetyl scutellarein (4
6,7,4 -O-triacetyl scutellarein (
based on 1H-NMR analysis. Following literature protocols [13
,
phenol hydroxyl group utilized the narrow peak shape and high chemical shift (12.90 ppm, CDCl3)
of the hydroxyl proton. The single free phenol hydroxyl group is at the C-5 position, and can form a
hydrogen bond with the carbonyl group at C-4 position [15].
Scheme 1. Reagents and conditions: a. Ac2O, pyridine, DMAP, reflux, 86%; b. RBr, K2CO3, DMF, 53–72%.
3
and
4
are converted to 7-O-aliphatic-5,6,40-O-triacetylscutellarein (
5
) and 7-O-aliphatic-6,40-
O-diacetylscutellarein (
6) by reacting with RBr using K2CO3 in N,N-dimethylformamide (DMF).
The position of aliphatic chain connected with scutellarein was clarified by using Hetero-nuclear
Multiple-Bond Connectivity (HMBC). The triplet at 4.08 ppm in the spectrum of 5d (Figure 2) belongs
to the OCH2 protons of the aliphatic chain. A cross peak is observed at 155.68 ppm, and belongs to
C-7. Similarly, the triplet at 4.06 ppm in the spectrum of 6a (Figure 3) belongs to the OCH2 protons of
the aliphatic chain. A cross peak is observed at 157.30 ppm, and belongs to C-7. The OCH2 protons of
the aliphatic chain were correlated with C-7 as shown in Figure 4 indicated that the aliphatic chain is
bonded to the C-7 position [16].
The biological activities of 7-O-aliphatic scutellarein derivatives 5a–d and 6a–d in inhibiting
cancer cell line proliferation were assayed in vitro using CellTiter 96® AQueous One Solution Cell
Proliferation Assay (MTS) according to the previously reported method [17]. Anticancer drug sodium
arsenite (NaAsO2) [18
were not able to inhibit the cancer cell proliferation at concentrations
However, the compounds 5a 5b 6a and 6b displayed anti-proliferation activity at concentrations
100 M, and their activities were higher than both scutellarin and scutellarein. In particular, 6a even
,19] was used as a positive control. Unexpectedly, most of the compounds
≤
100 M, as shown in Table 1.
µ
,
,
≤
µ
showed stronger antiproliferative effects than the positive control NaAsO2 on Jurkat and HCT-116 cell
lines. The results showed that the aliphatic chain enhanced the anti-proliferation activity. However,
the anti-proliferation activity is not stronger when the aliphatic chain is longer. A proper long aliphatic

Molecules 2018, 23, 310
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chain is beneficial to enhancing the anti-proliferative activity of scutellarein. 6a exhibited the strongest
antiproliferative effects on Jurkat (IC50 = 1.80 M), HCT-116 (IC50 = 11.50 µM) and MDA-MB-231
(IC50 = 53.91 M). In addition, 6b with a free phenol hydroxyl group at C-5 position exhibited stronger
µ
µ
anti-proliferative effects than 5b. These results indicate that the hydroxyl group at C-5 of scutellarein
derivatives may be important anti-proliferative activity.
Figure 2. HMBC spectrum of 5d.
Figure 3. HMBC spectrum of 6a.

Molecules 2018, 23, 310
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Figure 4. Key HMBC correlations of compounds of 5d and 6a.
Table 1. In vitro antiproliferative activities of compounds.
IC50 Values (µM)
Compound
Jurkat
HCT-116
MDA-MB-231
NaAsO2
4.70 ± 0.44
156.02 ± 7.21
95.77 ± 2.56
181.06 ± 6.21
>200
31.20 ± 3.35
8.57 ± 1.13
1
2
3
4
>200
>200
>200
>200
>200
>200
>200
>200
5a
5b
5c
5d
6a
6b
6c
6d
14.79 ± 2.69
22.47 ± 1.70
>200
76.23 ± 9.85
1.80 ± 0.49
19.12 ± 0.70
>200
22.02 ± 2.27
55.56 ± 7.21
>200
184.06 ± 7.31
11.50 ± 2.00
53.53 ± 8.25
>200
59.93 ± 4.46
68.54 ± 9.18
>200
>200
53.91 ± 4.04
145.01 ± 10.03
>200
>200
>200
>200
3. Materials and Methods
Reagents and solvents were obtained from commercial suppliers and used without further
purification unless stated otherwise. Pyridine was dried by boiling with CaH2 prior to distillation and
stored over KOH, DMF (N,N-dimethylformamide) was stored over 4 Å molecular sieves. Reactions
were monitored by thin-layer chromatography (TLC), and performed on 0.2 mm silica gel GF254 plates
using UV light as the visualizing agent. Chromatographic purification of products was accomplished
using forced-flow chromatography on 300–400 mesh silica gel. The 1H-NMR (400 MHz, CDCl3) and
13C-NMR (100 MHz, CDCl3) spectra were measured on a Bruker AV 400 MHz (Bruker, Karlsruhe,
Germany) in CDCl3 as solvent, using (TMS) as an internal standard, and chemical shifts are expressed
as δ ppm.
5,6,7,40-O-Tetraacetyl scutellarein ( ) and 6,7,40-O-triacetyl scutellarein (
3 4) Scutellarin (10 g, 21.6 mmol)
was dissolved into the Ac2O/Pyridine(50 mL, 3:2, v/v) solution and reacted reflux for 4 h. After the
reaction was completed (monitored by TLC), the solvent was removed, and the resulting residue was
then purified by column chromatography on silica gel using 50% ethyl acetate in petroleum ether as
eluent to afford 3 (5.3 g, 11.7 mmol, 54%) and 4 (2.1 g, 5.1 mmol, 23%).
0
1
5,6,7,4 -O-Tetraacetyl scutellarein (3) yellow solid. H-NMR (CDCl3, 400 MHz) δ: 7.88 (d, 2H, J = 8.4 Hz,
Ar0-H-2,6), 7.49 (s, 1H, Ar-H-8), 7.27 (d, 2H, J = 6.0 Hz, Ar0-H-3,5); 6.62 (s, 1H, Ar-H-3); 2.44 (s, 3H,
COCH3), 2.35 (s, 9H, COCH3 × 3).
6,7,40-O-Triacetyl scutellarein ( ) yellow solid, m.p. 261–264 ◦C. 1H-NMR (CDCl3, 400 MHz)
4 δ: 12.90
(s, 1H, OH), 7.91 (d, 2H, J = 7.8 Hz, Ar0-H-2,6), 7.29 (d, 2H, J = 7.9 Hz, 2H, Ar0-H-3,5), 6.96 (s, 1H,
Ar-H-3), 6.70 (s, 1H, Ar-H-8), 2.37 (s, 3H, COCH3), 2.35 (s, 6H, COCH3 × 2).
General Procedure for Preparation of 7-O-aliphatic-5,6,40-O-triacetyl scutellarein (5) and
7-O-aliphatic-6,40-O-diacetyl scutellarein (6).

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To a solution of compound
3
or
4
(1 mmol) in anhydrous DMF (10 mL) was added K2CO3 (691 mg,
5 mmol) and RX (1.5 mmol), then the reaction mixture was stirred overnight at room temperature.
The mixture was poured into water (50 mL), and then extracted with ethyl acetate (50 mL 3),
×
the organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under
reduced pressure. The crude material that appeared was then purified by column chromatography on
silica gel using 20% ethyl acetate in petroleum ether as eluent to afford 5 or 6.
7-O-Hexyl-5,6,40-O-triacetylscutellarein (5a); yellow solid; yield 72%; 1H-NMR (400 MHz, CDCl3)
δ 7.87
(d, J = 8.8 Hz, 2H, Ar0-H-2,6), 7.26 (d, J = 8.8 Hz, 2H, Ar0-H-3,5), 6.92 (s, 1H, Ar-H-3), 6.57 (s, 1H,
Ar-H-8), 4.09 (t, J = 6.5 Hz, 2H, OCH2), 2.44 (s, 3H, COCH3), 2.34 (s, 3H, COCH3), 2.33 (s, 3H, COCH3),
1.88–1.76 (m, 2H, CH2), 1.49–1.42 (m, 2H, CH2), 1.39–1.31 (m, 4H, CH2
×
2), 0.92 (t, J = 6.7 Hz, 3H,
CH3). 13C-NMR (100 MHz, CDCl3)
δ
176.23, 168.90, 168.73, 167.83, 161.23, 155.79, 155.69, 153.17,
141.77, 130.86, 128.94, 127.47, 122.32, 111.09, 108.26, 98.70, 69.63, 31.36, 28.69, 25.44, 22.52, 21.12, 20.85,
20.10, 13.94.
7-O-Dodecyl-5,6,40-O-triacetylscutellarein (5b) yellow solid; yield 72%; 1H-NMR (400 MHz, CDCl3)
δ
7.86 (d, J = 8.4 Hz, 2H, Ar0-H-2,6), 7.25 (d, J = 8.4 Hz, 2H, Ar0-H-3,5), 6.92 (s, 1H, Ar-H-3), 6.56 (s, 1H,
Ar-H-8), 4.08 (t, J = 6.4 Hz, 2H, OCH2), 2.44 (s, 3H, COCH3), 2.34 (s, 3H, COCH3), 2.33 (s, 3H, COCH3),
1.91–1.71 (m, 2H, CH2), 1.49–1.40 (m, 2H, CH2), 1.38–1.23 (m, 16H, CH2
×
8), 0.88 (t, J = 6.7 Hz, 3H,
CH3). 13C-NMR (100 MHz, CDCl3)
δ
176.20, 168.89, 168.72, 167.82, 161.21, 155.77, 155.68, 153.16, 141.75,
130.85, 128.91, 127.46, 122.31, 111.06, 108.22, 98.71, 69.62, 31.91, 29.69, 29.65, 29.63, 29.56, 29.53, 29.33,
29.23, 28.74, 25.78, 22.67, 21.12, 20.86, 20.11, 14.10.
0
7-O-Octadecanyl-5,6,4 -O-triacetylscutellarein (5c) yellow solid; yield 57%; 1H-NMR (400 MHz, CDCl3)
δ
7.87 (d, J = 8.4 Hz, 2H, Ar0-H-2,6), 7.25 (d, J = 8.4 Hz, 2H, Ar0-H-3,5), 6.92 (s, 1H, Ar-H-3), 6.57 (s, 1H,
Ar-H-8), 4.09 (t, J = 6.5 Hz, 2H, OCH2), 2.44 (s, 3H, COCH3), 2.34 (s, 3H, COCH3), 2.33 (s, 3H, COCH3),
1.91–1.74 (m, 2H, CH2), 1.51–1.39 (m, 2H, CH2), 1.26 (s, 28H, CH2
×
14), 0.88 (t, J = 6.7 Hz, 3H, CH3).
13C-NMR (100 MHz, CDCl3)
δ
176.22, 168.90, 168.73, 167.84, 161.24, 155.79, 155.70, 153.17, 141.78,
130.87, 128.96, 127.47, 122.33, 111.09, 108.28, 98.69, 69.63, 31.91, 29.69, 29.65, 29.57, 29.53, 29.34, 29.32,
29.23, 28.75, 25.79, 22.67, 21.13, 20.85, 20.11, 14.08.
7-O-Oleyl-5,6,40-O-triacetylscutellarein (5d) yellow solid; yield 70%; 1H-NMR (400 MHz, CDCl3) δ 7.86
(d, J = 8.8 Hz, 2H, Ar0-H-2,6), 7.24 (d, J = 8.8 Hz, 2H, Ar0-H-3,5), 6.91 (s, 1H, Ar-H-3), 6.56 (s, 1H,
Ar-H-8), 5.43–5.30 (m, 2H, CH
COCH3), 2.33 (s, 3H, COCH3), 2.08–1.95 (m, 4H, CH2
CH2), 1.39–1.18 (m, 20H, CH2
10), 0.87 (t, J = 6.7 Hz, 3H, CH3). 13C-NMR (100 MHz, CDCl3)
168.88, 168.71, 167.80, 161.21, 155.76, 155.68, 153.17, 141.76, 130.86, 130.02, 129.74, 128.92, 127.45, 122.31,
111.08, 108.24, 98.70, 69.60, 31.89, 29.75, 29.68, 29.52, 29.44, 29.31, 29.21, 28.75, 27.23, 27.20, 25.79, 22.67,
21.11, 20.85, 20.10, 14.09.
×
2), 4.08 (t, J = 6.4 Hz, 2H, OCH2), 2.44 (s, 3H, COCH3), 2.33 (s, 3H,
2), 1.88–1.77 (m, 2H, CH2), 1.50–1.40 (m, 2H,
176.18,
×
×
δ
7-O-Hexyl-6,40-O-diacetylscutellarein (6a) yellow solid; yield 72%; 1H-NMR (400 MHz, CDCl3)
δ 12.72
(s, 1H, OH), 7.89 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 6.63 (s, 1H), 6.54 (s, 1H), 4.06 (t, J = 6.5 Hz,
2H), 2.35 (s, 3H), 2.34 (s, 3H), 1.96–1.73 (m, 2H), 1.51–1.40 (m, 2H), 1.39–1.30 (m, 4H), 1.29–1.19 (m, 3H),
0.97–0.87 (m, 3H). 13C-NMR (100 MHz, CDCl3)
δ 182.42, 168.84, 168.43, 163.30, 157.30, 154.91, 153.48,
152.60, 128.74, 127.66, 123.55, 122.41, 105.85, 105.72, 91.29, 69.44, 31.39, 29.68, 28.76, 25.44, 22.53, 21.11,
20.21, 13.95.
0
7-O-Dodecyl-6,4 -O-diacetylscutellarein (6b) yellow solid; yield 68%; 1H-NMR (400 MHz, CDCl3)
δ 12.72
(s, 1H, OH), 7.90 (d, J = 8.8 Hz, 2H, Ar0-H-2,6), 7.27 (d, J = 8.1 Hz, 2H, Ar0-H-3,5), 6.64 (s, 1H, Ar-H-3),
6.56 (s, 1H, Ar-H-8), 4.07 (t, J = 6.5 Hz, 2H, OCH2), 2.36 (s, 3H, COCH3), 2.35 (s, 3H, COCH3), 1.96–1.70
(m, 2H, CH2), 1.51–1.39 (m, 2H, CH2), 1.39–1.14 (m, 16H, CH2
×
8), 0.88 (t, J = 6.7 Hz, 3H, CH3).

Molecules 2018, 23, 310
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13C-NMR (100 MHz, CDCl3)
δ
182.44, 168.84, 168.44, 163.31, 157.31, 154.93, 153.47, 152.63, 128.78,
127.67, 123.58, 122.42, 105.88, 105.77, 91.29, 69.45, 31.91, 29.69, 29.65, 29.63, 29.57, 29.54, 29.34, 29.25,
28.81, 25.78, 22.67, 21.12, 20.23, 14.08.
7-O-Octadecanyl-6,40-O-diacetylscutellarein (6c) yellow solid; yield 53%; 1H-NMR (400 MHz, CDCl3)
δ
7.83 (d, J = 8.8 Hz, 2H, Ar0-H-2,6), 7.20 (d, J = 8.5 Hz, 2H, Ar0-H-3,5), 6.57 (s, 1H, Ar-H-3), 6.49 (s, 1H,
Ar-H-8), 3.99 (t, J = 6.5 Hz, 2H, OCH2), 2.29 (s, 3H, COCH3), 2.27 (s, 3H, COCH3), 1.80–1.71 (m, 2H,
CH2), 1.42–1.33 (m, 2H, CH2), 1.32–1.12 (m, 28H, CH2
×
14), 0.81 (t, J = 6.7 Hz, 6H, CH3). 13C-NMR
(100 MHz, CDCl3) 182.43, 168.83, 168.42, 163.31, 157.30, 154.92, 153.48, 152.63, 130.02, 129.74, 128.77,
δ
127.67, 122.41, 105.88, 105.76, 91.28, 69.43, 31.89, 29.77, 29.74, 29.69, 29.65, 29.52, 29.44, 29.32, 29.30,
29.22, 28.82, 27.23, 27.20, 25.79, 22.67, 21.12, 20.23, 14.08.
7-O-Oleyl-6,40-O-diacetylscutellarein (6d) yellow solid; yield 59%; 1H-NMR (400 MHz, CDCl3)
(s, 1H, OH), 7.90 (d, J = 8.8 Hz, 2H, Ar0-H-2,6), 7.27 (d, J = 8.8 Hz, 2H, Ar0-H-3,5), 6.64 (s, 1H, Ar-H-3),
6.55 (s, 1H, Ar-H-8), 5.47–5.16 (m, 2H, CH 2), 4.06 (t, J = 6.5 Hz, 2H, OCH2), 2.36 (s, 3H, COCH3), 2.34
(s, 3H, COCH3), 2.09–1.92 (m, 4H, CH2 2), 1.87–1.76 (m, 2H, CH2), 1.51–1.40 (m, 2H, CH2), 1.40–1.21
(m, 20H, CH2 182.43, 168.83, 168.42,
10), 0.88 (t, J = 6.7 Hz, 3H, CH3). 13C-NMR (100 MHz, CDCl3)
δ 12.72
×
×
×
δ
163.31, 157.30, 154.92, 153.48, 152.63, 130.02, 129.74, 128.77, 127.67, 122.41, 105.88, 105.76, 91.28, 69.43, 31.89,
29.77, 29.74, 29.69, 29.65, 29.52, 29.44, 29.32, 29.30, 29.22, 28.82, 27.23, 27.20, 25.79, 22.67, 21.12, 20.23, 14.08.
Cell Culture and Treatment
Cells were plated in 96-well plates (Jet Bio-Filtration, Guangzhou, China, 5000 cells/well in
100
compounds (from 1 to 200
µ
L) and grown for 24 h at 37 ◦C before being treated with various concentrations of the tested
µ
M). After 48 h of incubation, CellTiter 96® AQueous One Solution Cell
Proliferation Assay (MTS) solution (Promega, Madison, WI, USA) was added to each well, and the
◦
plates were further incubated for 1 h at 37 C. The absorbance at 490 nm was measured with a Bio-Rad
680 Microplate Reader (Bio-Rad, Hercules, CA, USA). All measurements were performed in triplicate.
The experiments were performed independently three times. The IC50 was calculated using GraphPad
PRISM (GraphPad PRISM Software 6.0, San Diego, CA, USA).
4. Conclusions
In this study, we designed and synthesized a series of mono-aliphatic chain-modified scutellarein
derivatives, and evaluated their biological activity in inhibiting cancer cell proliferation. We identified
scutellarein derivatives 5a, 5b, 6a and 6b as new anti-proliferation agents for Jurkat, HCT-116
and MDA-MB-231 cells. The results showed that a proper long aliphatic chain enhanced the
anti-proliferative activity of scutellarein. For our further studies, compound 6a was selected as a
promising lead in order to generate more effective anticancer agents.
Acknowledgments: This work was supported by the Foundation of Yunnan Provincial Science and Technology
Department-Applied Basic Research Joint Special Funds of Yunnan University of Traditional Chinese Medicine
[2015FB205 (-029)], the National Natural Science Foundation of China (grant No. 81560558). The authors are
thankful to Kunming Key Laboratory for Metabolic Diseases Prevention and Treatment by Chinese Medicine for
the financial support.
Author Contributions: Gaoxiong Rao conceived the experiments; Guanghui Ni designed the synthetic route and
wrote this paper; Yanling Tang and Minxin Li performed the chemical experiments; Yuefeng He designed and
performed the biological experiments.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 1–6 in this article are available from the authors.
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