Anti-tumor activity of new artemisinin-chalcone hybrids

Article abstract of DOI:10.1002/ardp.201000391

In an attempt to develop potent and selective anti-tumor agents, three new series of artemisinin-chalcone hybrids 10a-10g, 11a-11g and 12a-12h were designed, synthesized and screened for their anti-tumor activity against five cell lines (HT-29, A549, MDA-MB-231, HeLa and H460) in vitro. Among compounds 10a-g and 11a-11g, most of them displayed enhanced activity and good selectivity toward HT-29 and HeLa cell lines with IC₅₀ values ranging from 0.12 to 0.85 μM as compared with DHA (dihydroartemisinin). Compounds 10a and 11a are most active toward HeLa cells with IC₅₀ values of 0.12 and 0.19 μM. The results revealed that the presence of chalcone moiety is beneficial to their activity and selectivity. In addition, compounds 12a-12h containing a 'reversed chalcone' moiety showed only slight improvement in activity than those of DHA. Three new series of artemisinin-chalcone hybrids (10a-10g, 11a-11g and 12a-12h) were synthesized and evaluated for their anti-tumor activity against five human cancer cell lines. Copyright

Full text of DOI:10.1002/ardp.201000391

Arch. Pharm. Chem. Life Sci. 2011, 344, 639–647
639
Full Paper
Anti-Tumor Activity of New Artemisinin–Chalcone Hybrids
Lijun Xie, Xin Zhai, Chun Liu, Peng Li, Yangxiong Li, Guoxian Guo, and Ping Gong
Key Laboratory of Original New Drugs Design and Discovery of Ministry of Education, School of
Pharmaceutical Engineering, Shenyang Pharmaceutical University, China
In an attempt to develop potent and selective anti-tumor agents, three new series of artemisinin–
chalcone hybrids 10a–10g, 11a–11g and 12a–12h were designed, synthesized and screened for their
anti-tumor activity against five cell lines (HT-29, A549, MDA-MB-231, HeLa and H460) in vitro. Among
compounds 10a–g and 11a–11g, most of them displayed enhanced activity and good selectivity toward
HT-29 and HeLa cell lines with IC50 values ranging from 0.12 to 0.85 mM as compared with DHA
(dihydroartemisinin). Compounds 10a and 11a are most active toward HeLa cells with IC50 values of
0.12 and 0.19 mM. The results revealed that the presence of chalcone moiety is beneficial to their
activity and selectivity. In addition, compounds 12a-12h containing a ‘reversed chalcone’ moiety
showed only slight improvement in activity than those of DHA.
Keywords: Anti-tumor activity / Artemisinin / Chalcone / Hybrid
Received: December 17, 2010; Revised: February 19, 2011; Accepted: February 25, 2011
DOI 10.1002/ardp.201000391
Introduction
nin and chalcone groups can act as anti-tumor agents via
different molecular mechanisms encourage us to design
hybrids containing these two moieties within their struc-
tures. They may have improved anti-tumor activity and be
less susceptible to the development of drug resistance.
Interestingly, a similar strategy had already been reported
that the anti-tumor potency of the C-10 acetal artemisinin
derivatives could be improved significantly [10]. The poten-
tial drawback in these derivatives is the presence of the
metabolically susceptible C-10 acetal linkage. Intrigued by
these findings, to search for more active artemisinin–chal-
cone hybrids with increased stability, we thought that the
linkage type between artemisinin nucleus and chalcone moi-
eties was an interesting point for further modification. In
order to explore the influence of chalcone moiety on bio-
activity, a ‘reversed’ chalcone moiety that the carbonyl and
ethylene groups present in chalcone moiety are interchanged
was also introduced. With these in mind, we have designed
and synthesized three series of new artemisinin derivatives
(Fig. 1), in which the chalcone and ‘reversed chalcone’ groups
were combined into the artemisinin nucleus through an
amide linkage, respectively.
The adverse effects of traditional chemotherapy and the
emergency of resistance with the newly molecularly targeted
anti-tumor drugs have shown the urgent need for develop-
ment of more effective anti-tumor agents [1]. Thus, the search
for novel anti-tumor agents that circumvent these limita-
tions has turned to natural products because of their ability
to interact with more to one target [2].
Artemisinin, a sesquiterpene endoperoxide isolated from
Artemisia annua L., is being widely used as an antimalaria drug
[3]. In recent years, the modification of artemisinin has been
of increasing interest since some derivatives showed good
activity against various cancer cell lines [4–10], even many
drug- and radiation-resistant cancer cell lines [11–12]. The
mechanism of artemisin analogues seem to be multimodal
but mainly rely on formation of free radical inducing apop-
tosis and antiangiogenic effects [13–17]. Chalcones were also
extensively studied for their anti-tumor activity [18–22],
which mainly results from the inhibition of tubulin
polymerization different from those of artemisinin
analogues [23–25]. The observations that both the artemisi-
Chemistry
Correspondence: Ping Gong, 103 Wenhua Road, Shenhe District,
110016 Shenyang, Liaoning, P. R. China
E-mail: gongpinggp@126.com
The synthetic routes of compounds are outlined in Scheme 1
and Scheme 2. Generally, a pair of isomers 10b-azidodihy-
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L. Xie et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 639–647
tuted aryl aldehydes were reacted with corresponding
inexpensive p-hydroxyacetophenone in ethanol/KOH at 0–
58C. Upon completion, the cooled reaction mixture was
poured into ice water and treated with HCl (10%) yielded
the desired chalcone analogues 6a–6h. The foregoing method
for the preparation of the 6a-6h was applied to prepare
compounds 7a–7h with substituted acetophenone and p-
hydroxybenzaldehyde.
Finally, the target compounds 10a–10g, 11a–11g and 12a–
12h were successfully prepared via reaction of intermediates
8 and 9 with 6a–6h and 8 with7a–7h in the presence of K2CO3
and sodium iodide in DMF at 608C, respectively. The products
were purified by column chromatography on silica gel.
The formation of 10b-azidoartemisinin (2) and 10a-azidoar-
1
temisinin (3) were confirmed by H-NMR and LC-MS data. In
our previous report, the stereochemistry of 2 had been deter-
mined by single crystal X-ray diffraction studies [28]. The
structure of 3 was elucidated by 1H-NMR and LC-MS analysis.
Specifically, the configuration of 3 at the C-10 position was
assigned as 10a based on the H-9/H-10 coupling constant
(J ¼ 10.1 Hz) and chemical shift H-10 (4.86 ppm).
Figure 1. The structures of DHA, chalcone and the target
compounds.
droartemisinin (2) and 10a-dihydroazidoartemisinin (3) was
synthesized by treating 1 with trimethylsilyl chloride,
sodium azide and sodium iodide at room temperature for
28 h, and individual pure isomer could be separated by
column chromatography. The azido compounds (2, 3) were
transformed to 10b-aminoartemisinin (4) and 10a-aminoar-
temisinin (5) via Staudinger reduction [26], respectively,
which subsequently reacted with chloroacetyl chloride to
afford two key intermediates (8, 9) as white solid.
The formation of two important intermediates (8, 9) was
confirmed by 1H-NMR and LC-MS data, The formation of
the title compounds 10a–10g, 11a–11g and 12a–12h
were evidenced by 1H-NMR spectral, IR, LC-MS and
element analysis data, which were explained in experimental
part.
Results and Discussion
On the side chain, the preparation of the chalcone
analogues (6a–6h, 7a–7h) was carried out via Claisen-
Schmidt condensation [27]. This method for the preparation
of chalcones is attractive since it predominantly generates
the (E)-isomer from simple building blocks, coupling con-
stants (Jtrans ¼ 15–16 Hz) from the proton nuclear magnetic
resonance (1H NMR) spectra of the title compounds indicated
clearly that derivatives 6a–6h and 7a–7h were both geometri-
cally pure and trans (E)-isomers. Thus, appropriate substi-
Biological evaluation
All compounds 10a–10g, 11a–11g and 12a–12h were eval-
uated for their anti-tumor activity on human colorectal can-
cer cell line (HT-29), human non-small-cell lung cancer cell
line (A549), human breast cancer cell line (MDA-MB-231),
human cervical carcinoma cell line (HeLa) and human lung
cancer cell line (H460) by the MTT assay [29], using DHA as a
positive control. The results expressed as IC50 were summa-
rized in Table 1, and the IC50 values were the average of at
least two independent experiments.
As shown in Table 1, the artemisinin-chalcone hybrids 10a–
10g and 11a–11g were more active than the corresponding
DHA in most cases, suggesting that the presence of chalcone
moiety enhanced their anti-tumor activity significantly. In
addition, it was worth to mention that most of the tested
compounds (10a–10g, 11a–11g) against HT-29 and HeLa cell
lines were several- to ten-fold more potent than against MDA-
MB-231, A549 and H460 cell lines, respectively. The results
demonstrated that the introduction of chalcone moiety
could enhance their selectivity for HT-29 and HeLa cell lines
significantly at the same time. Unfortunately, compounds
12a–12h showed only moderate activity with IC50 values
Scheme 1. Synthesis of 6a–6h and 7a–7h.
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Arch. Pharm. Chem. Life Sci. 2011, 344, 639–647
Novel Artemisinin–Chalcone Hybrids
641
Scheme 2. Synthesis of 10a–10g, 11a–11g and 12a–12h.
ranging from 1.5 to 27 mM, which were just slight improve-
ment compared with those of DHA. The results revealed
that the introduction of a ‘reversed’ chalcone moiety was
probably unsuitable in enhancing their activity and
selectivity.
IC50 value of 0.12 mM. Turning to the effects of 10d contain-
ing heteroaromatic chalcone moiety, interestingly, the bio-
isosteric replacement of substituted phenyl with pyridine
ring (9d) resulted in a decrease of the anti-tumor activity
on HT-29 cells.
The data in Table 1 revealed that substitution pattern on
the phenyl rings linked to the b-position of the enone system
affected their potency significantly. For compounds 10a–10g,
specifically with the halogen substituted derivatives (10b, c, f,
g), the dihalogen-substituted derivatives (10c, f, g) possessed
almost the same activity were favored over mono-substituted
derivative (10b). It was also observed that the presence of
electron-donating methoxyl group (10a) brought about
enhanced activity and selectivity against HeLa cells with
Regarding the anti-tumor activity of 11a–11h, bearing a
same molecular structure but only different C-10 stereochem-
istry, showed few differences in inhibitory effect as compared
with 10a–10h. The results revealed that the configuration of
C-10 was not essential for their activity. Compound 11a, the
most active compound of this series towards HeLa, possess
2,5-dimethoxyl group on the phenyl ring, which might be
played a very vital role in determine the activity and
selectivity.
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L. Xie et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 639–647
Table 1. Anti-tumor activity of the compounds against HT-29, A549,
MDA-MB-231, HeLa and H460 cell lines in vitro
stituted phenyl ring with pyridine ring might be detrimental
to the activity. All these data suggested that these hybrids
might be utilized for the development of new anti-tumor
candidates. Especially, the most potent and selective hybrids
10a and 11a deserve further evaluation to study their meta-
bolic stability and anti-tumor activity in vivo, and the research
results will be reported in due course.
Compd. no
IC50 (mM)a
HT-29 b A549 b MDA-MB-231 b HeLa b H460 b
10a
10b
10c
10d
10e
10f
10g
11a
11b
11c
11d
11e
11f
11g
12a
12b
12c
12d
12e
12f
12g
12h
DHA d
0.45
0.55
0.55
0.97
0.53
0.68
0.42
0.55
0.59
0.69
0.84
1.2
0.86
1.3
3.8
1.6
1.8
4.2
8.4
5.1
19
2.3
3.2
1.6
3.6
5.3
2.3
12.0
3.7
1.7
2
1.7
2.0
n.d c
5.0
11.0
4.4
n.d c
7.8
4.6
3.8
3.0
15.6
2.3
1.4
2.1
2.4
1.1
6.9
3.9
1.7
1.4
1.0
1.0
0.68
1.3
5.8
1.7
4.8
3.3
6.5
5.0
13
0.12
0.59
0.33
0.74
1.9
0.48
0.38
0.19
0.95
0.83
1.3
2.4
1.7
3.6
1.2
Experimental
0.8
n.d c
4.0
Chemistry
4.1
2.3
5.8
1.7
0.84
2.7
4.0
All melting points were obtained on a Bu¨chi Melting Point B-540
apparatus (Bu¨chi Labortechnik, Flawil, Switzerland) and were
uncorrected. Mass spectra (MS) were taken in ESI mode on
Agilent 1100 LC-MS (Agilent, Palo Alto, CA, USA). Proton (1H)
nuclear magnetic resonance spectroscopy was performed using
Bruker ARX-300, 300MHz spectrometers (Bruker Bioscience,
Billerica, MA, USA) with TMS as an internal standard. IR spectra
(KBr disks) were recorded with a Bruker IFS 55 instrument
(Bruker). Elemental analysis was determined on a Carlo-Erba
1106 Elemental analysis instrument (Carlo Erba, Milan, Italy).
Unless otherwise noted, all the materials were obtained from
commercially available sources and were used without further
purification.
0.77
2.1
0.21
8.5
6.3
1.5
n.d c
6.7
n.d c
2.6
4.1
27.0
3.9
6.8
7.1
13.0
2.9
n.d c
6.2
3.2
1.7
5.6
9.3
6.9
9.8
6.3
6.3
Preparation of 10b-azidodihydroartemisinin 2 and
10a-azidodihydroartemisinin 3
a
IC50: Concentration of the compound (mM) producing 50% cell
growth inhibition after 72 h of drug exposure, as determined by
the MTT assay. Each experiment was run at least two times, and
the results are presented as average values.b HT-29, human colon
cancer cell line; A549, non-small-cell lung adenocarcinoma cell
line; MDA-MB-231, human breast cancer cell line; HeLa, human
cervical carcinoma cell line; H460, lung cancer cell line.c n.d.:
not determined.d Used as a positive control.
Trimethylchlorosilane (300 mmol, 38.1 mL) was added gradually
to the mixture of dihydroartemisinin (200 mmol, 56.8 g) and
sodium azide (300 mmol, 19.5 g) in dry dichloromethane
(300 mL), then sodium iodide (5 mmol, 3.0 g) was added to
the reaction mixture at 0–58C. The reaction mixture was stirred
at room temperature for 28 h, and then the mixture was
quenched with a saturated NaHCO3 solution (100 mL) and
diluted with dichloromethane. The organic phase was washed
with brine, then collected and dried overnight over anhydrous
Na2SO4. After filtering, the solvent was evaporated under reduced
pressure. The crude mixture was purified by column chromatog-
raphy (silica, 1%–5% ethyl acetate/hexanes) to furnish the com-
pound 2 (29.0 g, 47%) and compound 3 as white solid (3.0 g, 5%).
Compound 2: M.p.: 41–438C; MS (ESI) m/z: 332.2 (M þ Na)þ;
1H-NMR (300 MHz, DMSO-d6) d: 5.76 (s, 1H), 5.54 (d, J ¼ 3.6 Hz,
1H), 2.46 (m, 1H), 2.26–2.12 (m, 1H), 2.07–1.96 (m, 1H), 1.87–1.78
(m, 1H), 1.77–1.65 (m, 1H), 1.58 (m, 2H), 1.48–1.33 (m, 3H), 1.31
(s, 3H), 1.16 (m, 1H), 0.89 (d, J ¼ 6.3 Hz, 3H), 0.84 (d, J ¼ 7.3 Hz,
3H).
Conclusion
In this study, three series of artemisinin–chalcone hybrids
were synthesized and evaluated for their anti-tumor activity.
The results demonstrated that most of compounds exhibited
potent activity. Especially, compound 10a, 11a bearing 2,5-
dimethoxyl group on the phenyl ring were found to be the
most potent anti-tumor agents with the IC50 value of 0.12 and
0.19 mM to HeLa-29 cells.
Compound 3: M.p.: 101–1038C; MS (ESI) m/z: 332.2 (M þ Na)þ;
1H-NMR (300 MHz, DMSO-d6) d: 5.53 (s, 1H), 4.86 (d, J ¼ 10.1 Hz,
1H), 2.29–2.06 (m, 2H), 2.05–1.94 (m, 1H), 1.87–1.76 (m, 1H), 1.65–
1.33 (m, 5H), 1.30 (s, 3H), 1.24–1.10 (m, 1H), 0.89 (d, J ¼ 6.2 Hz,
3H), 0.81 (d, J ¼ 7.1 Hz, 3H).
From the above results, some interesting structure activity
relationships can be disclosed that: (1) The configuration of
the C-10 position has no evident effect on the anti-tumor
activity. (2) The introduction of chalcone moiety was crucial
for improving their activity and selectivity, while a ‘reversed’
chalcone moiety had little impact on the activity. (3) The
substitution pattern had substantial impact on their potency.
Generally, the presence of a number of methoxy groups
seems to be a fundamental requirement to obtain potent
and selective anti-tumor agents. (4) The replacement of sub-
Preparation of 10b-aminodihydroartemisinin 4
A 100-mL round-bottomed flask was charged with compound 2
(16.0 g, 52 mmol) and THF (130 mL). To this solution, triphenyl
phosphine (20.4 g, 78 mmol) was added slowly and the reaction
mixture was stirred for 2 h at 608C. Distilled water (160 mmol,
3.0 mL) was added and the resulting suspension was stirred for
6 h. The mixture was concentrated under reduced pressure. The
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Arch. Pharm. Chem. Life Sci. 2011, 344, 639–647
Novel Artemisinin–Chalcone Hybrids
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crude mixture was purified by flash column chromatography
(dichloromethane/methanol, 200:1) to afford the desired com-
pound 4 (9.1 g, 62%) as yellow oil. MS (ESI) m/z: 284.1 (M þ H)þ;
1H-NMR (300 MHz, CDCl3) d: 5.34 (s, 1H), 4.21 (d, J ¼ 9.7 Hz, 1H),
2.44–2.31 (m, 1H), 2.30–2.17 (m, 1H), 2.08–1.94 (m, 4H), 1.94–1.83
(m, 2H), 1.81–1.61 (m, 3H), 1.60–1.46 (m, 2H), 1.44 (s, 3H), 0.97
(d, J ¼ 6.2 Hz, 3H), 0.94 (d, J ¼ 7.2 Hz, 3H).
was filtered, washed with water and dried. The residue was
recrystallized from ethanol to afford pure compounds 6a–6h.
General procedure for preparation of compounds 7a–7h
The foregoing method for the preparation of the 6a–6h was
applied to prepare the 7a–7h except that the starting materials
were substituted acetophenone and p-hydroxybenzaldehyde
instead of substituted aryl aldehydes and p-hydroxyaceto-
phenone.
Preparation of 10a-aminodihydroartemisinin 5
This compound was prepared according to compound 4 from
compound 3 (5.0 g, 16.2 mmol), triphenyl phosphine (6.4 g,
24.5 mmol) and water (52.0 mmol, 1 mL). Purification of
the resulting oil afforded 5 as colorless crystal (3.2 g, 70%);
mp: 468C; MS (ESI) m/z: 284.1 (M þ H)þ; 1H-NMR (300 MHz,
DMSO-d6) d: 5.31 (s, 1H), 4.08 (d, J ¼ 9.6 Hz, 1H), 2.23 (s, 2H,
NH2, D2O-exchangable), 2.21–2.10 (m, 1H), 2.08–1.89 (m, 2H),
1.86–1.72 (m, 1H), 1.65–1.52 (m, 2H), 1.45–1.29 (m, 4H), 1.26
(s, 3H), 0.89 (d, J ¼ 6.3 Hz, 3H), 0.79 (d, J ¼ 7.2 Hz, 3H).
General procedure for preparation of compounds 10a–10g,
compounds 11a–11g and compounds 12a–12h
K2CO3 (0.12 g, 0.84 mmol) was added to a stirred solution of
compound 7 or compound 8 (0.2 g, 0.57 mmol) and substituted
chalcone (0.57 mmol) in DMF (6 mL). The reaction mixture was
heated to 608C for 3–5 h. The mixture was poured into ice water,
stirred for 1 h and separated by filtration to give crude com-
pounds, which purified by column chromatography on silica gel
using (1%–5% petroleum ether/ethyl acetate) to obtain 10a–10g,
11a–11g and 12a–12h.
Preparation of (10R)-N-chloroacetyl-
aminodihydroartemisinin 8
Triethylamine (3.2 g, 31.8 mmol) was added to a solution of
compound 4 (6.0 g, 21.2 mmol) in dichloromethane (80 mL)
and then 2-chloroacetyl chloride (3.1 g, 27.6 mmol) was added
drop-wise to the reaction mixture at 0–108C. The reaction mix-
ture was stirred at room temperature for 1–3 h. After completion
of reaction as indicated by TLC, the mixture was quenched with
H2O (5 mL) and diluted with dichloromethane (50 mL). The
organic layer was washed with brine (200 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure.
The resultant solid products were collected by filtration and
recrystallized from methanol to give compound 8 (5.9 g, 78%).
M.p.: 171–1738C; MS (ESI) m/z: 382.1 (M þ Na)þ; 1H-NMR
(300 MHz, DMSO-d6) d: 8.96 (d, J ¼ 9.1 Hz, 1H), 5.47 (s, 1H),
5.08 (t, J ¼ 9.8 Hz, 1H), 4.09 (s, 2H), 2.40–2.25 (m, 1H), 2.18 (td,
J ¼ 14.0, 3.7 Hz, 1H), 2.04–1.93 (m, 1H), 1.87–1.75 (m, 1H), 1.66–
1.30 (m, 7H), 1.27 (s, 3H), 1.17 (m, 1H), 0.89 (d, J ¼ 6.3 Hz, 3H),
0.72 (d, J ¼ 7.1 Hz, 3H).
(10R)-N-{4-[3-(2,5-Dimethoxyphenyl)-2-(E)-
propenoyl]phenyloxyacetyl}aminodihydroartemisinin 10a
This compound was obtained as yellow solid in 82% yield. M.p.:
96–988C; MS (ESI) m/z: 645.7 (M þ K)þ; IR (KBr) cmꢀ1: 3240.7,
2925.9, 2872.9, 1692.9, 1661.2, 1605.6, 1254.2, 1218.8, 1172.0,
1089.1, 1038.3, 818.0, 751.8, 509.9. 1H-NMR (300 MHz, DMSO-d6)
d: 8.93 (d, J ¼ 9.0 Hz, 1H), 8.16 (2d, J ¼ 8.8 Hz, 2H), 8.01
(d, J ¼ 15.7 Hz, 1H), 7.90 (d, J ¼ 15.8 Hz, 1H), 7.55 (s, 1H), 7.10
(d, J ¼ 8.8 Hz, 2H), 7.07–7.00 (m, 2H), 5.47 (s, 1H), 5.17
(t, J ¼ 9.7 Hz, 1H), 4.71 (s, 2H), 3.84 (s, 3H), 3.80 (s, 3H),
2.45–2.37 (m, 1H), 2.25–2.12 (m, 1H), 2.04–1.94 (m, 1H), 1.86–
1.75 (m, 1H), 1.28 (s, 3H), 0.89 (d, J ¼ 6.2 Hz, 3H), 0.71
(d, J ¼ 7.1 Hz, 3H); Anal. calcd. for C34H41NO9 (in %): C, 67.20;
H, 6.80; N, 2.30; Found: C, 67.17; H, 6.91 and N, 2.23.
(10R)-N-{4-[3-(2-Fluorophenyl)-2-(E)-
propenoyl]phenyloxyacetyl}aminodihydroartemisinin 10b
This compound was obtained as pale yellow solid in 86% yield.
:
Preparation of (10S)-N-chloroacetyl-
aminodihydroartemisinin 9
M.p.: 106–1098C; MS (ESI) m/z: 588.3 (M þ Na)þ; IR (KBr) cmꢀ1
3422.1, 2926.1, 2873.1, 1684.4, 1664.0, 1605.3, 1538.0, 1508.1,
1257.9, 1217.6, 1172.5, 1038.5, 838.5, 761.9, 584.4; 1H-NMR
(300 MHz, DMSO-d6) d: 8.94 (d, J ¼ 9.4 Hz, 1H), 8.17 (d,
J ¼ 8.6 Hz, 2H), 8.14–8.09 (m, 1H), 8.00 (d, J ¼ 16.0 Hz, 1H),
7.81 (d, J ¼ 15.9 Hz, 1H), 7.58–7.47 (m, 1H), 7.39–7.27 (m, 2H),
7.12 (d, J ¼ 8.7 Hz, 2H), 5.47 (s, 1H), 5.17 (t, J ¼ 10.0 Hz, 1H), 4.72
(s, 2H), 2.45–2.34 (m, 1H), 2.25–2.11 (m, 1H), 2.05–1.93 (m, 1H),
1.87–1.73 (m, 1H), 1.28 (s, 3H), 0.89 (d, J ¼ 6.1 Hz, 3H), 0.71 (d,
J ¼ 7.1 Hz, 3H); Anal. calcd. for C32H36FNO7 (in %): C, 67.95; H,
6.42; N, 2.48; Found: C, 67.92; H, 6.56 and N, 2.42.
The product was prepared from 5 (3.0 g, 10.6 mmol) in a similar
manner as described for the preparation of compound 8.
The resultant solid products were collected by filtration and
recrystallized from methanol to give compound 9 (3.1 g, 81%).
M.p.: 175–1778C; MS (ESI) m/z: 382.2 (M þ Na)þ; 1H-NMR
(300 MHz, CDCl3) d: 5.45 (s, 1H), 5.36 (t, J ¼ 10.1 Hz, 1H), 4.09
(s, 2H), 2.55–2.41 (m, 1H), 2.41–2.32 (m, 1H), 2.11–2.00 (m, 1H),
1.98–1.86 (m, 1H), 1.85–1.70 (m, 2H), 1.71–1.46 (m, 4H), 1.45
(s, 3H), 1.39–1.24 (m, 2H), 0.99 (d, J ¼ 6.0 Hz, 3H), 0.88
(d, J ¼ 7.2 Hz, 3H).
(10R)-N-{4-[3-(3,4-Difluorophenyl)-2-(E)-
propenoyl]phenyloxyacetyl}aminodihydroartemisinin 10c
General procedure for preparation of compounds 6a–6h
A stirred solution of p-hydroxyacetophenone (8.1 g, 0.06 mol) in
ethanol (200 mL) was added to 60% KOH (6.7 g, 0.12 mol)
solution at 08C, the mixture was stirred at 0–58C for 1 h. The
substituted aryl aldehyde (0.06 mol) was added to the mixture
and the resulting mixture was stirred at room temperature for
24 h. The aqueous mixture was neutralized by the addition of
aqueous 10% HCl solution. The light yellow solid thus obtained
This compound was obtained as pale yellow solid in 79% yield.
:
M.p.: 112–1158C; MS (ESI) m/z: 606.5 (M þ Na)þ; IR (KBr) cmꢀ1
3423.4, 2927.0, 2874.0, 1691.8, 1661.4, 1602.2, 1513.0, 1276.1,
1173.3, 1038.5, 878.2, 823.8, 596.9, 558.9; 1H-NMR (300 MHz,
DMSO-d6) d: 8.93 (d, J ¼ 8.8 Hz, 1H), 8.19 (d, J ¼ 8.7 Hz, 2H),
8.15–8.08 (m, 1H), 7.99 (d, J ¼ 15.7 Hz, 1H), 7.79–7.72 (m, 1H),
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644
L. Xie et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 639–647
7.68 (d, J ¼ 15.9 Hz, 1H), 7.59–7.46 (m, 1H), 7.11 (d, J ¼ 8.9 Hz,
2H), 5.47 (s, 1H), 5.17 (t, J ¼ 9.7 Hz, 1H), 4.72 (s, 2H), 2.45–2.34
(m, 1H), 2.26–2.11 (m, 1H), 2.05–1.93 (m, 1H), 1.87–1.74 (m, 1H),
1.28 (s, 3H), 0.89 (d, J ¼ 6.0 Hz, 3H), 0.71 (d, J ¼ 7.0 Hz, 3H); Anal.
calcd. for C32H35F2NO7 (in %): C, 65.85; H, 6.04; N, 2.40; Found: C,
65.79; H, 6.15; N, 2.40.
(s, 2H), 2.52–2.32 (m, 2H), 2.11–2.01 (m, 1H), 1.97–1.86 (m, 1H),
1.83–1.71 (m, 2H), 1.45 (s, 3H), 0.99 (d, J ¼ 6.0 Hz, 3H), 0.82
(d, J ¼ 7.2 Hz, 3H); Anal. calcd. for C32H35Cl2NO7 (in %): C,
62.34; H, 5.72; N, 2.27; Found: C, 62.33; H, 5.78; N, 2.25.
(10S)-N-{4-[3-(2,5-Dimethoxyphenyl)-2-(E)-
propenoyl]phenyloxyacetyl}aminodihydroartemisinin 11a
This compound was obtained as yellow solid in 91% yield. M.p.:
106–1098C; MS (ESI) m/z: 630.5 (M þ Na)þ; IR (KBr) cmꢀ1: 3423.0,
2925.9, 1687.6, 1657.7, 1601.9, 1496.1, 1260.1, 1225.1, 1171.1,
1112.8, 1039.5, 802.3, 551.8; 1H-NMR (300 MHz, CDCl3) d: 8.14–
8.03 (m, 3H), 7.60 (d, J ¼ 15.8 Hz, 1H), 7.06 (d, J ¼ 8.4 Hz, 2H),
6.92 (d, J ¼ 3.6 Hz, 1H), 6.89 (d, J ¼ 3.7 Hz, 1H), 6.74 (s, 1H), 5.50–
5.42 (m, 2H), 4.62 (s, 2H), 3.90 (s, 3H), 3.73 (s, 3H), 2.53–2.27
(m, 2H), 2.13–1.98 (m, 1H), 1.98–1.85 (m, 1H), 1.84–1.71 (m,
2H), 1.44 (s, 3H), 0.99 (d, J ¼ 5.7 Hz, 3H), 0.81 (d, J ¼ 6.9 Hz,
3H); Anal. calcd. for C34H41NO9 (in %): C, 67.20; H, 6.80; N,
2.30; Found: C, 67.13; H, 6.93; N, 2.26.
(10R)-N-{4-[3-(4-Pyridyl)-2-(E)-
propenoyl]phenyloxyacetyl}aminodihydroartemisinin 10d
This compound was obtained as brown solid in 71% yield. M.p.:
99–1018C; MS (ESI) m/z: 571.3 (M þ Na)þ; IR (KBr) cmꢀ1: 3423.0,
2927.1, 2844.0, 1661.8, 1631.4, 1602.6, 1511.0, 1256.1, 1153.3,
1038.6, 876.2, 821.8, 566.9, 538.9; 1H-NMR (300 MHz, DMSO-d6) d:
8.94 (d, J ¼ 8.8 Hz, 1H), 8.67 (d, J ¼ 5.1 Hz, 2H), 8.25–8.11 (m, 3H),
7.84 (d, J ¼ 5.3 Hz, 2H), 7.65 (d, J ¼ 15.9 Hz, 1H), 7.12
(d, J ¼ 8.7 Hz, 2H), 5.47 (s, 1H), 5.17 (t, J ¼ 9.6 Hz, 1H), 4.73
(s, 2H), 2.45–2.34 (m, 1H), 2.26–2.11 (m, 1H), 2.05–1.93 (m, 1H),
1.86–1.75 (m, 1H), 1.28 (s, 3H), 0.89 (d, J ¼ 5.7 Hz, 3H), 0.71
(d, J ¼ 7.2 Hz, 3H); Anal. calcd. for C31H36N2O7 (in %): C, 67.87;
H, 6.61; N, 5.11; Found: C, 67.79; H, 6.73; N, 5.12.
(10S)-N-{4-[3-(2-Fluorophenyl)-2-(E)-
propenoyl]phenyloxyacetyl}aminodihydroartemisinin 11b
(10R)-N-{4-[3-(4-Methylsulfonylphenyl)-2-(E)-
propenoyl]phenyloxyacetyl}aminodihydroartemisinin 10e
This compound was obtained as pale yellow solid in 86% yield.
M.p.: 96–988C; MS (ESI) m/z: 588.3 (M þ Na)þ; IR (KBr) cmꢀ1
:
3421.9, 2926.1, 2873.5, 1663.6, 1605.1, 1575.8, 1531.4, 1333.5,
This compound was obtained as pale yellow solid in 71% yield.
M.p.: 116–1188C; MS (ESI) m/z: 648.1 (M þ Na)þ; IR (KBr) cmꢀ1
1
:
3421.6, 2918.9, 2862.8, 1665.8, 1609.5, 1552.5, 1508.4, 1428.6,
1257.6, 1217.6, 1172.4, 1038.5, 761.9, 584.7; H-NMR (300 MHz,
CDCl3) d: 8.09 (d, J ¼ 8.9 Hz, 2H), 7.92 (d, J ¼ 15.9 Hz, 1H), 7.72–
7.61 (m, 2H), 7.46–7.35 (m, 1H), 7.27–7.12 (m, 3H), 7.07
(d, J ¼ 8.9 Hz, 2H), 5.52–5.41 (m, 2H), 4.62 (s, 2H), 2.53–2.32
(m, 2H), 2.11–1.99 (m, 1H), 1.98–1.86 (m, 1H), 1.84–1.70
(m, 2H), 1.45 (s, 3H), 0.99 (d, J ¼ 5.9 Hz, 3H), 0.82
(d, J ¼ 7.1 Hz, 3H); Anal. calcd. for C32H36FNO7 (in %): C, 67.95;
H, 6.42; N, 2.48; Found: C, 67.95; H, 6.53; N, 2.46.
1
1266.3, 1230.1, 1161.8, 1028.5, 776.5, 598.3; H-NMR (300 MHz,
CDCl3) d: 8.10 (d, J ¼ 8.9 Hz, 2H), 8.05–7.97 (m, 3H), 7.65 (d,
J ¼ 15.7 Hz, 1H), 7.09 (d, J ¼ 8.9 Hz, 2H), 7.00 (d, J ¼ 8.9 Hz,
2H), 5.52–5.40 (m, 1H), 4.62 (s, 2H), 3.11 (s, 3H), 2.53–2.31
(m, 2H), 2.13–1.99 (m, 1H), 1.98–1.86 (m, 1H), 1.83–1.70 (m,
2H), 1.45 (s, 3H), 0.99 (d, J ¼ 5.8 Hz, 3H), 0.82 (d, J ¼ 7.3 Hz,
3H); Anal. calcd. for C33H39NO9S (in %): C, 63.34; H, 6.28; N,
2.24; Found: C, 63.32; H, 6.34; N, 2.23.
(10S)-N-{4-[3-(3,4-Difluorophenyl)-2-(E)-
propenoyl]phenyloxyacetyl}aminodihydroartemisinin 11c
(10R)-N-{4-[3-(4-Chloro-2-fluorophenyl)-2-(E)-
propenoyl]phenyloxyacetyl}aminodihydroartemisinin 10f
This compound was obtained as pale yellow solid in 82% yield.
:
M.p.: 108–1118C; MS (ESI) m/z: 606.2 (M þ Na)þ; IR (KBr) cmꢀ1
This compound was obtained as pale yellow solid in 71% yield.
:
3423.3, 2926.9, 2874.0, 1662.9, 1602.3, 1514.8, 1276.3, 1222.4,
1173.4, 1115.3, 1038.4, 823.6, 519.1; 1H-NMR (300 MHz, CDCl3)
d: 8.08 (d, J ¼ 8.9 Hz, 2H), 7.73 (d, J ¼ 15.6 Hz, 1H), 7.46
(d, J ¼ 15.6 Hz, 1H), 7.42–7.31 (m, 1H), 7.25–7.13 (m, 2H), 7.07
(d, J ¼ 8.9 Hz, 2H), 5.47 (t, J ¼ 10.2 Hz, 1H), 4.62 (s, 2H), 2.53–2.27
(m, 2H), 2.13–1.98 (m, 1H), 1.99–1.84 (m, 1H), 1.84–1.70 (m, 2H),
1.45 (s, 3H), 1.00 (d, J ¼ 5.9 Hz, 3H), 0.82 (d, J ¼ 7.2 Hz, 3H); Anal.
calcd. for C32H35F2NO7 (in %): C, 65.85; H, 6.04; N, 2.40; Found: C,
65.77; H, 6.09; N, 2.36.
M.p.: 111–1138C; MS (ESI) m/z: 622.1 (M þ Na)þ; IR (KBr) cmꢀ1
3421.7, 2925.2, 2853.0, 1663.9, 1627.4, 1601.9, 1509.0, 1258.4,
1152.9, 1038.4, 856.1, 811.6, 530.1; 1H-NMR (300 MHz, DMSO-d6)
d: 8.94 (d, J ¼ 9.1 Hz, 1H), 8.32 (dd, J ¼ 8.7, 6.3 Hz, 1H), 8.19 (d,
J ¼ 8.7 Hz, 2H), 8.01 (d, J ¼ 15.6 Hz, 1H), 7.94 (d, J ¼ 15.5 Hz, 1H),
7.59 (dd, J ¼ 8.8, 2.4 Hz, 1H), 7.38 (td, J ¼ 8.6, 2.6 Hz, 1H), 7.11 (d,
J ¼ 8.7 Hz, 2H), 5.47 (s, 1H), 5.16 (t, J ¼ 9.8 Hz, 1H), 4.72 (s, 2H),
2.46–2.34 (m, 1H), 2.19 (td, J ¼ 14.5, 3.8 Hz, 1H), 2.04–1.93
(m, 1H), 1.88–1.74 (m, 1H), 1.28 (s, 3H), 0.89 (d, J ¼ 6.2 Hz, 3H),
0.71 (d, J ¼ 7.0 Hz, 3H); Anal. calcd. for C32H35ClFNO7 (in %): C,
64.05; H, 5.88; N, 2.33; Found: C, 64.02; H, 5.93; N, 2.35.
(10S)-N-{4-[3-(4-Pyridyl)-2-(E)-
propenoyl]phenyloxyacetyl}aminodihydroartemisinin 11d
This compound was obtained as pale yellow solid in 69% yield.
:
M.p.: 119–1218C; MS (ESI) m/z: 571.1 (M þ Na)þ; IR (KBr) cmꢀ1
(10R)-N-{4-[3-(2,3-Dichlorophenyl)-2-(E)-
propenoyl]phenyloxyacetyl}aminodihydroartemisinin 10g
3422.5, 2923.7, 2864.3, 1662.7, 1612.8, 1524.8, 1276.3, 1235.4,
1161.6, 1125.3, 1038.4, 828.6, 519.3; 1H-NMR (300 MHz, CDCl3) d:
8.71 (d, J ¼ 5.1 Hz, 2H), 8.11–8.05 (m, 3H), 7.67 (d, J ¼ 16.8 Hz,
1H), 7.49 (d, J ¼ 5.0 Hz, 2H), 7.07 (d, J ¼ 8.9 Hz, 2H), 5.52–5.41 (m,
2H), 4.62 (s, 2H), 2.52–2.31 (m, 2H), 2.11–2.00 (m, 1H), 1.97–1.86
(m, 1H), 1.83–1.70 (m, 2H), 1.44 (s, 3H), 0.98 (d, J ¼ 5.9 Hz, 3H),
0.81 (d, J ¼ 7.2 Hz, 3H); Anal. calcd. for C31H36N2O7 (in %): C,
67.87; H, 6.61; N, 5.11; Found: C, 67.82; H, 6.73; N, 5.08
This compound was obtained as pale yellow solid in 81% yield.
M.p.: 111–1138C; MS (ESI) m/z: 638.2 (M þ Na)þ; IR (KBr) cmꢀ1
:
3420.2, 2926.9, 2874.0, 1655.8, 1598.5, 1531.5, 1500.4, 1421.4,
1
1226.8, 1220.4, 1173.9, 1038.5, 773.4, 596.3; H-NMR (300 MHz,
CDCl3) d: 8.18 (d, J ¼ 15.7 Hz, 1H), 8.08 (d, J ¼ 8.9 Hz, 2H), 7.67
(dd, J ¼ 7.9, 1.3 Hz, 1H), 7.53 (dd, J ¼ 8.0, 1.4 Hz, 1H), 7.47
(d, J ¼ 15.7 Hz, 1H), 7.12–7.03 (m, 3H), 5.52–5.40 (m, 2H), 4.62
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Arch. Pharm. Chem. Life Sci. 2011, 344, 639–647
Novel Artemisinin–Chalcone Hybrids
645
(10S)-N-{4-[3-(4-Methylsulfonylphenyl)-2-(E)-propenoyl]-
phenyloxyacetyl}aminodihydroartemisinin 11e
(10R)-N-{4-[(1E)-3-Oxo-3-(4-fluorophenyl)prop-1-en-1-yl]-
phenyloxyacetyl}aminodihydroartemisinin 12b
This compound was obtained as pale yellow solid in 81% yield.
:
This compound was obtained as pale yellow solid in 70% yield.
:
M.p.: 111–1138C; MS (ESI) m/z: 648.1 (M þ Na)þ; IR (KBr) cmꢀ1
M.p.: 111–1138C; MS (ESI) m/z: 588.4 (M þ Na)þ; IR (KBr) cmꢀ1
3423.9, 2925.9, 2872.9, 1662.1, 1598.7, 1533.7, 1380.5,
1307.4, 1222.6, 1171.5, 1148.2, 1038.2, 825.9, 548.6; 1H-NMR
(300 MHz, CDCl3) d: 8.06–7.96 (m, 3H), 7.84 (d, J ¼ 8.3 Hz, 2H),
7.65 (d, J ¼ 15.9 Hz, 1H), 7.58 (d, J ¼ 8.4 Hz, 2H), 7.00
(d, J ¼ 8.8 Hz, 2H), 5.46 (t, J ¼ 3.5 Hz, 1H), 4.59 (s, 2H), 3.03
(s, 3H), 2.52–2.31 (m, 2H), 2.11–2.00 (m, 1H), 1.98–1.87 (m, 1H),
1.85–1.71 (m, 2H), 1.44 (s, 3H), 0.99 (d, J ¼ 5.9 Hz, 3H),
0.80 (d, J ¼ 7.3 Hz, 3H); Anal. calcd. for C33H39NO9S (in %):
C, 63.34; H, 6.28; N, 2.24; Found: C, 63.27; H, 2.37; N,
2.16.
3421.2, 2925.8, 1693.6, 1663.7, 1591.1, 1508.3, 1447.2, 1253.6,
1189.5, 1038.4, 819.3, 707.8, 547.3; 1H-NMR (300 MHz, DMSO-d6)
d: 8.89 (d, J ¼ 9.2 Hz, 1H), 8.29–8.21 (m, 2H), 7.87 (d, J ¼ 8.8 Hz,
2H), 7.84 (d, J ¼ 15.4 Hz, 1H), 7.72 (d, J ¼ 15.5 Hz, 1H), 7.39
(t, J ¼ 8.9 Hz, 2H), 7.04 (d, J ¼ 8.8 Hz, 2H), 5.47 (s, 1H), 5.17
(t, J ¼ 9.8 Hz, 1H), 4.66 (s, 2H), 2.48–2.37 (m, 1H), 2.19 (td,
J ¼ 14.1, 3.5 Hz, 1H), 2.04–1.95 (m, 1H), 1.86–1.75 (m, 1H), 1.29
(s, 3H), 0.89 (d, J ¼ 6.3 Hz, 3H), 0.71 (d, J ¼ 7.1 Hz, 3H); Anal.
calcd. for C32H36FNO7 (in %): C, 67.95; H, 6.42; N, 2.48; Found: C,
67.89; H, 6.53; N, 2.42.
(10S)-N-{4-[3-(4-Chloro-2-fluorophenyl)-2-(E)-propenoyl]-
phenyloxyacetyl}aminodihydroartemisinin 11f
(10R)-N-{4-[(1E)-3-Oxo-3-(3-chlorophenyl)prop-1-en-1-yl]-
phenyloxyacetyl}aminodihydroartemisinin 12c
This compound was obtained as pale yellow solid in 89% yield.
:
This compound was obtained as pale yellow solid in 78% yield.
:
M.p.: 98–1018C; MS (ESI) m/z: 622.2 (M þ Na)þ; IR (KBr) cmꢀ1
M.p.: 114–1168C; MS (ESI) m/z: 604.1 (M þ Na)þ; IR (KBr) cmꢀ1
3423.6, 2927.0, 2873.8, 1663.0, 1599.6, 1532.7, 1508.3,
1487.3, 1235.8, 1172.9, 1115.2, 1039.9, 878.6, 542.3; 1H-NMR
(300 MHz, CDCl3) d: 8.13 (d, J ¼ 15.8 Hz, 1H), 8.07
(d, J ¼ 8.8 Hz, 2H), 7.92 (d, J ¼ 8.9 Hz, 1H), 7.83–7.73 (m, 1H),
7.45 (d, J ¼ 15.7 Hz, 1H), 7.07 (d, J ¼ 8.8 Hz, 2H), 6.94
(d, J ¼ 8.9 Hz, 1H), 5.51–5.39 (m, 2H), 4.62 (s, 2H), 2.52–2.32
(m, 2H), 2.11–2.00 (m, 1H), 1.98–1.86 (m, 1H), 1.83–1.71
(m, 2H), 1.45 (s, 3H), 0.99 (d, J ¼ 5.9 Hz, 4H), 0.81
(d, J ¼ 7.3 Hz, 3H); Anal. calcd. for C32H35ClFNO7 (in %):
C, 64.05; H, 5.88; N, 2.33; Found: C, 64.03; H, 5.98; N, 2.26.
3420.1, 2925.3, 1692.4, 1663.2, 1596.7, 1508.1, 1443.6, 1253.4,
1208.9, 1175.9, 1039.0, 827.9, 703.3, 547.8; 1H-NMR (300 MHz,
DMSO-d6) d: 8.90 (d, J ¼ 9.1 Hz, 1H), 8.19 (s, 1H), 8.10 (d,
J ¼ 7.8 Hz, 1H), 7.90 (d, J ¼ 8.8 Hz, 2H), 7.85 (d, J ¼ 15.5 Hz,
1H), 7.80–7.71 (m, 2H), 7.60 (t, J ¼ 7.9 Hz, 1H), 7.04 (d,
J ¼ 8.8 Hz, 2H), 5.47 (s, 1H), 5.17 (t, J ¼ 9.8 Hz, 1H), 4.66 (s,
2H), 2.47–2.36 (m, 1H), 2.19 (td, J ¼ 13.8, 3.8 Hz, 1H), 2.04–1.94
(m, 1H), 1.87–1.75 (m, 1H), 1.29 (s, 3H), 0.89 (d, J ¼ 6.3 Hz, 3H),
0.71 (d, J ¼ 7.1 Hz, 3H); Anal. calcd. for C32H36ClNO7 (in %): C,
66.03; H, 6.23; Cl, 6.09; N, 2.41; Found: C, 66.00; H, 6.34; N, 2.32.
(10S)-N-{4-[3-(2,3,4-Trimethoxyphenyl)-2-(E)-propenoyl]-
phenyloxyacetyl}aminodihydroartemisinin 11g
(10R)-N-{4-[(19E)-3-Oxo-3-phenylprop-1-en-1-yl]-
phenyloxyacetyl}aminodihydroartemisinin 12d
This compound was obtained as yellow solid in 87% yield. M.p.:
103–1058C; MS (ESI) m/z: 660.2 (M þ Na)þ; IR (KBr) cmꢀ1: 3419.9,
2926.4, 2874.7, 1682.6, 1661.5, 1608.3, 1502.0, 1317.6, 1216.1,
1168.2, 1117.5, 1038.58, 767.7, 560.1; 1H-NMR (300 MHz, CDCl3)
d: 8.07 (d, J ¼ 8.8 Hz, 2H), 8.01 (d, J ¼ 15.8 Hz, 1H), 7.57 (d,
J ¼ 15.8 Hz, 1H), 7.41 (d, J ¼ 8.8 Hz, 1H), 7.05 (d, J ¼ 8.9 Hz,
2H), 6.74 (d, J ¼ 8.8 Hz,1H), 5.52–5.41 (m, 2H), 4.61 (s, 2H),
3.97 (s, 3H), 3.93 (s, 3H), 3.91 (s, 3H), 2.54–2.32 (m, 2H), 2.11–
2.00 (m, 1H), 1.98–1.85 (m, 1H), 1.83–1.71 (m, 2H), 1.45 (s, 3H),
0.99 (d, J ¼ 5.9 Hz, 3H), 0.81 (d, J ¼ 7.1 Hz, 3H); Anal. calcd. for
C35H43NO10 (in %): C, 65.92; H, 6.80; N, 2.20; Found: C, 65.87; H,
6.82; N, 2.18.
This compound was obtained as pale yellow solid in 73% yield.
:
M.p.: 103–1058C; MS (ESI) m/z: 570.1 (M þ Na)þ; IR (KBr) cmꢀ1
3421.5, 2923.8, 1684.5, 1658.3, 1596.5, 1508.4, 1448.9, 1252.2,
1216.6, 1174.4, 1038.1, 828.3, 696.7, 546.4; 1H-NMR (300 MHz,
DMSO-d6) d: 8.90 (d, J ¼ 9.1 Hz, 1H), 8.14 (d, J ¼ 7.4 Hz, 2H), 7.87
(d, J ¼ 8.1 Hz, 2H), 7.83 (d, J ¼ 15.6 Hz, 1H), 7.72 (d, J ¼ 15.7 Hz,
1H), 7.72–7.62 (m, 1H), 7.62–7.52 (m, 2H), 7.04 (d, J ¼ 8.5 Hz, 2H),
5.47 (s, 1H), 5.17 (t, J ¼ 9.8 Hz, 1H), 4.66 (s, 2H), 2.44–2.36 (m, 1H),
2.19 (td, J ¼ 13.6, 2.5 Hz, 1H), 2.04–1.94 (m, 1H), 1.87–1.74 (m,
1H), 1.28 (s, 3H), 0.89 (d, J ¼ 5.6 Hz, 3H), 0.71 (d, J ¼ 6.9 Hz, 3H);
Anal. calcd. for C32H37NO7 (in %): C, 70.18; H, 6.81; N, 2.56; Found:
C, 70.16; H, 6.85; N, 2.52.
(10R)-N-{4-[(1E)-3-Oxo-3-(4-chlorophenyl)prop-1-en-1-yl]-
phenyloxyacetyl}aminodihydroartemisinin 12a
(10R)-N-{4-[(1E)-3-Oxo-3-(4-trifluoromethylphenyl)prop-
1-en-1-yl]phenyloxyacetyl}aminodihydroartemisinin 12e
This compound was obtained as pale yellow solid in 75% yield.
:
This compound was obtained as pale yellow solid in 81% yield.
M.p.: 118–1218C; MS (ESI) m/z: 638.4 (M þ Na)þ; IR (KBr) cmꢀ1
1
1251.6, 1202.3, 1170.4, 1037.8, 829.0, 542.9; H-NMR (300 MHz,
DMSO-d6) d: 8.90 (d, J ¼ 9.0 Hz, 1H), 8.32 (d, J ¼ 8.1 Hz, 2H),
7.94 (d, J ¼ 8.4 Hz, 2H), 7.89 (d, J ¼ 8.8 Hz, 2H), 7.84 (d,
J ¼ 15.7 Hz, 1H), 7.76 (d, J ¼ 15.6 Hz, 1H), 7.05 (d, J ¼ 8.7 Hz,
2H), 5.47 (s, 1H), 5.17 (t, J ¼ 9.7 Hz, 1H), 4.66 (s, 2H), 3.27–3.27 (m,
1H), 2.47–2.36 (m, 1H), 2.19 (td, J ¼ 14.2, 3.7 Hz, 1H), 2.05–1.94
(m, 1H), 1.85–1.75 (m, 1H), 1.28 (s, 3H), 0.89 (d, J ¼ 6.3 Hz, 3H),
0.71 (d, J ¼ 7.1 Hz, 3H); Anal. calcd. for C33H36F3NO7 (in %): C,
64.38; H, 5.89; N, 2.28; O, 18.19 Found: C, 64.32; H, 5.93; N, 2.26.
M.p.: 106–1098C; MS (ESI) m/z: 604.4 (M þ Na)þ; IR (KBr) cmꢀ1
:
3422.1, 2925.6, 1690.3, 1666.1, 1597.4, 1593.8, 1508.2, 1451.5,
3421.1, 2924.4, 1688.5, 1662.9, 1593.6, 1508.7, 1463.0, 1256.3,
1201.9, 1038.8, 828.4, 705.9, 548.7; 1H-NMR (300 MHz, DMSO-d6)
d: 8.89 (d, J ¼ 9.3 Hz, 1H), 8.17 (d, J ¼ 8.6 Hz, 2H), 7.88 (d,
J ¼ 8.8 Hz, 2H), 7.83 (d, J ¼ 15.6 Hz, 1H), 7.73 (d, J ¼ 15.5 Hz,
1H), 7.64 (d, J ¼ 8.6 Hz, 2H), 7.04 (d, J ¼ 8.8 Hz, 2H), 5.47 (s, 1H),
5.17 (t, J ¼ 9.8 Hz, 1H), 4.66 (s, 2H), 2.47–2.37 (m, 1H), 2.19 (td,
J ¼ 14.3, 3.8 Hz, 1H), 2.04–1.94 (m, 1H), 1.86–1.75 (m, 1H), 1.28 (s,
3H), 0.89 (d, J ¼ 6.3 Hz, 3H), 0.71 (d, J ¼ 7.1 Hz, 3H); Anal. calcd.
for C32H36ClNO7 (in %): C, 66.03; H, 6.23; N, 2.41; Found: C, 66.04;
H, 6.31; N, 2.32.
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www.archpharm.com

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L. Xie et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 639–647
wavelength) was measured with the ELISA reader. All of the
compounds were tested twice in each of the cell lines. The results
expressed as IC50 (inhibitory concentration 50%) were the aver-
ages of two determinations and calculated by using the Bacus
Laboratories Incorporated Slide Scanner (Bliss) software.
(10R)-N-{4-[(1E)-3-Oxo-3-(3-methoxyphenyl)prop-1-en-1-
yl]phenyloxyacetyl}aminodihydroartemisinin 12f
This compound was obtained as yellow solid in 75% yield. M.p.:
117–1198C; MS (ESI) m/z: 600.1 (M þ Na)þ; IR (KBr) cmꢀ1: 3420.6,
2926.4, 1691.5, 1661.6, 1592.5, 1508.4, 1450.2, 1252.5, 1174.4,
1
1037.3, 827.8, 740.2, 549.9; H-NMR (300 MHz, DMSO-d6) d: 8.89
This work was supported by the National S&T Major Project of China (No.
2009ZX09301-012)
(d, J ¼ 9.1 Hz, 1H), 7.88 (d, J ¼ 8.7 Hz, 2H), 7.81 (d, J ¼ 15.6 Hz,
1H), 7.78–7.67 (m, 2H), 7.60 (s, 1H), 7.49 (t, J ¼ 8.0 Hz, 1H), 7.23
(dd, J ¼ 8.2, 2.0 Hz, 1H), 7.04 (d, J ¼ 8.7 Hz, 2H), 5.47 (s, 1H), 5.17
(t, J ¼ 9.8 Hz, 1H), 4.66 (s, 2H), 3.86 (s, 3H), 2.47–2.38 (m, 1H),
2.26–2.12 (m, 1H), 2.05–1.92 (m, 1H), 1.86–1.75 (m, 1H), 1.29
(s, 3H), 0.89 (d, J ¼ 6.2 Hz, 3H), 0.71 (d, J ¼ 7.1 Hz, 3H); Anal.
calcd. for C33H39NO8 (in %): C, 68.61; H, 6.80; N, 2.42; Found: C,
68.60; H, 6.83; N, 2.42.
The authors have declared no conflict of interest.
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:
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