Synthetic Modification of 9α- and 9β-Hydroxyparthenolide by Heck or Acylation Reactions and Evaluation of Cytotoxic Activities

Article abstract of DOI:10.1055/s-0042-119864

Motivated by the widely reported anticancer activity of parthenolides and their derivatives, a series of new substituted parthenolides was efficiently synthesized. Structural modifications were performed at the C-9 and C-13 positions of 9α- and 9β-hydroxyparthenolide, which were isolated from the aerial parts of Anvillea radiata. Twenty-one derivatives were synthesized and evaluated for their in vitro cytotoxic activity against HS-683, SK-MEL-28, A549, and MCF-7 human cancer cell lines using the MTT colorimetric assay. Among the derivatives, seven exhibited excellent activity compared to 5-fluorouracil and etoposide against the four cell lines tested, with IC₅₀ values ranging from 1.1 to 9.4 μM.

Full text of DOI:10.1055/s-0042-119864

Original Papers
Synthetic Modification of 9α- and 9β-Hydroxyparthe-
nolide by Heck or Acylation Reactions and Evaluation of
Cytotoxic Activities
Authors
Abderrahman El Bouakher1, Badr Jismy1, Hassan Allouchi3, Eric Duverger4, Latifa Barkaoui1, Ahmed El Hakmaoui1,
Richard Daniellou2, Gérald Guillaumet2, Mohamed Akssira1
Affiliations
The affiliations are listed at the end of the article
Key words
Abstract
evaluated for their in vitro cytotoxic activity
against HS-683, SK‑MEL‑28, A549, and MCF-7 hu-
man cancer cell lines using the MTT colorimetric
assay. Among the derivatives, seven exhibited ex-
cellent activity compared to 5-fluorouracil and
etoposide against the four cell lines tested, with
IC50 values ranging from 1.1 to 9.4 µM.
"
l Anvillea radiate
!
"
l Asteraceae
Motivated by the widely reported anticancer ac-
tivity of parthenolides and their derivatives, a se-
ries of new substituted parthenolides was effi-
ciently synthesized. Structural modifications
were performed at the C-9 and C-13 positions of
9α- and 9β-hydroxyparthenolide, which were
isolated from the aerial parts of Anvillea radiata.
Twenty-one derivatives were synthesized and
"
l acylation
"
l cytotoxic activity
"
l Heck coupling
"
l 9α‑hydroxyparthenolide
"
l 9β‑hydroxyparthenolide
Supporting information available online at
http://www.thieme-connect.de/products
received
revised
accepted
April 13, 2016
October 12, 2016
October 20, 2016
Bibliography
DOI http://dx.doi.org/
10.1055/s-0042-119864
Published online
Planta Med © Georg Thieme
Verlag KG Stuttgart · New York ·
ISSN 0032‑0943
Introduction
widely used approach for obtaining novel thera-
!
peutic agents in medicinal chemistry [5–7]. Par-
"
Cancer is considered one of the most serious
health problems and a leading cause of death
worldwide [1–3]. Most conventional anticancer
drugs have substantial side effects as a result of
their lack of selectivity between cancer cells and
normal cells [4]. This clearly underlines the ur-
gent need to develop novel chemotherapeutic
agents with higher bioactivity and fewer side ef-
fects. A large number of biologically active com-
pounds have been obtained from plants. The
functionalization of natural products is the most
thenolide I (l Fig. 1) was first isolated from dried,
ground Chrysanthemum parthenium by Soucek et
al. [8]. It was shown to be a sesquiterpene lactone
of the germacrane type and a privileged natural
product with a wide range of biological activities
[9,10]. For example, in traditional herbal medi-
cine, it has been used for the treatment of fever,
migraine, and arthritis as well as as an anti-in-
flammatory agent for centuries [11–13]. Recently,
parthenolide and its sesquiterpene lactones were
investigated for the treatment of several cancers
Correspondence
Prof Mohamed Akssira
Laboratoire de Chimie Physique
& de Chimie Bioorganique,
URAC 22
Université Hassan II Casablanca
BP 146
28800 Mohammedia
Morocco
Phone: + 212523315353
Fax: + 212523315353
akssira@fstm.ac.ma
El Bouakher A et al. Synthetic Modification of… Planta Med

Original Papers
[14–18]. The anticancer properties of this drug have been associ-
ated to its ability to inhibit the transcription factor NF-κB, which
is known to control multiple tumor-related processes such as in-
flammation, proliferation, angiogenesis, and metastasis [19–21].
However, parthenolide I is poorly soluble in water, which limits
"
its potential therapeutic use in humans [22]. DMAPT II (l Fig. 1),
the water-soluble dimethylamino Michael adduct of partheno-
lide I, has entered preclinical or clinical trials for the treatment
of acute myeloid leukemia (AML), acute lymphoblastic leukemia
(ALL), and chronic lymphocytic leukemia (CLL) in the United King-
dom [23,24]. Despite this progress, improvements in partheno-
lide anticancer potency have not been achieved to date.
In a previous paper [25], we reported the synthesis and anti-
cancer activity evaluation of a series of their 9-hydroxy and 1β-
10α-epoxy analogs of types III, IV, and V (l Fig. 1). However, the
Fig. 1 Some bioactive parthenolide derivatives and target molecules.
"
activity of these derivatives was found to be no better than that of
their parent compounds 9α- and 9β-hydroxyparthenolide 1 and
2. The latter were isolated in gram-scale from Anvillea radiate,
which is a wild plant found mainly in the steppes of North Africa
(Morocco and Algeria) and a renewable source of 9α- and 9β-hy-
droxyparthenolide 1 and 2 [26]. Recently, it was reported that
structural modifications at the C9 positions of parthenolide led
to derivatives possessing increased antitumor activity [27]. In
fact, 9β-hydroxyparthenolide 2 was synthetized by C-9 hydroxyl-
ation of parthenolide I using enzymatic oxidation. The isolated
hydroxylation product 2 was then further processed to generate
a panel of 9-substituted parthenolide derivatives, with potent ac-
tivity and high selectivity against AML cells, using direct acyla-
tion of 2 with acyl chloride reagents [27].
Fig. 2 Acylation of 9α- and 9β-hydroxyparthenolides (1 and 2).
We believe that the anticancer properties of 9-hydroxypartheno-
lide derivatives depend on the structural modifications at the C9
positions and the presence of the α-methylene-γ-lactone moiety.
We report herein the synthesis and in vitro anticancer evaluation
of novel C9- and C13- substituted parthenolides of type VI, VII,
"
and VIII (l Fig. 1) with a view to producing promising anticancer
agents.
Results and Discussion
!
The 9α- and 9β-hydroxyparthenolide 1 and 2 were extracted
from the aerial parts of naturally occurring A. radiata by soxhlet
extraction using ethyl acetate. The concentrated ethyl acetate ex-
tract was subjected to column chromatography over silica gel us-
ing hexane/ethyl acetate (9/1 up to 6/4) to yield 9α- and 9β-hy-
droxyparthenolide 1 and 2. The structure modification of 9α-
and 9β-hydroxyparthenolide 1 and 2, used as the leading com-
pounds, was done at positions C9 and C13.
In our previous report, it was shown that the addition of amines
[25] or azide [28] to the α-methylene-γ-lactone of 9-hydroxypar-
thenolide via Michael addition reactions led to a decrease in anti-
tumor activity. This result demonstrated that the α-methylene-γ-
lactone is responsible for the cytotoxic activity.
Based on these observations, we herein report the synthesis and
in vitro anticancer evaluation of C9-substituted parthenolides
(using acylation or arylation reactions), C13-substituted 9α-hy-
droxyparthenolides (using the Heck reaction to keep the α-meth-
ylene-γ-lactone moiety) and C9,C13-disubstituted parthenolides.
9α- and 9β-Hydroxyparthenolide 1 and 2 were reacted with ace-
tic anhydride or aryl chloride in a mixture of dichloromethane/
pyridine (9:1) at room temperature for 12 h to give the C9-sub-
Fig. 3 Heck couplings with 9α-hydroxyparthenolide 1 and aryl iodides.
stituted parthenolides 3–11 in high yields after purification
"
(l Fig. 2).
The palladium-catalyzed arylation of the α-methylene-γ-lactone
of 9α-hydroxyparthenolide 1 was shown to produce E-olefinic
coupling products selectively in good yields (60–75%). Novel E-
olefinic coupling products of 9α-hydroxyparthenolide 1 were
prepared under Heck reaction conditions utilizing palladium (II)
acetate as the catalyst in DMF and heating the mixture with an
appropriate iodo-aromatic compound in the presence of triethyl-
amine for 24 h [29]. After purification by column chromatogra-
phy, C13-substituted 9α-hydroxyparthenolides 12–19 were iso-
"
lated in good yields (l Fig. 3). The E-olefin for compound 12 was
"
verified using X‑ray diffraction (l Fig. 4). The H13 vinyl proton of
compounds 12–19 had a chemical shift between 7.46–7.93 ppm.
To prepare C9, C13-disubstituted parthenolides 20–23, com-
El Bouakher A et al. Synthetic Modification of… Planta Med

Original Papers
pounds 12–15 were acetylated using 1.3 equivalents of acetic an-
hydride in a mixture of dichloromethane and pyridine (9:1) at
room temperature for 12 h. The desired compounds 20–23 were
obtained in good yields (70–82%) after purification by column
"
chromatography (l Fig. 5).
In view of the cytotoxic potential of parthenolide derivatives, the
new compounds 4–23 were screened for their cytotoxicity
against HS-683 (glioma cancer), SK‑MEL‑28 (melanoma cancer),
A549 (Lung cancer), and MCF-7 (breast cancer) cell lines in vitro
using the MTT assay. The results of cytotoxicity are expressed as
the IC50 (µM). Etoposide and 5-fluorouracil were used as positive
"
controls. The results are reported in terms of IC50 values in l Ta-
ble 1. The c logP values for these compounds were calculated us-
"
ing ChemBioDraw Ultra v.12 software (l Table 1). Compounds 4–
11 showed excellent antiproliferative effects. Among them, com-
pounds 4–8, 10, and 11 displayed potent inhibitory activities,
which were more potent than those of the positive control 5-
fluorouracil against HS-683, A549, and MCF-7 cells. The 9α-(2-
fluorobenzoyloxy)parthenolide 5 was the most potent against
HS-683 cells (IC50 = 5.5 µM), SK‑MEL‑28 (IC50 = 4.1 µM), and
A549 cells (IC50 = 4.6 µM), while it exhibited excellent activity
against MCF-7 cells (IC50 = 2.1 µM). Conversely, 9β-(2-fluoroben-
zoyloxy)parthenolide 9 was less active than the stereoisomer 9α-
Fig. 4 ORTEP of compound 12 (probability 50%). (Color figure available
online only.)
(2-fluorobenzoyloxy)parthenolide
5 with an IC50 value of
19.4 µM for HS-683, 11.5 µM for SK‑MEL‑28, and 11.2 µM for
A549 cells. Compound 9 exhibited similar activity to 5 against
MCF-7 (IC50 = 2.0 µM).
9α-Hydroxyparthenolide 1 was of particular interest to us, be-
cause it is a valuable intermediate, not accessible via currently
available synthetic methods. Compared with 9α-substituted-
oxyparthenolide derivatives 4–7, 9β-substituted-oxypartheno-
lide derivatives 8–11 displayed lower antiproliferative activities.
Fig. 5 Acetylation of 9α-hydroxy-13-substituted parthenolides.
"
As shown in l Table 1, C13-substituted-9α-hydroxyparthenolide
derivatives 12–19 exhibited a large decrease or complete loss of
cytotoxic activity compared with 9α-substituted-oxypartheno-
lides 4–7 or 9α-hydroxyparthenolide 1 [25].
Material and Methods
!
Compounds 12–15 were acetylated to obtain C13-substituted-
9α-acetoxyparthenolide derivatives 20–23. As expected, the anti-
proliferative effects of compounds 20–23 were not improved in
General experimental procedures
1H NMR and 13C NMR spectra were recorded on a Bruker DPX
400 MHz instrument using CDCl3. The chemical shifts are re-
ported in parts per million (δ scale) and all coupling constant (J)
values are in Hertz (Hz). The following abbreviations were used
to explain the multiplicities: s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), and dd (doublet doublet). Melting points
are uncorrected. HRMS were recorded on a Bruker maXis mass
spectrometer. Monitoring of the reactions was performed using
silica gel TLC plates (silica Merck 60 F254). Spots were visualized
on TLC plates under UV or by heating silica gel plates sprayed
with 5% phosphomolibdic acid in EtOH. Column chromatogra-
phies were performed using silica gel 60 (0.063–0.200 mm,
Merck).
"
comparison with compounds 12–19 (l Table 1).
This result confirms that the α-methylene-γ-lactone moiety un-
substituted at C13-position is very important for cytotoxic activ-
ity. It is also critical for mediating parthenolide pharmacological
effects, serving as an electrophilic center in Michael-type addi-
tion reactions with sulphydryl groups in the various cellular
components (e.g., NF-κB, IκK, glutathione) targeted by the mole-
cule [27,30].
In conclusion, a series of C9-, C13-substituted-9α-hydroxypar-
thenolide and C9, C13-disubstituted parthenolide derivatives
were efficiently synthesized and tested for their cytotoxic activ-
ities against four human cancer cell lines. In vitro bioassays dem-
onstrated that C9-substituted parthenolide derivatives 4–11 dis-
played good to excellent cytotoxic activities against HS-683
(IC50 = 5.5 µM as compound 5), SK‑MEL‑28 (IC50 = 4.1 µM as com-
pound 5), A549 (IC50 = 4.6 µM as compound 5), and MCF-7 cell
lines (IC50 = 1.1 µM as compounds 11 and 4). We have shown that
the modifications of 9α-hydroxyparthenolide at the C13 position
led to a decrease in its cytotoxicity, and that the α-methylene-γ-
lactone moiety free at the C13 position is necessary for activity.
Further structural optimization of substituted-parthenolide de-
rivatives is well under way with the aim of improving their level
of antitumor potency.
Plant material
The aerial parts of A. radiata (Coss. & Durieu) were collected by
the team of Professor El Oualidi Jalal during the flowering period
in May 2011 (second week) from Errachidia Road P21, Morocco.
GPS coordinates were: Latitude (32.204086355917944) and
Longitude (− 4.383201599121094). A voucher specimen has
been deposited in the Herbarium of the Scientific Institute, Rabat,
Morocco (No. RAB9913). The harvested parts were screened and
freed of contaminating portions and then shade dried at room
temperature. After drying, the plant material was stocked in the
dark in the lab and was ground to a fine powder using a basic
El Bouakher A et al. Synthetic Modification of… Planta Med

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Table 1 Cytotoxic activity.
N°
4
Human cancer cell lines IC50 (µM)1
c Log P
Compound
HS-683 glioma
SK‑MEL‑28 melanoma
A549 lung cancer
MCF-7 breast cancer
5.9 (0.6–11.2)
5.2 (1.6–8.8)
4.1 (2.9–5.3)
6.3 (2.5–10.1)
5.2 (2.2–8.2)
1.1 (0.7–1.5)
3.11
5
6
5.5 (2.7–8.3)
7.9 (5.5–9.3)
4.6 (3.4–5.8)
5.8 (2.8–8.8)
2.1 (0.1–4.1)
1.2 (0.7–1.7)
3.27
2.98
7
6.2 (3.2–9.2)
7.8 (4.7–10.9)
8.3 (3.3–13.3)
1.4 (0.6–2.2)
3.67
8
9
7.4 (5.3–9.5)
5.7 (3.8–7.6)
5.0 (2.6–7.4)
2.7 (0.2–5.2)
2.0 (1.2–2.8)
1.21
3.27
19.4 (4.4–34.4)
11.5 (8.3–14.7)
11.2 (4.5–16.9)
10
11
8.2 (5.3–10.1)
9.4 (5.8–13.0)
5.7 (3–8.4)
8.9 (6.9–10.9)
7.3 (3.3–11.3)
2.3 (1.4–3.2)
1.1 (0.3–1.9)
2.98
3.67
6.4 (4.1–8.7)
12
13
14
15
16
230 (196–264)
213 (153–273)
175 (149–201)
200 (152–248)
200 (128–272)
200 (152–248)
200 (100–300)
176 (142–210)
2.54
2.70
2.41
2.41
*
*
*
*
*
*
**
**
**
174 (74–274)
200 (100–300)
*
2.41
continued
El Bouakher A et al. Synthetic Modification of… Planta Med

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Table 1 Continued
N°
17
Human cancer cell lines IC50 (µM)1
c Log P
Compound
HS-683 glioma
SK‑MEL‑28 melanoma
A549 lung cancer
MCF-7 breast cancer
180 (130–230)
130 (112–138)
200 (140–260)
*
142 (118–166)
50 (26–74)
134 (72–196)
103 (45–161)
3.02
2.15
1.73
18
19
20
**
*
190 (158–222)
*
*
*
*
163 (47–279)
157 (79–235)
132 (84–180)
169 (85–253)
2.77
2.92
2.64
2.64
21
22
23
*
*
*
160 (152–168)
229 (187–271)
205 (143–267)
**
*
*
Etoposide
4.0 (3.4–4.6)
6.5 (5.5–7.5)
3.0 (2.0–4.0)
3.5 (2.9–4.1)
25.0 (23.4–26.6)
19.5 (15.5–23.5)
5-Fluorouracile
16.7 (1.4–32.0)
13.4 (10.2–16.6)
1IC50 values (µM): drug concentration responsible for the inhibition of 50% of the growth of the specified cell line after 72 h. Values are the geometric mean 50% inhibitory con-
centration; 95% confidence limits are given in brackets. Final DMSO concentration is less than 1% (see experimental part). *Growth reduced by 20–30% at 200 µM. **No growth
inhibition detected at 200 µM.
grinder just before extraction. The air-dried aerial parts of
A. radiata (500 g) were extracted using a soxhlet apparatus with
ethyl acetate. After concentration under reduced pressure, the
residue (30 g, 6%) was chromatographed over a silica gel column
with a gradient of hexane/EtOAc to give 5 g of 9α-hydroxyparthe-
nolide 1 (1%) and 3 g of 9β-hydroxyparthenolide 2 (0.6%).
J = 8.5 Hz, 1H), 3.24 (t, J = 8.0 Hz, 1H), 3.91 (t, J = 8.5 Hz, 1H), 5.22
(d, J = 5.7 Hz, 1H), 5.45 (d, J = 10.8 Hz, 1H), 5.59 (d, J = 3.0 Hz, 1H),
6.35 (d, J = 3.0 Hz, 1H) ppm. 13C NMR (101 MHz, CDCl3) δ 16.4
(CH3, C-14), 17.2 (CH3, C-15), 21.1 (CH3, CH3CO2R), 23.5 (CH2, C-
2), 35.6 (CH2, C-3), 36.1 (CH2, C-8), 38.7 (CH, C-7), 61.3 (Cq, C-4),
66.5 (CH, C-5), 73.2 (CH, C-9), 82.2 (CH, C-6), 121.4 (CH2, C-13),
122.6 (CH, C-1), 133.5 (Cq, C-10), 139.2 (Cq, C-11), 168.9 (CO, C-
12) 169.5 (CO) ppm. IR (ATR diamond): ν = 2932, 1760, 1729,
1376, 1123, 1010, 985 cm−1. HRMS (ESI): calcd. for C17H23O5 [M
+ H]+ 307.1540, found 307.1540.
General procedure to prepare compounds 3–11
Aroyl chloride or acetic anhydride (0.65 mmol) at 0°C was added
to
a solution of 9α- or 9β-hydroxyparthenolide (134 mg,
0.5 mmol) in a dry mixture of CH2Cl2 and pyridine (9:1)
(20 mL). The solution was stirred at room temperature for 12 h
and poured into saturated aqueous NH4Cl (10 mL). The aqueous
phase was extracted with CH2Cl2 (3 × 10 mL), and the combined
organic extracts were washed with brine (10 mL), dried (MgSO4),
and filtered. Concentration of the filtrate followed by column
chromatography (PE-EtOAc, 8:2) provided compounds 3–11 as
a white oil.
9α-Benzoyloxyparthenolide (4)
[α]2D0 − 5.4 (c 1.0, CH2Cl2); yield = 90%; 1H NMR (400 MHz, CDCl3) δ
1.23–1.33 (m, 1H), 1.35 (s, 3H), 1.87 (s, 3H), 2.06–2.32 (m, 3H),
2.39–2.69 (m, 2H), 2.81 (d, J = 8.5Hz, 1H), 3.34–3.49 (m, 1H), 3.97
(t, J = 8.5 Hz, 1H), 5.45 (d, J = 5.7 Hz, 1H), 5.51–5.60 (m, 1H), 5.64
(d, J = 3.5 Hz, 1H), 6.34 (d, J = 3.5 Hz, 1H), 7.44–7.55 (m, 2H),
7.59–7.67 (m, 1H), 8.03–8.08 (m, 2H) ppm. 13C NMR (101 MHz,
CDCl3) δ 16.5 (CH3, C-14), 17.3 (CH3, C-15), 23.5 (CH2, C-2), 35.8
(CH2, C-3), 36.1 (CH2, C-8), 38.9 (CH, C-7), 61.3 (Cq, C-4), 66.7 (CH,
C-5), 73.7 (CH, C-9), 82.2 (CH, C-6), 121.6 (CH2, C-13), 122.7 (CH,
C-1), 128.5 (CHar), 128.7 (CHar), 129.5 (CHar), 129.7 (Car), 130.2
(CHar), 133.6 (Cq, C-10), 133.7 (CHar), 139.2 (Cq, C11), 165.0 (CO),
9α-Acetoxyparthenolide (3)
[α]2D0 – 6.0 (c 1.0, CH2Cl2); yield = 86%; 1H NMR (400 MHz, CDCl3)
δ 1.26–1.30 (m, 1H), 1.32 (s, 3H), 1.79 (s, 3H), 1.94–2.07 (m, 1H),
2.16 (s, 3H), 2.17–2.31 (m, 2H), 2.42–2.52 (m, 2H), 2.76 (d,
El Bouakher A et al. Synthetic Modification of… Planta Med

Original Papers
169.0 (CO, C-12) (ppm. IR (ATR diamond): ν = 2933, 1765, 1722,
1314, 1269, 1177, 1139, 987, 727, 711 cm−1. HRMS (ESI): calcd.
for C22H25O5 [M + H]+ 369.1697, found 369.1696.
5.22 (d, J = 10.8 Hz, 1H), 5.53 (d, J = 10.4 Hz, 1H), 5.71 (d,
J = 3.2 Hz, 1H), 6.38 (d, J = 3.2 Hz, 1H) ppm. 13C NMR (101 MHz,
CDCl3) δ 11.7 (CH3, C-14), 17.3 (CH3, C-15), 21.2 (CH3, CH3CO2R),
23.7 (CH2, C-2), 36.0 (CH2, C-3), 36.1 (CH2, C-8), 44.1 (CH, C-7),
61.3 (Cq, C-4), 66.0 (CH, C-5), 80.7 (CH, C-9), 81.6 (CH, C-6),
121.9 (CH2, C-13), 127.8 (CH, C-1), 133.0 (Cq, C-10), 138.0 (Cq, C-
11), 168.6 (CO, C-12), 170.0 (CO) ppm. IR (ATR diamond):
ν = 2931, 1760, 1724, 1374, 1238, 1126, 1016, 986, 946, 890,
868, 812 cm−1. HRMS (ESI): calcd. for C17H23O5 [M + H]+
307.1540, found 307.1538.
9α-(2-Fluorobenzoyloxy)parthenolide (5)
[α]2D0 − 2.1 (c 1.0, CH2Cl2); yield = 84%; 1H NMR (400 MHz, CDCl3) δ
1.26–1.33 (m, 1H), 1.34 (s, 3H), 1.86 (s, 3H), 2.09–2.30 (m, 3H),
2.51 (qd, J = 13.1, 5.6 Hz, 1H), 2.61 (dd, J = 15.6, 6.0 Hz, 1H), 2.81
(d, J = 8.5 Hz, 1H), 3.38 (t, J = 7.8 Hz, 1H), 3.96 (t, J = 8.5 Hz, 1H),
5.45 (d, J = 5.7 Hz, 1H), 5.54 (d, J = 9.9 Hz, 1H), 5.62 (d, J = 3.2 Hz,
1H), 6.34 (d, J = 3.2 Hz, 1H), 7.32 (td, J = 8.3, 1.0 Hz, 1H), 7.48 (dd,
J = 13.7, 7.8 Hz, 1H), 7.72 (d, J = 9.1 Hz, 1H), 7.85 (d, J = 7.8 Hz,
1H) ppm. 13C NMR (101 MHz, CDCl3) δ 16.6 (CH3, C-14), 17.3
(CH3, C-15), 23.5 (CH2, C-2), 35.8 (CH2, C-3), 36.1 (CH2, C-8), 38.8
(CH, C-7), 61.3 (Cq, C-4), 66.6 (CH, C-5), 74.2 (CH, C-9), 82.2 (CH,
C-6), 116.4 (d, J = 23.0 Hz, CHar), 120.6 (d, J = 21.3 Hz, CHar), 121.6
(CH2, C-13), 122.8 (CH, C-1), 125.2 (d, J = 3.1 Hz, CHar), 130.4 (d,
J = 7.8 Hz, CHar), 131.9 (d, J = 7.4 Hz, Car), 133.4 (Cq, C-10), 139.1
(Cq, C-11), 162.6 (d, J = 247.9 Hz, Car), 163.9 (d, J = 3.0 Hz, CO),
168.9 (CO, C-12) ppm. IR (ATR diamond): ν = 2934, 1766, 1720,
1269, 1234, 1138, 1094, 1013, 910, 796, 755, 727 cm−1. HRMS
(ESI): calcd. for C22H24FO5 [M + H]+ 387.1602, found 387.1602.
9β-(2-Fluorobenzoyloxy)parthenolide (9)
[α]2D0 − 5.2 (c 1.0, CH2Cl2); yield = 77%; 1H NMR (400 MHz, CDCl3) δ
1.27–1.35 (m, 1H), 1.38 (s, 1H), 1.86 (s, 1H), 2.14–2.24 (m, 2H),
2.30–2.39 (m, 2H), 2.53 (qd, J = 13.1, 5.1 Hz, 1H), 2.78 (d,
J = 8.7 Hz, 1H), 3.03 (t, J = 8.3 Hz, 1H), 3.93 (t, J = 8.7 Hz, 1H), 5.48
(d, J = 10.8 Hz, 1H), 5.63 (d, J = 10.3 Hz, 1H), 5.75 (d, J = 3.0 Hz,
1H), 6.40 (d, J = 3.0 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.47 (dd,
J = 13.6, 7.8 Hz, 1H), 7.73 (d, J = 9.1 Hz, 1H), 7.86 (d, J = 7.8 Hz,
1H) ppm. 13C NMR (101 MHz, CDCl3) δ 11.9 (CH3, C-14), 17.4
(CH3, C-15), 23.8 (CH2, C-2), 36.0 (CH2, C-3), 36.1 (CH2, C-8), 44.0
(CH, C-7), 61.3 3 (Cq, C-4), 66.0 (CH, C-5), 81.6 (CH, C-9), 81.7 (CH,
C-6), 116.5 (d, J = 23.0 Hz, CHar), 120.4 (d, J = 21.3 Hz, CHar), 122.1
(CH2, C-13), 125.4 (d, J = 3.1 Hz, CHar), 128.2 (CH, C-1), 130.2 (d,
J = 7.8 Hz, CHar), 132.2 (d, J = 7.4 Hz, Car), 132.8 (Cq, C-10), 137.9
(Cq, C-11), 162.6 (d, J = 247.4 Hz, Car), 164.3 (d, J = 3.0 Hz, CO),
168.6 (CO, C-12) ppm. IR (ATR diamond): ν = 2929, 1769, 1720,
1327, 1313, 1277, 1268, 1251, 1239, 1094, 1021, 978, 965, 944,
889, 793, 748 cm−1. HRMS (ESI): calcd. for C22H24FO5 [M + H]+
387.1602, found 387.1602.
9α-(2-Methoxybenzoyloxy)parthenolide (6)
[α]2D0 − 8.0 (c 1.0, CH2Cl2); yield = 79%; 1H NMR (400 MHz, CDCl3) δ
1.21–1.32 (m, 1H), 1.34 (s, 3H), 1.85 (s, 3H), 2.01–2.30 (m, 3H),
2.40–2.67 (m, 2H), 2.79 (d, J = 9.0 Hz, 1H), 3.43–3.54 (m, 1H),
3.88 (s, 3H), 3.96 (t, J = 9.0 Hz, 1H), 5.45 (d, J = 6.0 Hz, 1H), 5.57–
5.60 (m, 1H), 5.64 (d, J = 3.5 Hz, 1H), 6.34 (d, J = 3.5 Hz, 1H), 7.00–
7.08 (m, 2H), 7.48–7.59 (m, 1H), 7.86 (m, 1H) ppm. 13C NMR
(101 MHz, CDCl3) δ 16.4 (CH3, C-14), 17.3 (CH3, C-15), 23.6 (CH2,
C-2), 35.7 (CH2, C-3), 36.3 (CH2, C-8), 39.0 (CH, C-7), 55.8 (OCH3),
61.3 (Cq, C-4), 66.6 (CH, C-5), 73.8 (CH, C-9), 82.3 (CH, C-6), 112.1
(CHar), 119.4 (Car), 120.4 (CHar), 121.5 (CH2, C-13), 122.9 (CH, C-
1), 132.0 (CHar), 133.3 (Cq, C-10), 134.1 (CHar), 139.3 (Cq, C-11),
159.3 (Car), 165.1 (CO), 169.1 (CO, C-12) ppm. IR (ATR diamond):
ν = 2934, 1765, 1721, 1465, 1489, 1276, 1181, 1165, 1131, 1020,
910, 868, 757, 727 cm−1. HRMS (ESI): calcd. for C23H27O6 [M + H]+
399.1802, found 399.1800.
9β-(2-Methoxybenzoyloxy)parthenolide (10)
[α]2D0 − 12.1 (c 1.0, CH2Cl2); yield = 70%; 1H NMR (400 MHz, CDCl3)
δ 1.23–1.33 (m, 1H), 1.35 (s, 3H), 1.85 (s, 3H), 2.03–2.22 (m, 2H),
2.27–2.37 (m, 2H), 2.51 (qd, J = 13.0, 5.1 Hz, 1H), 2.77 (d, J = 8.8 Hz,
1H), 3.01 (t, J = 8.3 Hz, 1H), 3.88–3.91 (m, 4H), 5.45 (d, J = 10.6 Hz,
1H), 5.58 (d, J = 10.0 Hz, 1H), 5.75 (d, J = 3.0 Hz, 1H), 6.36 (d,
J = 3.0 Hz, 1H), 7.00 (dd, J = 7.9, 4.1 Hz, 2H), 7.51 (t, J = 7.9 Hz, 1H),
7.82 (d, J = 7.9 Hz, 1H) ppm. 13C NMR (101 MHz, CDCl3) δ 11.9
(CH3, C-14), 17.3 (CH3, C-15), 23.8 (CH2, C-2), 36.0 (CH2, C-3),
36.2 (CH2, C-8), 44.1 (CH, C-7), 55.9 (OCH3), 61.3 (Cq, C-4), 66.0
(CH, C-5), 81.1 (CH, C-9), 81.7 (CH, C-6), 112.1 (CHar), 119.7 (Car),
120.2 (CHar), 122.1 (CH2, C-13), 127.6 (CH, C-1), 131.7 (CHar),
133.2 (Cq, C-10), 133.9 (CHar), 138.0 (Cq, C-11), 159.4 (Car), 165.0
(CO), 168.8 (CO, C-12) ppm. IR (ATR diamond): ν = 2933, 1758,
1716, 1437, 1405, 1394, 1336, 1260, 1229, 1201, 1182, 1066,
1021, 898, 787, 765 cm−1. HRMS (ESI): calcd. for C23H27O6 [M +
H]+ 399.1802, found 399.1802.
9α-(3-Chloroybenzoyloxy)parthenolide (7)
[α]2D0 + 1.4 (c 1.0, CH2Cl2); yield = 76%; 1H NMR (400 MHz, CDCl3) δ
1.22–1.32 (m, 1H), 1.34 (s, 3H), 1.86 (s, 3H), 2.09–2.31 (m, 3H),
2.51 (qd, J = 13.1, 5.5 Hz, 1H), 2.62 (dd, J = 15.6, 6.0 Hz, 1H), 2.81
(d, J = 8.5 Hz, 1H), 3.36 (t, J = 7.8 Hz, 1H), 3.96 (t, J = 8.5 Hz, 1H),
5.44 (d, J = 5.7 Hz, 1H), 5.54 (d, J = 10.0 Hz, 1H), 5.63 (d, J = 3.2 Hz,
1H), 6.35 (d, J = 3.2 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.60 (d,
J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 8.00 (s, 1H) ppm. 13C NMR
(101 MHz, CDCl3) δ 16.6 (CH3, C-14), 17.3 (CH3, C-15), 23.5 (CH2,
C-2), 35.8 (CH2, C-3), 36.1 (CH2, C-8), 38.8 (CH, C-7), 61.2 (Cq, C-4),
66.6 (CH, C-5), 74.2 (CH, C-9), 82.2 (CH, C-6), 121.6 (CH2, C-13),
122.9 (CH, C-1), 127.6 (CHar), 129.6 (CHar), 130.1 (CHar), 131.5
(Car), 133.4 (CHar), 133.6 (Cq, C-10), 134.9 (Car), 139.1 (Cq, C-11),
163.9 (CO), 168.8 (CO, C-12) ppm. IR (ATR diamond): ν = 2933,
1766, 1719, 1278, 1253, 1072, 1012, 943, 727 cm−1. HRMS (ESI):
calcd. for C22H24ClO5 [M + H]+ 403.1307, found 403.1306.
9β-(3-Chlorobenzoyloxy)parthenolide (11)
[α]2D0 − 8.9 (c 1.0, CH2Cl2); yield = 80%; 1H NMR (400 MHz, CDCl3) δ
1.23–1.34 (m, 1H), 1.36 (s, 3H), 1.85 (s, 3H), 2.24–2.15 (m, 2H),
2.28–2.37 (m, 2H), 2.52 (qd, J = 13.1, 5.1 Hz, 1H), 2.77 (d,
J = 8.7 Hz, 1H), 3.03 (t, J = 8.3 Hz, 1H), 3.92 (t, J = 8.7 Hz, 1H), 5.47
(d, J = 10.6 Hz, 1H), 5.62 (d, J = 9.9 Hz, 1H), 5.73 (d, J = 3.0 Hz, 1H),
6.37 (d, J = 3.0 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz,
1H), 7.94 (d, J = 8.0 Hz, 1H), 8.01 (s, 1H) ppm. 13C NMR (101 MHz,
CDCl3) δ 11.9 (CH3, C-14), 17.4 (CH3, C-15), 23.8 (CH2, C-2), 36.0
(CH2, C-3), 36.1 (CH2, C-8), 44.0 (CH, C-7), 61.3 (Cq, C-4), 66.0 (CH,
C-5), 81.6 (CH, C-9), 81.7 (CH, C-6), 122.0 (CH2, C-13), 127.7 (CH,
C-1), 128.3 (CHar), 129.6 (CHar), 129.9 (CHar), 131.8 (Car), 132.7
(Cq, C-10), 133.3 (CHar), 134.6 (Car), 137.9 (Cq, C-11), 164.2 (CO),
9β-Acetoxyparthenolide (8)
[α]2D0 − 24.6 (c 1.0, CH2Cl2); yield = 88%; 1H NMR (400 MHz, CDCl3)
δ 1.23–1.31 (m, 1H), 1.34 (s, 3H), 1.76 (s, 3H), 1.97–2.09 (m, 1H),
2.11 (s, 3H), 2.17–2.30 (m, 3H), 2.50 (qd, J = 13.0, 5.1 Hz, 1H), 2.73
(d, J = 8.6 Hz, 1H), 2.94 (t, J = 8.3 Hz, 1H), 3.87 (t, J = 8.6 Hz, 1H),
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168.6 (CO, C-12) ppm. IR (ATR diamond): ν = 2933, 1767, 1716,
1315, 1280, 1253, 1020, 908, 795, 728 cm−1. HRMS (ESI): calcd.
for C22H24ClO5 [M + H]+ 403.1307, found 403.1307.
1H), 5.68 (ddd, J = 12.3, 2.8, 1.3 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H),
7.01 (t, J = 7.6 Hz, 1H), 7.37–7.41 (m, 1H), 7.70 (dd, J = 7.6, 1.2 Hz,
1H), 7.93 (d, J = 3.2 Hz, 1H) ppm. 13C NMR (101 MHz, CDCl3) δ 16.3
(CH3, C-14), 17.5 (CH3, C-15), 23.8 (CH2, C-2), 35.1 (CH2, C-3), 36.0
(CH2, C-8), 37.9 (CH, C-7), 55.8 (OCH3), 61.5 (Cq, C-4), 66.5 (CH, C-
5), 71.8 (CH, C-9), 81.9 (CH, C-6), 110.9 (CHar), 120.1 (CHar), 122.3
(CH, C-1), 122.5 (Car), 128.8 (Cq, C-11), 131.1 (CHar), 131.3 (CHar),
133.9 (CH, C-13), 137.1 (Cq, C-10), 158.1 (Car), 171.2 (CO, C-
12) ppm. IR (ATR diamond): ν = 3490, 2930, 1716, 1599, 1511,
1441, 1199, 1171, 1017, 940, 814, 780, 750, 696 cm−1. HRMS
(ESI): calcd. for C22H27O5 [M + H]+ 371.1850, found 371.1853.
General procedure to prepare compounds 12–19
A mixture of 9α-hydroxyparthenolide (108 mg, 0.4 mmol), tri-
ethylamine (1.2 mmol, 3 equivalents), and iodoaryl (0.45 mmol)
in DMF (2 mL) was treated with palladium (II) acetate (5 mg,
0.02 mmol) and then heated at 80°C. After 24 h, the reaction mix-
ture was allowed to cool to room temperature, water (10 mL) was
added, and the resulting mixture was extracted with Et2O
(10 mL × 5). The organics were dried over Na2SO4 and concen-
trated under reduced pressure. Purification by column chroma-
tography (PE-EtOAc, 8:2 up to 0:10) afforded compounds 12–19.
9α-Hydroxy-13-(3-methoxyphenyl)parthenolide (15)
[α]2D0 + 208.4 (c 1.0, CH2Cl2); yield = 60%; m.p. 180°C; 1H NMR
(400 MHz, CDCl3) δ 1.30–1.38 (m, 1H), 1.34 (s, 3H), 1.63–1.67
(m, 1H), 1.66 (s, 3H), 1.92 (s, 1H), 2.20 (ddd, J = 12.6, 4.8, 1.9 Hz,
1H), 2.30 (d, J = 13.5 Hz, 1H), 2.47–2.61 (m, 2H), 2.87 (d,
J = 7.6 Hz, 1H), 3.87 (s, 3H), 3.93–3.96 (m, 2H), 4.20 (d, J = 4.6 Hz,
1H), 5.71 (ddd, J = 12.6, 2.8, 1.3 Hz, 1H), 6.95 (dd, J = 8.0, 1.9 Hz,
1H), 7.21 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H),
7.67 (d, J = 2.0 Hz, 1H) ppm. 13C NMR (101 MHz, CDCl3) δ 16.3
(CH3, C-14), 17.6 (CH3, C-15), 23.9 (CH2, C-2), 35.2 (CH2, C-3),
35.9 (CH2, C-8), 37.8 (CH, C-7), 55.5 (OCH3), 61.5 (Cq, C-4), 66.3
(CH, C-5), 71.8 (CH, C-9), 81.9 (CH, C-6), 115.3 (CHar), 116.0
(CHar), 122.5 (CH, C-1), 123.3 (CHar), 129.1 (Car), 129.5 (CHar),
134.6 (Cq, C-11), 137.1 (Cq, C-10), 138.4 (CH, C-13), 159.5 (Car),
171.1 (CO, C-12) ppm. IR (ATR diamond): ν = 3491, 2930, 1716,
1637, 1489, 1475, 1228, 1191, 1172, 1033, 918, 815, 734,
684 cm−1. HRMS (ESI): calcd. for C22H27O5 [M + H]+ 371.1851,
found 371.1853.
9α-Hydroxy-13-phenylparthenolide (12)
[α]2D0 + 173.5 (c 1.0, CH2Cl2); yield = 75%; m.p. 250°C; 1H NMR
(400 MHz, CDCl3) δ 1.29–1.39 (m, 1H), 1.35 (s, 3H), 1.62–1.65
(m, 1H), 1.67 (s, 3H), 1.82 (s, 1H), 2.21 (ddd, J = 7.0, 4.7, 1.8 Hz,
1H), 2.31 (d, J = 13.5 Hz, 1H), 2.47–2.62 (m, 2H), 2.87 (d,
J = 7.6 Hz, 1H), 3.92–3.96 (m, 2H), 4.20 (d, J = 4.8 Hz, 1H), 5.71
(ddd, J = 12.3, 2.7, 1.2 Hz, 1H), 7.38–7.46 (m, 3H), 7.70 (dd, J = 8.0,
2.0 Hz, 2H), 7.73 (d, J = 1.5 Hz, 1H) ppm. 13C NMR (101 MHz,
CDCl3) δ 16.3 (CH3, C-14), 17.6 (CH3, C-15), 23.9 (CH2, C-2), 35.0
(CH2, C-3), 35.9 (CH2, C-8), 37.8 (CH, C-7), 61.5 (Cq, C-4), 66.4 (CH,
C-5), 72.0 (CH, C-9), 81.9 (CH, C-6), 122.5 (CH, C-1), 128.4 (2 ×
CHar), 128.6 (Car), 129.7 (CHar), 130.9 (2 × CHar), 133.2 (Cq, C-11),
137.5 (Cq, C-10), 138.5 (CH, C-13), 171.2 (CO, C-12) ppm. IR (ATR
diamond): ν = 3363, 2933, 1720, 1648, 1622, 1592, 1199, 1170,
1070, 872, 762, 688 cm−1. HRMS (ESI): calcd. for C21H25O4 [M +
H]+ 341.1744, found 341.1747. Crystallographic data for the
structure 12 have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication nos. CCDC
1402812 (12). Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[Fax:+44 (1223)336033; E-mail: deposit@ccdc.cam.ac.uk].
9α-Hydroxy-13-(4-methoxyphenyl)parthenolide (16)
[α]2D0 + 78.9 (c 1.0, CH2Cl2); yield = 66%; m.p. 170°C; 1H NMR
(400 MHz, CDCl3) δ 1.31–1.39 (m, 1H), 1.35 (s, 3H), 1.62–1.66
(m, 1H), 1.69 (s, 3H), 1.87 (s, 1H), 2.21 (ddd, J = 6.8, 4.6, 1.7 Hz,
1H), 2.31 (d, J = 13.6 Hz, 1H), 2.48–2.59 (m, 1H), 2.67 (dd, J = 15.3,
5.7 Hz, 1H), 2.87 (d, J = 7.6 Hz, 1H), 3.87 (s, 3H), 3.89–3.97 (m, 2H),
4.25 (d, J = 4.0 Hz, 1H), 5.72 (dd, J = 12.2, 3.8 Hz, 1H), 6.95 (d,
J = 8.8 Hz, 2H), 7.63 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 8.8 Hz, 2H) ppm.
13C NMR (101 MHz, CDCl3) δ 16.3 (CH3, C-14), 17.6 (CH3, C-15),
23.6 (CH2, C-2), 34.9 (CH2, C-3), 35.9 (CH2, C-8), 37.9 (CH, C-7),
55.4 (OCH3), 61.5 (Cq, C-4), 66.4 (CH, C-5), 72.2 (CH, C-9), 81.8
(CH, C-6), 113.9 (2 × CHar), 122.6 (CH, C-1), 125.7 (Car), 125.8 (Cq,
C-11), 133.1 (2 × CHar), 137.6 (Cq, C-10), 138.3 (CH, C-13), 160.8
(Car), 171.7 (CO, C-12) ppm. IR (ATR diamond): ν = 3489, 2930,
9α-Hydroxy-13-(2-fluorophenyl)parthenolide (13)
[α]2D0 + 251.1 (c 1.0, CH2Cl2); yield = 82%; m.p. 220°C; 1H NMR
(400 MHz, CDCl3) δ 1.28–1.38 (m, 1H), 1.35 (s, 3H), 1.60 (s, 1H),
1.66 (s, 3H), 1.69–1.71 (m, 1H), 2.19–2.23 (m, 1H), 2.30 (d,
J = 13.5 Hz, 1H), 2.45–2.58 (m, 2H), 2.87 (d, J = 7.9 Hz, 1H), 3.90–
3.97 (m, 2H), 4.16 (dd, J = 5.9, 2.3 Hz, 1H), 5.70 (dd, J = 12.3,
3.8 Hz, 1H), 7.14 (t, J = 9.0 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 7.40 (td,
J = 7.4, 1.3 Hz, 1H), 7.82–7.86 (m, 2H) ppm. 13C NMR (101 MHz,
CDCl3) δ 16.3 (CH3, C-14), 17.5 (CH3, C-15), 23.9 (CH2, C-2), 35.1
(CH2, C-3), 35.9 (CH2, C-8), 37.9 (CH, C-7), 61.5 (Cq, C-4), 66.3 (CH,
C-5), 71.8 (CH, C-9), 82.0 (CH, C-6), 115.6 (d, J = 21.6 Hz, CHar),
121.4 (d, J = 13.2 Hz, Car), 122.5 (CH, C-1), 123.8 (d, J = 3.7 Hz,
CHar), 130.6 (d, J = 4.9 Hz, CHar), 131.0 (Cq, C-11), 131.5 (d,
J = 3.6 Hz, CHar), 131.6 (d, J = 2.9 Hz, CH, C-13), 137.3 (Cq, C-10),
161.0 (d, J = 252.3 Hz, Car), 170.6 (CO, C-12) ppm. IR (ATR dia-
mond): ν = 3487, 2953, 1719, 1651, 1523, 1369, 1350, 1248,
1224, 1109, 1088, 1062, 910, 815, 754, 740 cm−1. HRMS (ESI):
calcd. for C21H24FO4 [M + H]+ 359.1649, found 359.1653.
1716, 1600, 1511, 1457, 1239, 1198, 1057, 814, 752, 695 cm−1
.
HRMS (ESI): calcd. for C22H27O5 [M + H]+ 371.1850, found
371.1853.
9α-Hydroxy-13-(4-methylphenyl)parthenolide (17)
[α]2D0 + 111.8 (c 1.0, CH2Cl2); yield = 75%; m.p. 107°C; 1H NMR
(400 MHz, CDCl3) δ 1.30–1.38 (m, 1H), 1.35 (s, 3H), 1.61–1.65
(m, 1H), 1.67 (s, 3H), 1.89 (s, 1H), 2.20 (ddd, J = 7.0, 4.7, 1.9 Hz,
1H), 2.30 (d, J = 13.6 Hz, 1H), 2.40 (s, 3H), 2.48–2.58 (m, 1H), 2.63
(dd, J = 15.2, 5.8 Hz, 1H), 2.87 (d, J = 7.6 Hz, 1H), 3.84–4.00 (m, 2H),
4.21 (d, J = 5.0 Hz, 1H), 5.71 (ddd, J = 12.3, 2.8, 1.2 Hz, 1H), 7.24 (d,
J = 8.0 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 2.5 Hz, 1H) ppm.
13C NMR (101 MHz, CDCl3) δ 16.3 (CH3, C-14), 17.6 (CH3, C-15),
21.5 (CH3-Ph), 23.9 (CH2, C-2), 34.9 (CH2, C-3), 35.9 (CH2, C-8),
37.9 (CH, C-7), 61.5 (Cq, C-4), 66.4 (CH, C-5), 72.1 (CH, C-9), 81.9
(CH, C-6), 122.5 (CH, C-1), 127.4 (Car), 129.1 (2 × CHar), 130.3 (Cq,
C-11), 131.1 (2 × CHar), 137.5 (Cq, C-10), 138.6 (CH, C-13), 140.1
9α-Hydroxy-13-(2-methoxyphenyl)parthenolide (14)
[α]2D0 + 194.2 (c 1.0, CH2Cl2); yield = 62%; m.p. 168°C; 1H NMR
(400 MHz, CDCl3) δ 1.27–1.37 (m, 1H), 1.33 (s, 3H), 1.59–1.65
(m, 1H), 1.64 (s, 3H), 1.81 (s, 1H), 2.19 (ddd, J = 7.5, 4.7, 1.8 Hz,
1H), 2.29 (d, J = 13.5 Hz, 1H), 2.44–2.56 (m, 2H), 2.86 (d,
J = 7.5 Hz, 1H), 3.86–3.93 (m, 2H), 3.89 (s, 3H), 4.11 (d, J = 4.8 Hz,
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(Car), 171.5 (CO, C-12) ppm. IR (ATR diamond): ν = 3467, 2929,
(CH, C-7), 61.5 (Cq, C-4), 66.3 (CH, C-5), 73.6 (CH, C-9), 81.6 (CH,
C-6), 122.9 (CH, C-1), 128.0 (Car), 128.3 (2 × CHar), 129.9 (CHar),
130.1 (2 × CHar), 133.1 (Cq, C-11), 133.4 (Cq, C-10), 138.9 (CH, C-
13), 169.0 (CO), 170.7 (CO, C-12) ppm. IR (ATR diamond):
ν = 2936, 1742, 1720, 1644, 1297, 1228, 1186, 905, 765,
725 cm−1. HRMS (ESI): calcd. for C23H27O5 [M + H]+ 383.1853,
found 383.1853.
1746, 1639, 1338, 1197, 1175, 1057, 849, 816, 774, 732 cm−1
.
HRMS (ESI): calcd. for C22H27O4 [M + H]+ 355.1901, found
355.1903.
9α-Hydroxy-13-(4-hydroxyphenyl)parthenolide (18)
[α]2D0 + 180.0 (c 1.0, CH2Cl2); yield = 65%; m.p. 200°C; 1H NMR
(400 MHz, acetone-d6) δ 1.26–1.31 (m, 1H), 1.32 (s, 3H), 1.72 (s,
3H), 1.83 (dd, J = 15.0, 8.6 Hz, 1H), 2.12 (ddd, J = 12.3, 4.9, 2.0 Hz,
1H), 2.24 (d, J = 14.2 Hz, 1H), 2.53–2.68 (m, 2H), 2.89 (d,
J = 8.3 Hz, 1H), 3.92–3.98 (m, 1H), 4.07 (dd, J = 8.3, 6.6 Hz, 1H),
4.24 (s, 1H), 4.42 (d, J = 2.1 Hz, 1H), 5.82 (ddd, J = 12.4, 2.7, 1.3 Hz,
1H), 6.91 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 3.0 Hz, 1H), 7.83 (d,
J = 8.7 Hz, 2H), 8.87 (s, 1H) ppm. 13C NMR (101 MHz, acetone-d6)
δ 15.5 (CH3, C-14), 17.0 (CH3, C-15), 23.6 (CH2, C-2), 34.4 (CH2,
C-3), 35.8 (CH2, C-8), 37.8 (CH, C-7), 60.9 (Cq, C-4), 66.1 (CH, C-
5), 71.5 (CH, C-9), 81.4 (CH, C-6), 115.2 (2 × CHar), 122.1 (CH, C-
1), 124.8 (Car), 126.2 (Cq, C-11), 133.6 (2 × CHar), 136.9 (CH, C-
13), 138.0 (Cq, C-10), 158.9 (Car), 171.2 (CO, C-12) ppm. IR (ATR
diamond): ν = 3517, 3287, 2951, 1719, 1651, 1634, 1447, 1330,
1311, 1248, 1225, 1168, 991, 909, 751, 739 cm−1. HRMS (ESI):
calcd. for C21H25O5 [M + H]+ 357.1694, found 357.1696.
9α-Acetoxy-13-(2-fluorophenyl)parthenolide (21)
[α]2D0 + 27.3 (c 1.0, CH2Cl2); yield = 83%; m.p. 221°C; 1H NMR
(400 MHz, CDCl3) δ 1.27–1.34 (m, 1H), 1.36 (s, 3H), 1.71 (s, 3H),
1.75–1.82 (m, 1H), 2.19–2.26 (m, 2H), 2.30 (s, 3H), 2.36 (dd,
J = 15.6, 5.7 Hz, 1H), 2.49 (qd, J = 13.1, 4.9 Hz, 1H), 2.89 (d,
J = 8.1 Hz, 1H), 3.73–3.78 (m, 1H), 3.96–4.00 (m, 1H), 5.05 (d,
J = 5.3 Hz, 1H), 5.45 (dd, J = 12.2, 3.8 Hz, 1H), 7.09–7.18 (m, 2H),
7.41 (td, J = 7.5, 1.4 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.78 (d,
J = 3.0 Hz, 1H) ppm. 13C NMR (101 MHz, CDCl3) δ 16.2 (CH3, C-
14), 17.5 (CH3, C-15), 21.3 (CH3CO2R), 23.9 (CH2, C-2), 33.2 (CH2,
C-3), 35.8 (CH2, C-8), 40.0 (CH, C-7), 61.5 (Cq, C-4), 66.1 (CH, C-5),
73.1 (CH, C-9), 81.4 (CH, C-6), 116.0 (d, J = 21.4 Hz, CHar), 121.4 (d,
J = 14.3 Hz, Car), 123.1 (CH, C-1), 123.8 (d, J = 3.6 Hz, CHar), 130.4
(d, J = 2.6 Hz, CHar), 131.0 (Cq, C-11), 131.5 (d, J = 3.0 Hz, CHar),
131.7 (d, J = 8 Hz, CH, C-13), 133.1(Cq, C-10), 160.4 (d,
J = 252.1 Hz, Car), 169.1 (CO), 170.0 (CO, C-12) ppm. IR (ATR dia-
mond): ν = 2934, 1743, 1722, 1647, 1390, 1274, 1227, 1186,
1163, 1127, 905, 723, 694 cm−1. HRMS (ESI): calcd. for C23H26FO5
[M + H]+ 401.1759, found 401.1759.
9α-Hydroxy-13-(4-aminophenyl)parthenolide (19)
[α]2D0 + 26.1 (c 1.0, CH2Cl2); yield = 60%; m.p. 153°C; 1H NMR
(400 MHz, CDCl3) δ 1.31–1.38 (m, 1H), 1.34 (s, 3H), 1.60–1.64
(m, 1H), 1.68 (s, 3H), 2.02 (s, 1H), 2.20 (ddd, J = 12.4, 4.6, 1.8 Hz,
1H), 2.30 (d, J = 13.4 Hz, 1H), 2.53 (qd, J = 13.1, 4.9 Hz, 1H), 2.71
(dd, J = 15.2, 5.7 Hz, 1H), 2.86 (d, J = 7.8 Hz, 1H), 3.85–3.94 (m,
2H), 4.05 (s, 2H), 4.24 (d, J = 4.2 Hz, 1H), 5.71 (ddd, J = 12.3, 2.7,
1.2 Hz, 1H), 6.69 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 3.0 Hz, 1H), 7.59
(d, J = 8.5 Hz, 2H) ppm. 13C NMR (101 MHz, CDCl3) δ 16.3 (CH3, C-
14), 17.6 (CH3, C-15), 24.0 (CH2, C-2), 34.9 (CH2, C-3), 35.9 (CH2,
C-8), 38.0 (CH, C-7), 61.5 (Cq, C-4), 66.5 (CH, C-5), 72.2 (CH, C-9),
81.7 (CH, C-6), 114.4 (2 × CHar), 122.5 (CH, C-1), 123.2 (Car), 123.4
(Cq, C-11), 133.3 (2 × CHar), 137.7 (Cq, C-10), 139.1 (CH, C-13),
148.3 (Car), 172.1(CO, C-12) ppm. IR (ATR diamond): ν = 3365,
2930, 1720, 1622, 1596, 1339, 1199, 1170, 1122, 906, 870, 779,
728 cm−1. HRMS (ESI): calcd. for C21H26NO4 [M + H]+ 356.1851,
found 356.1856.
9α-Acetoxy-13-(2-methoxyphenyl)parthenolide (22)
[α]2D0 + 41.3 (c 1.0, CH2Cl2); yield = 70%; m.p. 218°C; 1H NMR
(400 MHz, CDCl3) δ 1.30–1.36 (m, 1H), 1.34 (s, 3H), 1.69–1.75
(m, 1H), 1.71 (s, 3H), 2.18–2.28 m, 2H), 2.31 (s, 3H), 2.43–2.55
(m, 2H), 2.87 (d, J = 8.2 Hz, 1H), 3.78–3.83 (m, 1H), 3.89 (s, 3H),
3.94–3.98 (m, 1H), 5.03 (d, J = 5.3 Hz, 1H), 5.41 (dd, J = 11.9,
3.3 Hz, 1H), 6.89 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 7.5 Hz, 1H), 7.38 (t,
J = 7.5 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.97 (d, J = 3.0 Hz, 1H) ppm.
13C NMR (101 MHz, CDCl3) δ 16.2 (CH3, C-14), 17.5 (CH3, C-15),
21.3 (CH3CO2R), 23.9 (CH2, C-2), 32.9 (CH2, C-3), 35.8 (CH2, C-8),
39.4 (CH, C-7), 55.6 (OCH3), 61.5 (Cq, C-4), 66.4 (CH, C-5), 73.5
(CH, C-9), 81.5 (CH, C-6), 110.9 (CHar), 119.5 (CHar), 122.2 (Car),
122.6 (CH, C-1), 127.7 (Cq, C-11), 129.7 (CHar), 131.6 (CHar),
133.5 (Cq, C-10), 134.5 (CH, C-13), 158.3 (Car), 169.0 (CO), 170.7
(CO, C-12) ppm. IR (ATR diamond): ν = 2995, 1748, 1728, 1578,
1391, 1372, 1355, 1240, 1227, 1099, 1066, 854, 812, 736,
703 cm−1. HRMS (ESI): calcd. for C24H29O6 [M + H]+ 413.1958,
found 413.1958.
General procedure to prepare compounds 20–23
Acetic anhydride (0.65 mmol) at 0°C was added to a solution of
9α-hydroxy-13-arylparthenolide (0.5 mmol) in a dry mixture of
CH2Cl2 and pyridine (9:1) (20 mL). The solution was stirred at
room temperature for 12 h and poured into saturated aqueous
NH4Cl (10 mL). The aqueous phase was extracted with CH2Cl2
(3 × 10 mL), and the combined organic extracts were washed
with brine (10 mL), dried (MgSO4), and filtered. Concentration of
the filtrate followed by column chromatography (PE-EtOAc, 7:3)
provided compounds 20–23.
9α-Acetoxy-13-(3-methoxyphenyl)parthenolide (23)
[α]2D0 + 18.7 (c 1.0, CH2Cl2); yield = 75%; m.p. 203°C; 1H NMR
(400 MHz, CDCl3) δ 1.29–1.36 (m, 1H), 1.35 (s, 3H), 1.69–1.75
(m, 1H), 1.72 (s, 3H), 2.18–2.28 (m, 2H), 2.34 (s, 3H), 2.43–2.55
(m, 1H), 2.60 (dd, J = 15.5, 5.8 Hz, 1H), 2.88 (d, J = 8.1 Hz, 1H),
3.81–3.85 (m, 1H), 3.83 (s, 3H), 3.96–4.00 (m, 1H), 5.09 (d,
J = 5.3 Hz, 1H), 5.42 (ddd, J = 12.3, 2.7, 1.1 Hz, 1H), 6.92 (dd,
J = 8.2, 2.0 Hz, 1H), 7.09–7.11 (m, 2H), 7.31 (t, J = 8.2 Hz, 1H), 7.69
(d, J = 3.0 Hz, 1H) ppm. 13C NMR (101 MHz, CDCl3) δ 16.2 (CH3, C-
14), 17.5 (CH3, C-15), 21.2 (CH3CO2R), 23.9 (CH2, C-2), 32.8 (CH2,
C-3), 35.8 (CH2, C-8), 39.5 (CH, C-7), 55.2 (OCH3), 61.5 (Cq, C-4),
66.2 (CH, C-5), 73.4 (CH, C-9), 81.6 (CH, C-6), 113.6 (CHar), 117.2
(CHar), 122.6 (CH, C-1), 122.7 (CHar), 128.4 (Car), 129.4 (CHar),
133.5 (Cq, C-11), 134.3 (Cq, C-10), 138.7 (CH, C-13), 159.5 (Car),
169.4 (CO), 170.7 (CO, C-12) ppm IR (ATR diamond): ν = 2935,
9α-Acetoxy-13-phenylparthenolide (20)
[α]2D0 + 34.7 (c 1.0, CH2Cl2); yield = 80%; m.p. 237°C; 1H NMR
(400 MHz, CDCl3) δ 1.27–1.37 (m, 1H), 1.35 (s, 3H), 1.73 (s, 3H),
1.74–1.78 (m, 1H), 2.21 (ddd, J = 12.9, 5.0, 1.9 Hz, 1H), 2.27 (d,
J = 13.6 Hz, 1H), 2.35 (s, 3H), 2.44–2.57 (m, 2H), 2.88 (d,
J = 8.1 Hz, 1H), 3.82–3.87 (m, 1H), 3.98–4.01 (m, 1H), 5.08 (d,
J = 5.2Hz, 1H), 5.43 (dd, J = 11.8, 3.4 Hz, 1H), 7.37–7.40 (m, 3H),
7.53–7.55 (m, 2H), 7.73 (d, J = 3.0 Hz, 1H) ppm. 13C NMR
(101 MHz, CDCl3) δ 16.3 (CH3, C-14), 17.5 (CH3, C-15), 21.3
(CH3CO2R), 23.9 (CH2, C-2), 33.1 (CH2, C-3), 35.8 (CH2, C-8), 39.5
El Bouakher A et al. Synthetic Modification of… Planta Med

Original Papers
1742, 1645, 1612, 1297, 1227, 1886, 1163, 1127, 1020, 905, 785,
727, 676 cm−1. HRMS (ESI): calcd. for C24H29O6 [M + H]+ 413.57,
found 413.1958.
Affiliations
1
Laboratoire de Chimie Physique & de Chimie Bioorganique, URAC 22, Uni-
versité Hassan II Casablanca, Mohammedia, Morocco
Institut de Chimie Organique et Analytique (ICOA), Université dʼOrléans, UMR
CNRS 7311, Orléans, France
2
3
4
Laboratoire de Chimie Physique, équipe RICM UMR‑ISP 1282, Faculté de
Pharmacie, Tours, France
GLYcoDIAG, Université dʼOrléans, Orléans, France
Determination of in vitro cytotoxic activity
"
Cancer cell lines (l Table 1) were commercially obtained from
the Cell Lines Service of GmbH. Cytotoxic activity was deter-
mined on four cancer cell lines using a colorimetric MTT (thia-
zolyl blue tetrazolium bromide) assay. Human skin melanoma
SK‑Mel-28 and human brain glioma HS-683 were grown in
DMEM supplemented with 4.5 g/L glucose, L-glutamine, and
10% FBS. The human lung carcinoma cell line A549 was grown
in DMEM:Hamʼs F12 (1:1) supplemented with L-glutamine and
5% FBS and human breast adenomacarcinoma MCF-7 in EMEM
supplemented with L-glutamine, sodium pyruvate, NEAA, and
10% FBS. The MTT assay is based on the reduction of the yellow
product MTT to purple-blue formazan by mitochondrial dehy-
drogenase of metabolically active cells. The number of living cells
after incubation in the presence (or absence, control) of the
tested molecule is directly proportional to the blue color that
was measured by spectrophotometry. Briefly, cells were seeded
(200 µL of a 5 × 104 cells/mL suspension) in 96-well culture plates
(TPP) and incubated for 24 h. Each compound (starting from
DMSO solutions) was assessed in serial dilution (four concentra-
tions) in 6 replicates of 2–3 independent experiments (n = 2–3)
and incubated for 72 h. Thereafter, MTT (5 mg/mL solution in
PBS) was added to each well (10% v/v) and cells were further in-
cubated for 4 h. Then, after removing the culture medium, the
blue crystals were dissolved in 100 µL SDS-acidic-isopropanol so-
lution (0.5% SDS; 80 mM HCl) and absorbance measured at
540 nm using a 620 nm reference. Absorbance of the serial dilu-
tion of each cell line treated under the same conditions, but with-
out the tested compounds, was measured to generate a standard
curve allowing cell number determination. Individual IC50 s (de-
fined as the concentration reducing cell number by 50%) were
calculated by using linear regression equation (as given by Excel
software) of the curve obtained in the presence of four concen-
trations of compound. IC50 values are the geometric mean from
two to three independent experiments. 95% Confidence limits
were determined using the Excel confidence interval function.
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