Antitumor activity of novel deoxoartemisinin monomers, dimers, and trimer

Article abstract of DOI:10.1021/jm020119d

The first primary amines 9 and bromoalkyl analogues 7 of deoxoartemisinin with nonacetal functionality at C-12 are prepared as versatile intermediates for the synthesis of various derivatives. Eight C-12 nonacetal type dimers and one trimer of deoxoartemi

Full text of DOI:10.1021/jm020119d

J . Med. Chem. 2003, 46, 987-994
987
An titu m or Activity of Novel Deoxoa r tem isin in Mon om er s, Dim er s, a n d Tr im er
Mankil J ung,*,† Sangmin Lee,† J ungyeob Ham,† Kyunghoon Lee,† Hanjo Kim,† and Soo Kie Kim‡
Department of Chemistry, Yonsei University, Seoul 120-749, Korea, and Department of Microbiology,
Institute of Basic Medical Science, Wonju College of Medicine, Research Institute of Functional Biomaterials,
Yonsei University, Wonju 220-710, Korea
Received March 13, 2002
The first primary amines 9 and bromoalkyl analogues 7 of deoxoartemisinin with nonacetal
functionality at C-12 are prepared as versatile intermediates for the synthesis of various
derivatives. Eight C-12 nonacetal type dimers and one trimer of deoxoartemisinin were prepared
using novel chemistry. Dimers, particularly 12a , 18a ,b, and trimer 17, were especially potent
and selective at inhibiting the growth of certain human cancer cell lines and were comparable
to that of clinically used anticancer drugs. The linker with one amide- or one sulfur-centered
two ethylene groups of the dimers is essential for high anticancer activity. Trimer 17 shows
very potent activity against most of the human cancer cell lines tested.
Sch em e 1
In tr od u ction
Artemisinin (Qinghaosu) 1, a sesquiterpene lactone
endoperoxide, is the first natural trioxane isolated from
Artemisia annua, L. (Scheme 1). This compound is of
special biological interest because of its outstanding
antimalarial activity1 and in vitro activity against
Pneumocystis carinii2 and Toxoplasma gondii.3 The anti-
human immunodeficiency virus (HIV) activity of arte-
misinin-related trioxanes was also first reported by our
group.4 Artemisinin has been subjected to a number of
reviews5-14 because of its novel structure and outstand-
ing antimalarial activity. Most first generation C-12
acetal type derivatives are hydrolytically unstable, and
most semisyntheses have involved replacing the C-12
acetal functionality in ether derivatives by less hydro-
lytically prone functional groups. Deoxoartemisinin 1a ,
prepared from either artemisinin or artemisinic acid 2
by J ung et al.,15 is the first nonacetal type analogue of
artemisinin and shows more antimalarial activity than
that of artemisinin both in vitro and in vivo.16 Nonacetal
type analogues of deoxoartemisinin recently drew at-
tention due to better bioavailability, such as acid
stability, than acetal type analogues. Furthermore,
evidence that analogues not possessing exo-oxygen at
C-12 are less neurotoxic in animal studies than acetal
type artemisinin is also emerging and may thus in the
future bypass the current clinically used acetal type
analogues (artemether, arteether, artesunate, and arte-
linic acid).17 After the preparation of 12-n-butyl-
deoxoartemisinin as the first hydrolytically stable non-
acetal type analogue18 containing a C-C bond at C-12
was reported, a series of nonacetal type derivatives
including a few heteroaryl and unsaturated substit-
uents at C-12 have been prepared.19-27 Although most
studies have focused on antimalarial activities, a few
research groups have recently reported on cytotoxicity
of artemisinin and its related derivatives.28-33 We first
reported that artemsinin-related sesquiterpene, arte-
annuin B 2a , shows good in vitro antineoplastic activity
(IC50 ) 12 µM against L-1210).34 Because of their higher
rate of cell division, most cancer cells express a higher
surface concentration of transferrin receptors than
normal cells35,36 and have high rates of iron intake.37,38
A unique structure bearing endoperoxide could be a
trigger for the generation of active oxygen radicals via
homolytic cleavage of the weak oxygen peroxide bond
accelerated by higher ferrous ion concentration of cancer
cells,38 which may mediate for the selective and prefer-
able damage to vital cellular structures of the relatively
active cancer cells. This concept, coupled with prelimi-
nary results, prompted us to prepare deoxoartemisinin-
related compounds and evaluate their in vitro cytotox-
icity. Some dimeric chemical structures showed especially
high biological activities. Although some dimers of acetal
type derivatives of artemisinin have been prepared39
and show antitumor activities,40,41 yields are low and
most of them possess either aromatic linkers or still
acetal types at the C-12 position, which are neurotoxic,
acid unstable, and show low antitumor activities. In this
paper, we report a novel preparation of C-12 nonacetal
type derivatives of deoxartemisinin as monomers, dimers,
and one trimer and their exceptionally high antitumor
activities.
Resu lts a n d Discu ssion
Ch em istr y. We designed nonacetal type analogues
for increasing bioavailability such as acid stability or
water solubility of the lead compound artemisinin 1.
Because artemisinin is much more expensive than
artemisinic acid 2 and because the direct introduction
of a C-C bond at C-12 of artemisinin for the preparation
* To whom correspondence should be addressed. Tel: +82-2-2123-
2648. Fax: +82-2-364-7050. E-mail: mkjung@alchemy.yonsei.ac.kr.
† Department of Chemistry, Yonsei University.
‡ Department of Microbiology, Institute of Basic Medical Science,
Wonju College of Medicine, Research Institute of Functional Bio-
materials, Yonsei University.
10.1021/jm020119d CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/15/2003

988 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6
J ung, et al.
Sch em e 2a
Sch em e 4
Sch em e 5
a
Regents and conditions: (a) Mg, Br(CH2)nCHCH2 (n ) 0, 1,
2), Et2O, 0 °C (80-97%). (b) (i) O2, Rose Bengal, 500 W tungsten
lamp, CH2Cl2/CH3CN (1/1), -23 °C for 4 h; (ii) TFA, O2, CH2Cl2/
CH3CN (1/9), room temperature for 12 h (25-40%). (c) KMnO4,
NaHCO3, acetone, room temperature for 1 h, 1 M HCl, room
temperature for 5 h (73%). (d) 9-BBN, 3 M NaOH, H2O2, room
temperature for 1 h (73-97%). (e) TPP, CBr4, CH2Cl2, 0 °C (91%).
(f) NaN3, DMF, room temperature for 5 h (92%). (g) LAH, THF,
-10 °C for 4 h (79%).
Sch em e 3
of a series of novel analogues may cause destruction of
the biologically essential endoperoxide, we applied our
photooxygenative cyclization15,16,18 of more abundant
artemisinic acid 2 as a key step. A series of novel
analogues have been prepared from artemisinic acid as
useful chiral synthons, as outlined in Schemes 2-5.
(a ) Mon om er . Reaction of dihydroartemisinyl alde-
hyde 3, prepared from artemisinic acid 2 by a known
procedure,18 with vinyl-, 1-propenyl-, and 1-butenyl-
magnesium chlorides gave homologated alcohols 4a -c
(80-97% yield), respectively. As previously men-
tioned,15,16,18 photooxygenative cyclization of alcohol 4c
provided analogue 10 (41% yield) and a C-C bond
introduced at C-12. Water soluble 12-carboxyethyl-
deoxoartemisinin 11 (as sodium salt) was also prepared
from the olefinic deoxoartemisinin 10 by a known
procedure42 in a single step by direct oxidation (KMnO4)
of the terminal olefin in 73% yield. Direct hydroborative
oxidation (9BBN followed by NaOH/H2O2) of the termi-
nal olefin of the olefinic alcohols 4a ,c afforded the
dialcohols 5a ,b in 73-97% yield, respectively. Treat-
ment of 5a ,b with CBr4/PPh3 in methylene chloride (0
°C, 1 h) gave the new bromo alcohols 6a ,b (91% yield).
As previously mentioned,15,16,18 photooxygenative cycli-
zation of bromo alcohols 6a ,b provided new bromo-
alkyl deoxoartemisinins 7a ,b (40% yield). Direct bro-
mination (CBr4, PPh3, CH2Cl2, room temperature) of
hydroxyalkyldeoxoartemisinin19 did not provide 7a ,b.
Treatment of 7a ,b with sodium azide in dimethyl
formamide (DMF; 92% yield) and subsequent reduction
of 8a ,b finally afforded novel aminoalkyl deoxoartemisi-
nins 9a ,b (79% yield), respectively (Scheme 2). In the
preparation of compounds 7-11, â-epimer was obtained

Novel Deoxoartemisinin Monomers, Dimers, and Trimer
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6 989
Ta ble 1. In Vitro Cytotoxicities of Deoxoartemisinin-Related Trioxane Monomers, Dimers, and Trimers on Murine and Human
Cancer Cell Linesa
IC50 (µg/mL)
cell line
8b
9b
12b
12a
18a
18b
19b
16
14b
17
20
21
22
P388
EL4
Bewo
HT-29
MCF7
10.30
1.61
>20
2.76
11.6
6.18
5.63
>20
10.40
6.29
7.50
0.69
0.005
0.40
0.23
14.20
0.24
5.60
0.54
1.04
0.38
0.025
8.40
10.00
8.50
0.38
5.6
>20
15.60
16.50
>20
6.50
15.3
0.12
1.07
18.30
0.09
0.39
0.67
6.24
0.10
0.12
1.50
3.94
0.85
0.02
0.93
2.27
1.34
7.39
0.01
>20
>20
>20
>20
>20
2.20
0.02
20.20
>20
8.60
13.4
0.017
0.017
0.0001
a
Compound 20, adriamycin; 21, mitomycin; 22, taxol; P388, mouse fibroblast, leukemia; EL4, mouse thymoma; Bewo, human
choriocarcinoma; HT-29, human colorectal adenocarcinoma; and MCF7, human breast cancer.
exclusively (J 11,12 ) 9.8 Hz). No 12R-isomer was isolated.
We found bromo- and amino-alkyldeoxoartemisins 7, 9,
and 11 to be versatile intermediates for the preparation
of dimers and the trimer, as shown below.
and exo C-O bond at C-12, they are projected to possess
increased stability in simulated stomach acid, as ex-
perimentally proven,43 and longer half-life in the body,
pointing the way to potential next-generation anticancer
analogues.
(b) Dim er s. Dimeric deoxoartemisinin derivatives
with alkylamide and sulfur linkers of various lengths
and flexibility were obtained in good yields from
amino-, bromo-, and carboxyl-deoxoartemisinin mono-
mers (Schemes 3 and 4). Coupling of 9 with 11 in the
presence of EDC and HOBt (methylene chloride, room
temperature, 4 h) gave 12 in 81% yield. Direct coupling
of 9a with the protected glutarate afforded 13a in 84%
yield. Removal of the benzyl group of the ester of 13a
(LiOH, H2O/tetrahydrofuran (THF)) to the acid 13b
(87% yield) and subsequent coupling with 9a in EDC/
HOBt afforded 14a (51% yield). Deprotection of tBOC
of the amino group of 14a with trifluoroacetic acid (TFA)
(methylene chloride, 0 °C, 4 h) gave 14b (yield 72%).
The dimeric amine 14b is five times more water soluble
(5.21 mg/mL) than artemisinin. Dimeric deoxoarte-
misinin derivatives 18 and 19 with alkyl-sulfide or
-sulfone linkers of various lengths and flexibility were
obtained via a bis-nucleophilic coupling reaction in good
yields from bromoalkyldeoxoartemisinin monomer 7a
(Scheme 4). Treatment of 7a with sodium sulfide in
ethanol afforded 18a (76% yield). Oxidation of 18a with
mCPBA gave the dimeric sulfone 18b (91% yield). In a
similar fashion, bis-nucleophilic reaction (KOH/dimethyl
sulfoxide (DMSO), room temperature, 1 h) of 2 mol of
7a with 1,3-propanedithiol gave 19a (65% yield), and
subsequent oxidation of 19a with mCPBA gave 19b in
72% yield.
(c) Tr im er . Coupling of carboxyethyl deoxoartemisi-
nin 11 with L-glutamic diethylester as a linker in the
presence of EDC/HOBt gave 15 (84% yield) (Scheme 5).
Hydrolysis of two ester groups of 15 with LiOH in
aqueous THF and subsequent acidification provided the
diacid 16 (82% yield). Finally, double coupling of 16 with
2 mol of aminoethyldeoxoartemisinin 9a in the presence
of EDC/HOBt at room temperature afforded the tris
adduct trimer 17 as a colorless solid in 74% yield.
All new monomers 7-11, dimers 12, 14, 18, and 19,
and trimer 17 and their stereochemistries were fully
and satisfactorily characterized by spectral data, as
shown in the Schemes 2-5. Most analogues in this
paper possess increased bioavailability in terms of
stability or water solubility with retention of biologically
essential endoperoxide. Compounds 7a ,b and 9a ,b are
the first primary amines and bromo analogues of
deoxoartemisinin with C-12 nonacetal functionality and
are versatile intermediates for the synthesis of various
derivatives. Because all deoxoartemisinin-derived ana-
logues prepared in this paper lack the carbonyl function
An titu m or Activity
The in vitro cytotoxicity of artemisinin and its related
trioxanes against murine and human cancer cells was
defined by the microculture tetrazolium assay as previ-
ously described.44 The IC50 values are presented in Table
1. Sulfide dimer 18a is active comparable to adriamycin
and four times more active than mitomycin against
mouse fibroblast leukemia (P388). Trimer 17 is three
times more active than adriamycin, 12 times more
active than mitomycin, and 20 times more active than
taxol against P388. Sulfur-linked dimers 18a ,b and
trimer 17 are also comparable to adriamycin against
mouse thymoma cells (EL4). Most are inactive, although
sulfone-linked dimer 18b is active comparable to mito-
mycin and six times more active than adriamycin and
taxol against human placental choriocarcinoma cells
(Bewo). The free azide 8b is inactive against most cancer
cell lines. Trimer 17 is comparable to adriamycin
against human colorectal adenocarcinoma cell line
(HT29) and is twice as active than taxol (IC50 ) 5.76
µg/mL) against human pancreas epitheloid carcinoma
cells (PANC-1). While most compounds are inactive
against human ovarian carcinoma (SKOV3), amino-
butyldeoxoartemisinin 9b, amide-linked dimer 12a , and
trimer 17 are comparable to taxol (IC50 ) 12.30 µg/mL).
Aminobutyldeoxoartemisinin 9b , amide-linked dimer
12a , sulfide-linked dimer 18a , sulfone-linked dimer 18b,
and trimer 17 are highly active against human breast
carcinoma (MCF7). Dimer 12a , particularly, is 24 times
more active than adriamycin and 200 times more active
than mitomycin but 50 times less active than taxol.
While most compounds tested are inactive against
human lung cancer (A549), trimer 17 is comparable to
mitomycin (IC50 ) 1.85 µg/mL). Most compounds are
inactive against mouse melanoma (B16), human gastric
cancer cell line (AGS), PANC-1, human brain tumor
cells (A172), SKOV3, and A549. Trimer 17 shows very
potent activity against most of the murine and human
cancer cell lines tested. Analogous to n-butyldeoxo-
artemisinin,18 12-(4′-aminobutyl)deoxoartemisinin 9b
shows good antitumor activity, thus suggesting that the
n-butyl group is crucial for both anti-HIV4 and anti-
tumor activities. Generally, the dimers and the trimer
of deoxoartemisinin are shown to have much more
potent antitumor activity than monomers. It is note-
worthy to say that the anticancer activities of the dimers
are dependent on the length of the linker between two

990 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6
J ung, et al.
P r ep a r a tion of 12-(2′-Br om oeth yl)d ih yd r oa r tem isin yl
Alcoh ol (6a ) fr om Diol (5a ). A solution of 12-(2′-hydroxy-
ethyl)dihydroartemisinyl diol (5a ) (399 mg, 1.503 mmol) in dry
CH2Cl2 (20 mL) was stirred with TPP (393 mg, 1.503 mmol)
at 0 °C for 30 min. The reaction mixture was warmed to room
temperature, and CBr4 (498 mg, 1.503 mmol) was slowly
added. The reaction mixture was stirred at room temperature
for 30 min and then was quenched with methanol (10 mL).
The mixture was extracted with ethyl acetate (20 mL × 3) and
washed with brine (20 mL × 2). The extract was dried over
MgSO4 and concentrated in vacuo to give crude product and
was purified by a silica gel column (hexane/ethyl acetate )
5/2 as eluent) to obtain 12-(2′-bromoethyl)dihydroartemisinyl
deoxoartemisinins. The linker with one amide- or one
sulfur-centered two ethylene groups of the dimers is
essential for high anticancer activity, as shown in
dimers 12a and 18a ,b. The longer linker of one amide-
or one sulfur-centered two ethylene groups of the dimers
dramatically decreases most anticancer activity, as
shown in dimers 12b, 14a ,b, and 19b. Lipophilicity may
play an important role here. Increased lipophilicity due
to the aminobutyl side chains (12b) or the methylene
groups located between two amides or two sulfides of
the dimers (14b and 19b) may decrease cytotoxicity.28,45
1
alcohol (6a ) (470 mg) in 95% yield as a colorless oil. H NMR
Con clu sion
(CDCl3, 250 MHz): δ 5.14 (s, 1H, H-5), 4.1 (d, 1H, J ) 7.5 Hz,
H-12), 3.57-3.52 (t, 2H, J ) 7.5 Hz), 2.31 (s, 1H), 1.94-1.71
(m, 6H), 1.54 (s, 3H, CH3-15), 1.53-1.25 (m, 9H), 0.84 (d, 6H,
J ) 5.0 Hz, CH3-13, 14). 13C NMR (CDCl3, 63 MHz): δ 135.5,
120.7, 69.8, 42.8, 42.4, 39.1, 38.9, 37.8, 36.0, 31.9, 28.0, 27.0,
26.4, 26.1, 24.1, 20.1, 10.2. IR (neat): υmax 3427 (OH), 2910,
1726, 1447, 1378, 1259, 992, 908, 734 cm-1. MS (EI): m/z 328
([M+]), 310 ([M+] - H2O), 249 ([M+] - Br).
In conclusion, this structure-activity relationship of
deoxoartemisinin may be used as a lead for the possible
development of new, hydrolytically stable and orally
active anticancer agents related to virtually nontoxic
artemisinin (LD50 ) 4228 mg/kg orally administered to
mice). The linker with one amide- or one sulfur-centered
two ethylene groups of the dimers is essential for high
anticancer activity. Monomer 9b, dimers 12a and 18a ,b,
and trimer 17 are comparable to or more active than in
vitro anticancer activities of clinically used adriamycin,
mitomycin, and taxol. Trimer 17, in particular, shows
very potent activity against most human cancer cell
lines tested and should receive more attention as a
possible anticancer drug candidate.
P r ep a r a tion of 12-(2′-Br om oeth yl)d eoxoa r tem isin in
(7a ) fr om Br om oeth yl Diol (6a ). A solution of 12-(2′-
bromoethyl)dihydroartemisinyl diol (6a ) (250 mg, 0.665 mmol)
in CH3CN/CH2Cl2 (1/1) (60 mL), containing catalytic Rose
Bengal, was irradiated with white light (500 W tungsten lamp)
at -23 °C for 4 h under oxygen. TLC analysis indicated the
disappearance of the majority of the starting material. The
mixture was poured onto saturated NaHCO3 solution (50 mL),
and products were extracted into diethyl ether (20 mL × 3).
The Rose Bengal remained in the aqueous phase. The com-
bined ether extracts were washed with brine (20 mL × 3) and
dried with MgSO4. Removal of solvent under reduced pressure
left a colorless foam. This was dissolved in CH3CN/CH2Cl2 (9/
1) (10 mL), and the resultant solution was cooled to -40 °C
and was followed by in situ treatment of acidic catalyst TFA.
The mixture was stirred at this temperature under an oxygen
atmosphere for 12 h. The reaction mixture was quenched with
saturated NH4Cl solution (10 mL), and the products were
extracted with diethyl ether (30 mL × 3). The extract was
washed with water (30 mL × 2) and brine (30 mL × 2) and
dried with MgSO4. The extract was concentrated in vacuo to
give crude product and was purified by a silica gel column
(hexane/ethyl acetate ) 5/1 as eluent) to obtain 12-(2′-
bromoethyl)-deoxoartemisinin (7a ) (99 mg) in 40% yield as
Exp er im en ta l Section
Ch em istr y. Merck Kieselgel 60 F 254 precoated silica
plates for thin-layer chromatography (TLC) were obtained
from BDH, Poole, Dorset, U.K. Column chromatography was
carried out on Merck Kieselgel 60 (230-400 mesh). Melting
points were determined using a Meltemp apparatus (Labora-
tory Devices, Holliston, MA). Infrared spectra were recorded
in the range of 4000-600 cm-1 using a Nicolet Impact 400
spectrometer. Spectra of liquids were taken as films. Sodium
chloride plates (Nujol mull) and KBr disks were used as
indicated. Nuclear magnetic resonance (NMR) spectra were
obtained on Bruker AC250 or DRX500 spectrometers using
Me4Si as an internal standard. Gas chromatography-mass
spectrometry (GC-MS) spectra were operated on an HP 5980II
GC-HP 5988 (Hewlett-Packard) in the EI mode. High-resolu-
tion mass spetrometry (HRMS) was obtained on a Trio2000
(VG-Biotec) and a J MS-700 Mstation (J EOL) spectrometer in
fast atom bombardment (FAB) mode. Specific rotations were
recorded on a Rudolph AP III-589 polarimeter.
18
1
white solid; [R]D ) +96.3° (c 0.1 CHCl3); mp 94 °C. H NMR
(CDCl3, 500 MHz): δ 5.26 (s, 1H, H-5), 4.33-4.27 (m, 1H,
H-12), 3.56-3.51 (m, 2H, H-2′), 2.60-2.45 (m, 2H), 2.30 (ddd,
1H, J ) 4.1, 3.8, 4.1 Hz), 2.05-1.89 (m, 4H), 1.83-1.48 (m,
4H), 1.39 (s, 3H, CH3-15), 1.28-1.22 (m, 2H), 0.94 (d, 3H, J )
4.8 Hz, CH3-13), 0.87 (d, 3H, J ) 7.4 Hz, CH3-14), 0.78 (m,
1H). 13C NMR (CDCl3, 125 MHz): δ 103.4, 89.5, 81.2, 73.2,
52.4, 44.4, 37.7, 37.3, 35.8, 34.8, 33.7, 31.6, 30.3, 26.3, 25.0,
20.4, 13.1. IR (KBr): υmax 2950, 1451, 1377, 1272, 1117, 1042,
1010, 880 (O-O), 756 cm-1. MS (EI): m/z 376 (M+2), 342 ([M+]
- O2).
P r ep a r a tion of 12-(2′-Hyd r oxyeth yl)d ih yd r oa r tem is-
in yl Alcoh ol (5a ) fr om Olefin ic Dih yd r oa r t em isin yl
Alcoh ol (4a ). Under
a nitrogen atmosphere, 12-vinyldi-
hydroartemisinyl alcohol (4a ) (568 mg, 2.290 mmol) was slowly
mixed with THF solution of 0.5 M 9BBN (9.1 mL, 4.58 mmol).
The mixture was stirred at room temperature for 30 min and
then was treated with 30% H2O2/3 N NaOH(1/1, 2 mL). This
solution was stirred at room temperature for 1 h. The reaction
mixture was extracted with ether (40 mL × 2) and was washed
with saturated NaHCO3 (20 mL) and brine (20 mL × 2). The
extract was dried over MgSO4 and concentrated in vacuo to
give crude product and was purified by a silica gel column
(hexane/ethyl acetate ) 1/1 as eluent) to obtain 12-(2′-
hydroxyethyl)dihydroartemisinyl alcohol (5a ) (591.8 mg) in
97% yield as a colorless oil. 1H NMR (CDCl3, 250 MHz): δ
5.15 (s, 1H, H-5), 4.14 (d, 1H, J ) 9.8 Hz, H-12), 3.89-3.80
(m, 2H, H-2′), 2.47 (s, 1H), 1.94-1.72 (m, 6H), 1.54 (s, 3H, CH3-
15), 1.53-1.25 (m, 9H), 0.84 (d, 3H, J ) 7.3 Hz, CH3-13), 0.87
(d, 3H, J ) 6.6 Hz, CH3-14). 13C NMR (CDCl3, 63 MHz): δ
135.5, 120.9, 72.0, 62.6, 42.6, 42.5, 39.7, 37.8, 37.6, 36.0, 28.1,
27.0, 26.4, 26.2, 24.1, 20.1, 10.4. IR (neat): υmax 3435 (OH),
2921, 1647, 1622, 1386, 1124, 1088, 1016 cm-1. MS (EI): m/z
266 ([M+]), 248 ([M+] - H2O), 203 ([M+] - C2H5O).
1.1. Syn th esis of Azid e Der iva tives (8). A solution of
bromo alkyldeoxoartemisinin derivatives 7 in DMF (5 mL) was
stirred at room temperature with sodium azide (45.7 mg, 0.704
mmol) for 5 h. The mixture was poured onto water (30 mL)
and then was extracted with ethyl acetate (50 mL × 2) and
washed with brine (40 mL × 2). The extract was dried over
MgSO4 and concentrated in vacuo to give crude product and
was purified by a silica gel column (hexane/ethyl acetate )
5/2 as eluent) to obtain azide derivatives 8.
P r ep a r a tion of 12-(2′-Eth yl a zid e)d eoxoa r tem isin in
(8a ) fr om 12-(2′-Br om oeth yl)d eoxoa r tem isin in (7a ). This
compound was prepared from 12-(2′-bromoethyl)deoxoarte-
misinin (7a ) (128 mg, 0.352 mmol) using the general procedure
in section 1.1 to give the azide (8a ) (109 mg) in 92% yield as
a colorless oil; [R]D23 ) +64.2° (c 0.47 CHCl3). 1H NMR (CDCl3,
250 MHz): δ 5.28 (s, 1H, H-5), 4.31-4.27 (m, 1H, H-12), 3.56-
3.53 (m, 1H), 3.44-3.38 (m, 1H), 2.69-2.64 (m, 1H), 2.31 (ddd,

Novel Deoxoartemisinin Monomers, Dimers, and Trimer
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6 991
1H, J ) 4.1, 3.8, 4.1 Hz), 2.03-1.75 (m, 5H), 1.67-1.60 (m,
3H), 1.40 (s, 3H, CH3-15), 1.33-1.27 (m, 3H), 0.96 (d, 3H, J )
5.6 Hz, CH3-13), 0.87 (d, 3H, J ) 7.5 Hz, CH3-14), 0.82 (m,
1H). 13C NMR (CDCl3, 63 MHz): δ 103.5, 89.5, 81.3, 72.3, 52.5,
49.8, 44.5, 37.8, 36.9, 34.7, 30.4, 29.5, 26.3, 25.1, 25.1, 20.4,
13.1. IR (neat): υmax 2927, 2875, 2095 (N3), 1733, 1454, 1377,
1277, 1098, 1011, 880 (O-O), 756 cm-1. MS (EI): m/z 337 [M+],
305 ([M+] - O2).
4.92-5.07 (m, 2H, H-4′), 4.05-4.13 (m, 1H, H-12), 1.50 (s, 3H,
CH3-15). IR (neat): υmax 3074, 2877, 1453, 1382, 1210, 1141,
1100 cm-1. MS (EI): m/z 306 ([M+] - 16). Anal. (C19H30O4) C,
H.
P r ep a r a tion of 12-Ca r boxyeth yld eoxoa r tem isin in (11)
fr om 12-(3′-Bu ten yl)d eoxoa r tem isin in (10). This com-
pound was prepared from the 12-(3′-butenyl)deoxoartemisinin
(10) (200 mg, 0.621 mmol) using the known procedure39 to give
24
P r ep a r a tion of 12-(4′-Bu tyl a zid e)d eoxoa r tem isin in
(8b) fr om 12-(Br om oeth yl)d eoxo-a r tem isin in (7b). This
compound was prepared from 12-(4′-bromoethyl)deoxoarte-
misinin (7b) (137.9 mg, 0.352 mmol) using the general
procedure in section 1.1 to give azide (8b) (116.9 mg) in 92%
11 (155 mg) in 73% yield as a colorless oil; [R]D ) +41.4° (c
1
0.2 CHCl3). H NMR (CDCl3, 250 MHz): δ 5.29 (s, 1H, H-5),
4.14 (m, 1H, H-12), 2.30 (m, 2H, H-2′), 1.39 (s, 3H, CH3-15),
0.95 (d, J ) 5.4 Hz, 3H, CH3-13), 0.89 (d, J ) 7 Hz, 3H, CH3-
14). 13C NMR (CDCl3, 63 MHz): δ 178.7, 103.4, 89.3, 81.1, 75.2,
52.7, 44.6, 36.9, 34.8, 33.2, 32.2, 30.6, 26.4, 25.4, 25.3, 25.1,
20.6, 13.3. IR (neat): υmax 3341, 2930, 1710, 1210 cm-1. MS
(EI): m/z 342 ([M + 2]). Anal. (C18H28O6) C, H.
yield as a colorless oil; [R]D ) +71.3° (c 0.1 CHCl3). 1H NMR
24
(CDCl3, 250 MHz): δ 5.29 (s, 1H, H-5), 4.19-4.12 (m, 1H,
H-12), 3.26 (t, 2H, J ) 6.6 Hz, H-4′), 2.64-2.62 (m, 1H), 2.31
(ddd, 1H, J ) 4.1, 3.8, 4.1 Hz), 2.04-1.89 (m, 2H), 1.68-1.65
(m, 2H), 1.63-1.58 (m, 7H), 1.40 (s, 3H, CH3-15), 1.34-1.22
(m, 4H), 0.96 (d, 3H, J ) 5.7 Hz, CH3-13), 0.86 (d, 3H, J ) 7.5
Hz), 0.82 (m, 1H). 13C NMR (CDCl3, 63 MHz): δ 103.4, 89.4,
81.4, 75.3, 52.6, 51.7, 44.6, 37.7, 36.9, 34.7, 30.6,29.3,29.0, 26.4,
25.2, 25.0, 25.0, 20.5, 13.2. IR (neat): υmax 2927, 2876, 2095
(N3), 1597, 1454, 1379, 1255, 1097, 1012, 946, 881 (O-O), 643
cm-1. MS (FAB): 366.4 ([M + H]+).
1.3. Syn th esis of Am id e-Lin k er ed Dim er s (12). A solu-
tion of carboxylethyl deoxoartemisinin (11) in dry CH2Cl2 (3
mL) was treated with HOBt (38 mg, 0.256 mmol) and EDC
(47 mg, 0.256 mmol). The reaction mixture was stirred at room
temperature for 30 min, and then, aminoalkyl deoxoartemisi-
nin (9) was added and further stirred at room temperature
for 4 h. The mixture was extracted with ethyl acetate (20 mL
× 3) and washed with brine (10 mL × 2). The extract was dried
over MgSO4 and concentrated in vacuo to give crude product
and was purified by a silica gel column (hexane/ethyl acetate
) 1/2 as eluent) to obtain dimer 12.
1.2. Syn th esis of Am in e Der iva tives (9). A solution of
azide derivatives 8 in dry THF (10 mL) was cooled at -78 °C.
The mixture was treated with LAH (35.1 mg, 0.925 mmol) at
-78 °C, was stirred for 1 h, then was slowly warmed to -10
°C, and was further stirred at -10 °C for 1 h. The mixture
was extracted with ethyl acetate (50 mL × 2) and washed with
brine (40 mL × 2). The extract was dried over MgSO4 and
concentrated in vacuo to give crude product and was purified
by a silica gel column (100% methanol as eluent) to obtain
amine derivatives 9.
P r ep a r a tion of 12-(2′-Am in oeth yl)d eoxoa r tem isin in
Dim er (12a ) fr om 12-(Am in oeth yl)d eoxoa r tem isin in (9a ).
This compound was prepared from 12-(carboxylethyl)deoxo-
artemisinin (11) (32 mg, 0.086 mmol) and 12-(2′-aminoethyl)-
deoxoartemisinin (9a ) (30 mg, 0.096 mmol) using the general
procedure in section 1.3 to give dimer 12a (44 mg) in 81% yield
as a colorless oil; [R]D ) +111.3° (c 0.38, CHCl3). 1H NMR
23
P r ep a r a tion of 12-(Am in oeth yl)d eoxoa r tem isin in (9a )
fr om 12-(2′-Eth yl a zid e)d eoxo-a r tem isin in (8a ). This com-
pound was prepared from 12-(2′-ethyl azide)deoxoartemisinin
(8a ) (137.9 mg, 0.352 mmol) using the general procedure in
section 1.2 to give amine (9a ) (85.4 mg) in 78% yield as a white
(CDCl3, 500 MHz): δ 6.28 (s, 1H, NH), 5.30 (s, 1H, H-5), 5.29
(s, 1H, H-5), 4.33-4.31 (m, 1H, H-12), 4.06-4.04 (m, 1H, H-12),
3.58-3.56 (m, 1H, H-2′), 3.28-3.26 (m, 1H, H-2′), 2.73-2.69
(m, 1H), 2.65-2.62 (m, 1H), 2.51-2.44 (m, 1H), 2.35-2.32 (t,
2H, J ) 13.5 Hz), 2.24-2.15 (m, 1H), 2.04-1.98 (m, 2H), 1.95-
1.89 (m, 3H), 1.78-1.71 (m, 4H), 1.66-1.64 (m, 4H), 1.40 (s,
6H, CH3-15), 1.37-1.24 (m, 9H), 0.96 (d, 3H, J ) 5.3 Hz, CH3-
13), 0.95 (d, 3H, J ) 5.7 Hz, CH3-13), 0.88 (d, 3H, J ) 7.5 Hz,
CH3-14), 0.86 (d, 3H, J ) 7.5 Hz, CH3-14), 0.84 (m, 2H). 13C
NMR (CDCl3, 63 MHz): δ 173.8, 126.8, 126.1, 118.0, 111.2,
103.7, 103.5, 89.6, 89.0, 81.5, 81.4, 76.4, 74.7, 52.8, 52.5, 44.8,
44.3, 37.8, 37.6, 36.8, 35.1, 34.8, 34.7, 30.7, 30.5, 26.5, 26.4,
25.4, 25.1, 25.0, 20.5, 20.4, 13.7, 13.6. IR (neat): υmax 3380
(NH), 2941, 2877, 1653 (CdO), 1545, 1446 (C-N), 1379, 1097,
1051, 1013, 915, 878 (O-O), 733 cm-1. HRMS (FAB): m/z
634.3995 ([M + H] +, obsd), 633.3877 (calcd for C35H55NO9).
Anal. (C35H55NO9) C, H, N.
23
solid; [R]D ) +38.7° (c 0.1, CHCl3); mp 103 °C. 1H NMR
(CDCl3, 250 MHz): δ 5.32 (s, 1H, H-5), 4.29-4.21 (m, 1H,
H-12), 2.93-2.84 (m, 3H), 2.69-2.64 (m, 1H), 2.32 (ddd, 1H,
J ) 4.0, 3.7, 4.0 Hz), 2.05-1.82 (m, 3H), 1.80-1.74 (m, 2H),
1.62-1.50 (m, 2H), 1.40 (s, 3H, CH3-15), 1.32-1.26 (m, 4H),
0.96 (d, 3H, J ) 5.7 Hz, CH3-13), 0.87 (d, 3H, J ) 7.5 Hz, CH3-
14), 0.83 (m, 1H). 13C NMR (CDCl3, 63 MHz): δ 103.5, 89.4,
81.5, 74.2, 52.7, 44.7, 41.0, 37.8, 36.9, 34.8, 33.2, 30.6, 26.5,
25.1, 25.0, 20.5, 13.4. IR (KBr): υmax 3365 (NH), 2924, 2874,
1663, 1570, 1455, 1377, 1114, 1054, 1011, 944, 877 (O-O), 753
cm-1. HRMS (FAB): m/z 312.2175 ([M + H]+, obsd), 311.2097
(calcd for C17H29NO4). Anal. (C17H29NO4) C, H, N.
P r ep a r a tion of 12-(Am in obu tyl)d eoxoa r tem isin in (9b)
fr om 12-(4′-Bu tyl a zid e)d eoxoa r tem isin in (8b). This com-
pound was prepared from 12-(4′-butyl azide)deoxoartemisinin
(8b) (128.8 mg, 0.352 mmol) using the general procedure in
section 1.2 to give the amine (9b) (94.3 mg) in 79% yield as a
white solid; [R]D25 ) +49.4° (c 0.1, CHCl3); mp 105 °C. 1H NMR
(CDCl3, 250 MHz): δ 5.29 (s, 1H, H-5), 4.16-4.09 (m, 1H,
H-12), 2.71-2.66 (m, 3H), 2.32 (ddd, 1H, J ) 4.1, 3.8, 4.1 Hz),
2.08-2.04 (m, 2H), 1.87-1.72 (m, 3H), 1.66-1.53 (m, 4H),
1.51-1.45 (m, 4H), 1.41 (s, 3H, CH3-15), 1.36-1.24 (m, 4H),
0.96 (d, 3H, J ) 4.3 Hz), 0.86 (d, 3H, J ) 7.5 Hz), 0.83 (m,
1H). 13C NMR (CDCl3, 63 MHz): δ 103.5, 89.4, 81.5, 76.0, 52.6,
51.8, 44.8, 38.4, 36.9, 34.8, 31.2,29.4, 29.0, 26.5, 25.3, 25.2, 25.1,
20.5, 13.3. IR (KBr): υmax 3378 (NH), 2925, 1591, 1454, 1379,
1117, 1038, 1005, 887 (O-O), 748 cm-1. HRMS (FAB): m/z
340.2402 ([M + H]+, obsd), 339.2410 (calcd for C19H33NO4).
Anal. (C19H33NO4) C, H, N.
P r ep a r a tion of 12-(4′-Am in obu tyl)d eoxoa r tem isin in
Dim er (12b) fr om 12-(Am in obu tyl)deoxoar tem isin in (9b).
This compound was prepared from 12-(carboxyethyl)deoxo-
artemisinin (11) (32 mg, 0.086 mmol) and 12-(4′-aminobutyl)-
deoxoartemisinin (9b) (28 mg, 0.096 mmol) using the general
procedure in section 1.3 to give the dimer 12b (46 mg) in 81%
23
yield as a colorless oil; [R]D ) +104.2° (c 0.23, CHCl3). 1H
NMR (CDCl3, 250 MHz): δ 5.68 (s, 1H, NH), 5.28 (s, 2H, H-5),
4.13-4.03 (m, 2H, H-12), 3.25-3.21 (m, 2H, H-4′), 2.72-2.65
(m, 2H), 2.39-2.21 (m, 4H), 2.11-1.67 (m, 9H), 1.61-1.46 (m,
10H), 1.40 (s, 6H, CH3-15), 1.36-1.22 (m, 7H), 0.96 (d, 6H, J
) 4.6 Hz, CH3-13), 0.89 (d, 3H, J ) 7.4 Hz, CH3-14), 0.86 (d,
3H, J ) 7.4 Hz, CH3-14), 0.83 (m, 2H). 13C NMR (CDCl3, 63
MHz): δ 173.3, 126.5, 126.3, 118.2, 112.5, 103.7, 103.6, 89.4,
89.1, 81.5, 76.9, 76.4, 75.9, 52.8, 52.5, 44.8, 44.3, 37.8, 37.0,
36.4, 36.1, 35.2, 35.1, 34.8, 34.3, 30.6, 30.6, 26.6, 26.4, 25.2,
25.1, 25.1, 25.1, 20.6, 20.5, 13.7, 13.6. IR (neat): υmax 3388
(NH), 2936, 2875, 1650 (CdO), 1539, 1452 (C-N), 1379, 1216,
1097, 1051, 1005, 873 (O-O), 753 cm-1. HRMS (FAB): m/z
662.4173 ([M + H]+, obsd), 661.4190 (calcd for C37H59NO9).
Anal. (C37H59NO9) C, H, N.
P r ep a r a tion of 12-(3′-Bu ten yl)d eoxoa r tem isin in (10)
fr om Hom ologa ted Alcoh ol (4c). This compound was pre-
pared from the homologated alcohol 4c (250 mg, 0.776 mmol)
using the same procedure for the preparation of 7a from 6a
to give 10 (50 mg) in 25% yield as a colorless oil. 1H NMR
(CDCl3, 250 MHz): δ 5.78 (m, 1H, H-3′), 5.27 (s, 1H, H-5),
P r epar ation of 12-[2′-(N-tBOC-glu tam ic-γ-ben zylester )-
r-a m id e]d eoxoa r tem isin in (13a ) fr om 12-(Am in oeth yl)-

992 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6
J ung, et al.
d eoxoa r tem isin in (9a ). A solution of N-t-BOC-L-glutamic
acid γ-benzyl ester (35 mg, 0.11 mmol) in dry CH2Cl2 (5 mL)
was treated with HOBt (52 mg, 0.342 mmol) and EDC (63 mg,
0.342 mmol). The reaction mixture was stirred at room
temperature for 30 min, and then, 12-(2′-aminoethyl)deoxo-
artemisinin (9a ) (42 mg, 0.135 mmol) was added and further
stirred at room temperature for 3 h. The mixture was extracted
with ethyl acetate (20 mL × 3) and washed with brine (10 mL
× 2). The extract was dried over MgSO4 and concentrated in
vacuo to give crude product and was purified by a silica gel
column (hexane/ethyl acetate ) 1/2 as eluent) to obtain
5H), 0.96 (d, 6H, J ) 5.3 Hz, CH3-13), 0.86 (d, 6H, J ) 7.5 Hz,
CH3-14), 0.83 (m, 2H). 13C NMR (CDCl3, 63 MHz): δ 173.3,
173.2, 171.5, 171.4, 103.5, 103.4, 89.8, 89.6, 81.4, 81.4, 76.9,
74.3, 52.5, 52.5, 44.4, 44.3, 39.3, 37.8, 36.8, 34.7, 30.8, 28.9,
28.7, 26.4, 25.2, 25.1, 20.5, 14.5, 13.0, 12.8. IR (neat): υmax 3379
(NH), 2877, 1713 (CdO), 1656 (CdO), 1545, 1451, 1379, 1268,
1030, 917, 880 (O-O), 732 cm-1. LCMS (ESI): m/z 834 ([M +
H]).
P r ep a r a tion of 12-[2′-(N-Glu ta m ic)-r,â-a m id e]d eoxo-
a r tem isin in Dim er (14b) fr om Dim er 14a . To a stirred
solution of dimer 14a (28 mg, 0.036 mmol) in dry CH2Cl2 (2
mL at 0 °C for 30 min, TFA (4.92 mg, 1.2 equiv) was slowly
dropped. The reaction mixture was stirred at 0 °C for 4 h and
was extracted with ethyl acetate (20 mL × 3) and washed with
brine (10 mL × 2). The extract was dried over MgSO4 and
concentrated in vacuo to give crude product and was purified
by a silica gel column (hexane/ethyl acetate ) 1/2 as eluent)
to obtain dimer 14b (19 mg) in 72% yield as a colorless oil:
25
compound (13a ) (71.5 mg) in 84% yield as a colorless oil; [R]D
1
) +73.6° (c 0.47, CHCl3). H NMR (CDCl3, 250 MHz): δ 7.36
(s, 5H, aromatic H), 7.02 (br, 1H, NH), 5.33 (s, 1H, H-5), 5.11
(s, 2H, benzyl), 4.40-4.39 (m, 1H, H-12), 4.29-4.27 (m, 1H),
4.15-4.13 (m, 1H), 3.58-3.56 (m, 1H, H-2′), 3.28-3.24 (m, 1H,
H-2′), 2.61-2.43 (m, 3H), 2.36-2.14 (m, 3H), 2.12-1.98 (m,
4H), 1.91-1.65 (m, 4H), 1.44 (s, 9H, t-BOC), 1.42 (s, 3H, CH3-
15), 1.35-1.26 (m, 3H), 0.96 (d, 3H, J ) 5.6 Hz, CH3-13), 0.85
(d, 3H, J ) 7.6 Hz, CH3-14), 0.82 (m, 1H). 13C NMR (CDCl3,
63 MHz): δ 173.2, 171.5, 155.2, 136.1, 128.8, 128.8, 128.5,
128.5, 128.4, 128.4, 103.8, 89.9, 81.3, 74.4, 66.6, 61.2, 53.1, 52.3,
44.0, 39.4, 37.7, 36.7, 34.6, 30.8, 28.6, 28.5, 28.5, 26.2, 25.1,
25.0, 20.4, 12.6. IR (neat): υmax 3364 (NH), 2932, 2876, 1736
(CdO), 1663 (CdO), 1538, 1453, 1393, 1249, 1163, 1051, 880
(O-O), 702, 610 cm-1. HRMS (FAB): m/z 631.3507 ([M + H]+,
obsd), 630.3516 (calcd for C34H50N2O9).
25
1
[R]D ) +120.8° (c 0.48, CHCl3). H NMR (CDCl3, 250 MHz):
δ 6.83 (s, 1H, NH), 5.74 (s, 1H, NH), 5.34 (s, 1H, h-5), 5.31 (s,
1H, H-5), 4.35-4.33 (m, 2H, H-12), 4.15-4.12 (m, 1H), 3.53-
3.49 (m, 2H), 3.27-3.24 (m, 2H), 2.64-2.62 (m, 2H), 2.32-2.30
(m, 2H), 2.15-1.58 (m, 12H), 1.53-1.41 (m, 10H), 1.39 (s, 6H,
CH3-15), 1.34-1.28 (m, 6H), 0.97 (d, 6H, J ) 5.3 Hz, CH3-14),
0.86 (d, 6H, J ) 7.5 Hz, CH3-14), 0.82 (m, 2H). 13C NMR (63
MHz, CDCl3): δ 173.4, 173.3, 171.5, 171.3, 103.6, 103.4, 89.8,
89.7, 84.4, 84.3, 76.9, 74.3, 52.6, 52.4, 44.5, 44.3, 39.3, 37.9,
36.7, 34.6, 30.9, 30.8, 28.7, 26.4, 25.2, 25.1, 20.5, 20.4, 14.5,
13.3, 12.7. IR (neat): υmax 3367 (NH), 3098 (NH), 2956, 2868,
P r ep a r a tion of 12-[2′-(N-tBOC-glu ta m ic a cid )-r-a m id e]-
d eoxoa r tem isin in (13b) fr om 12-[2′-(N-tBOC-glu ta m ic-γ-
ben zylester )-r-a m id e]d eoxoa r tem isin in (13a ). A solution
1689 (CdO), 1558, 1446, 1380, 1209, 1137, 998, 887 (O-O),
+
847, 757, 729 cm-1. HRMS (FAB): m/z 734.4592 ([M + H]
obsd), 733.4513 (calcd for C39H63N3O10). Anal. (C39H63N3O10
C, H, N.
,
of
12-[2′-(N-tBOC-glutamic-γ-benzylester)-R-amide]deoxo-
)
artemisinin (13a ) (36 mg, 0.057 mmol) in dry THF/H2O(1/1, 5
mL) was treated with 1 N LiOH (1 mL) and then was stirred
at room temperature for 2 h. The reaction mixture was poured
onto 1 N HCl (1 mL) for acidification, and then extracted with
ethyl acetate (20 mL × 3) and washed with brine (10 mL ×
2). The extract was dried over MgSO4 and concentrated in
vacuo to give crude product and was purified by a silica gel
column (hexane/ethyl acetate ) 1/2 as eluent) to obtain
P r ep a r a tion of 12-(2′-Eth ylsu lfu r )d eoxoa r tem isin in
Dim er (18a) fr om 12-(Eth ylbr om o)deoxoar tem isin in (7a).
A solution of 12-(2′-bromoethyl)deoxoartemisinin (7a ) (45 mg,
0.124 mmol) in absolute ethanol (4 mL) was stirred at room
temperature for 10 min, and then, Na2S (4.8 mg, 0.5 equiv)
was slowly added. The reaction mixture was stirred at room
temperature for 7 h, then was extracted with ethyl acetate
(10 mL × 3), and washed with brine (10 mL × 2). The extract
was dried over MgSO4 and concentrated in vacuo to give crude
product and was purified by a silica gel column (hexane/ethyl
acetate ) 5/1 as eluent) to obtain dimer 18a (58.7 mg) in 76%
yield as a colorless oil; [R]D25 ) +58.7° (c 0.23, CHCl3). 1H NMR
(CDCl3, 250 MHz): δ 5.29 (s, 2H, H-5), 4.24-4.19 (m, 2H,
H-12), 2.91-2.84 (m, 2H), 2.71-2.70 (m, 2H), 2.55-2.49 (m,
2H), 2.33 (ddd, 2H, J ) 3.1, 3.5, 4.0 Hz), 2.03-1.78 (m, 8H),
1.67-1.55 (m, 10H), 1.41 (s, 6H, CH3-15), 1.36-1.26 (m, 4H),
0.96 (d, 6H, J ) 5.8 Hz, CH3-13), 0.88 (d, 6H, J ) 7.4 Hz, CH3-
14), 0.83 (m, 2H). 13C NMR (63 MHz, CDCl3): δ 103.6, 89.2,
81.4, 76.8, 75.5, 52.7, 44.8, 37.7, 36.9, 34.8, 30.5, 30.1, 26.5,
25.2, 25.0, 20.6, 13.5. IR (neat): υmax 2925, 2876, 1617, 1459,
1379, 1119, 1054, 1011, 887 (O-O), 735 cm-1. HRMS (FAB):
m/z 645.3541 ([M + Na]+, obsd), 622.3539 (calcd for C34H54O8S).
Anal. (C34H54O8S) C, H, S.
P r ep a r a tion of S,S′-[12-(2′-Eth yl)d eoxoa r tem isin in ]-
d ith iop r op a n e (19a ) fr om 12-(2′-Br om oeth yl)d eoxoa r te-
m isin in (7a ). After the powdered KOH (12.36 mg, 0.22 mmol)
was stirred at room temperature in DMSO (2 mL) for 1 h, this
solution was treated with 1,3-propanedithiol (6.46 µ, 0.054
mmol) and 12-(2′-bromoethyl)deoxoartemisinin (7a ) (41 mg,
0.112 mmol) and then further stirred at room temperature for
1 h. The reaction mixture was extracted with ethyl acetate
(30 mL × 3) and washed with brine (20 mL × 2). The extract
was dried over MgSO4 and concentrated in vacuo to give crude
product and was purified by a silica gel column (hexane/ethyl
acetate ) 5/2 as eluent) to obtain dimer 19a (50.7 mg) in 65%
yield as a colorless oil: [R]D24 ) +112.3° (c 0.4, CHCl3). 1H NMR
(CDCl3, 250 MHz): δ 5.29 (s, 2H, H-5), 4.22-4.17 (m, 2H,
H-12), 2.83-2.66 (m, 10H), 2.41-2.29 (m, 2H), 2.05-1.76 (m,
10H), 1.66-1.53 (m, 10H), 1.41 (s, 6H, CH3-15), 1.33-1.26
(m, 4H), 0.96 (d, 6H, J ) 5.7 Hz, CH3-13), 0.88 (d, 3H, J ) 7.5
Hz, CH3-14), 0.83 (m, 2H). 13C NMR (CDCl3, 63 MHz): δ 103.6,
25
compound 13b (26.8 mg) in 87% yield as a colorless oil; [R]D
1
) +66.4° (c 0.34, CHCl3). H NMR (CDCl3, 250 MHz): δ 5.60
(d, 1H, J ) 7.9 Hz, NH), 5.33 (s, 1H, H-5), 4.34-4.32 (m, 1H,
H-12), 4.20-4.15 (m, 1H), 3.49-3.47 (m, 1H, H-2′), 3.33-3.31
(m, 1H, H-2′), 2.66-2.58 (m, 1H), 2.48-2.40 (m, 2H), 2.30 (ddd,
1H, J ) 2.2, 1.9, 3.7 Hz), 2.03-1.73 (m, 5H), 1.67-1.61 (m,
6H), 1.41 (s, 9H, t-BOC), 1.38 (s, 3H, CH3-15), 1.33-1.21 (m,
3H), 0.95 (d, 3H, J ) 5.1 Hz, CH3-13), 0.84 (d, 3H, J ) 7.4 Hz,
CH3-14), 0.81 (m, 1H). 13C NMR (CDCl3, 63 MHz): δ 176.6,
172.2, 103.7, 89.7, 81.4, 76.9, 74.7, 53.4, 52.5, 44.3, 39.1, 37.8,
36.8, 34.7, 30.7, 30.6, 29.8, 28.7, 28.7, 28.7, 28.7, 26.2, 25.2,
25.0, 20.5, 13.0. IR (neat): υmax 3352 (CO2H and NH), 2933,
2879, 1714 (CdO), 1657 (CdO), 1533, 1459, 1379, 1275, 1170,
1053, 914, 882 (O-O), 733 cm-1. LCMS (ESI): m/z 540 ([M+]).
P r ep a r a tion of 12-[2′-(N-tBOC-glu ta m ic)-r,â-a m id e]-
d eoxoa r t em isin in Dim er (14a ) fr om 12-[2′-(N-tBOC-
glu ta m ic-γ-ca r boxylic a cid )-r-a m id e]d eoxoa r tem isin in
(13b). A solution of 12-[2′-(N-tBOC-glutamic-γ-carboxylic acid)-
R-amide]deoxoartemisinin (13b) (21 mg, 0.039 mmol) in dry
CH2Cl2 (2 mL) was treated with HOBt (22 mg, 0.119 mmol)
and EDC (29 mg, 0.119 mmol). The reaction mixture was
stirred at room temperature for 30 min, and then, 12-(2′-
aminoethyl)deoxoartemisinin (9a ) (18 mg, 0.058 mmol) was
added and further stirred at room temperature for 3 h. The
mixture was extracted with ethyl acetate (20 mL × 3) and
washed with brine (10 mL × 2). The extract was dried over
MgSO4 and concentrated in vacuo to give crude product and
was purified by a silica gel column (hexane/ethyl acetate )
1/2 as eluent) to obtain dimer 14a (16.6 mg) in 51% yield as a
colorless oil: [R]D25 ) +114.6° (c 0.46, CHCl3). 1H NMR (CDCl3,
250 MHz): δ 6.71 (s, 1H, NH), 5.87 (s, 1H, NH), 5.34 (s, 1H,
H-5), 5.33 (s, 1H, H-5), 4.34-4.31 (m, 2H, H-12), 4.13-4.10
(m, 1H), 3.53-3.48 (m, 2H), 3.25-3.23 (m, 2H), 2.62-2.60 (m,
2H), 2.39-2.29 (m, 6H), 2.05-1.88 (m, 8H), 1.86-1.62 (m,
12H), 1.43 (s, 9H, t-BOC), 1.39 (s, 6H, CH3-15), 1.28-1.25 (m,

Novel Deoxoartemisinin Monomers, Dimers, and Trimer
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6 993
89.3, 81.4, 75.3, 52.7, 44.7, 38.8, 37.8, 36.9, 34.8, 32.2, 30.5,
30.2, 29.1, 26.5, 25.2, 25.0, 20.5, 13.4. IR (neat): υmax 2928,
2873, 1655, 1719, 1452, 1378, 1215, 1120, 1036, 877 (O-O),
755 cm-1. HRMS (FAB): m/z 719.3701 ([M + Na]+, obsd),
696.3730 (calcd for C37H60O8S2). Anal. (C37H60O8S2) C, H, S.
61.0, 52.7, 52.0, 44.8, 37.7, 36.8, 34.8, 34.8, 31.2, 30.7, 30.5,
27.8, 26.4, 25.2, 25.0, 20.5, 14.5, 13.5. IR (neat): υmax 3370
(NH), 2939, 2878, 1737 (CdO), 1669 (CdO), 1533, 1446, 1372,
1054, 1012, 880 (O-O), 742 cm-1. MS (FAB): m/z 526.5 ([M
+ H] +). Anal. (C27H43NO9) C, H, N.
P r ep a r a tion of N-[12-(â-Deoxoa r tem isin in )p r op ion yl]-
L-glu ta m ic Dia cid (16) fr om Ester 15. A solution of N-[12-
(â-deoxoartemisinin)propionyl]-L-glutamic diethyl ester (15) (2
mg, 0.08 mmol) in dry THF/H2O (1/1, 5 mL) was treated with
1 N LiOH (1 mL) and then was stirred at room temperature
for 2 h. The reaction mixture was poured onto 1 N HCl (1 mL)
for acidification and then extracted with ethyl acetate (20 mL
× 3) and washed with brine (10 mL × 2). The extract was dried
over MgSO4 and concentrated in vacuo to give crude product
and was purified by a silica gel column (hexane/ethyl acetate
) 1/2 as eluent) to obtain compound 16 (30.8 mg) in 82% yield
1.4. Oxid a tion of Su lfu r -Lin k ed Dim er s (18a a n d 19a ).
A solution of sulfide deoxoartemisinin dimer 18a or 19a in
dry CH2Cl2 (2 mL) was stirred at room temperature for 10 min,
and then, m-CPBA (2.2 eq) was slowly added. The reaction
mixture was stirred at room temperature for 3 h and then was
poured onto saturated NaHCO3 solution (3 mL). The mixture
was extracted with ethyl acetate (10 mL × 3) and washed with
brine (10 mL × 2). The extract was dried over MgSO4 and
concentrated in vacuo to give crude product and was purified
by a silica gel column (hexane/ethyl acetate ) 2/1 as eluent)
to obtain sulfone dimer 18b or 19b.
26
as a colorless solid; [R]D ) +76.8° (c 0.22, CHCl3); mp 106
P r ep a r a tion of 12-(2′-Eth yl su lfon e)d eoxoa r tem isin in
Dim er (18b) fr om Su lfid e 18a . This compound was prepared
from 12-(2′-ethyl sulfide)deoxoartemisinin dimer (18a ) (28 mg,
0.041 mmol) and m-CPBA (15.7 mg, 0.091 mmol) using the
general procedure in section 1.4 to give the dimer 18b (24.6
1
°C. H NMR (CDCl3, 250 MHz): δ 8.96 (br, 2H, CO2H), 7.08
(d, 1H, J ) 6.5 Hz, NH), 5.34 (s, 1H, H-5), 4.62-4.60 (m, 1H),
4.12-4.04 (m, 1H, H-12), 2.72-2.70 (m, 1H), 2.48-2.26 (m,
6H), 2.08-1.98 (m, 3H), 1.82-1.78 (m, 3H), 1.71-1.42 (m, 4H),
1.41 (s, 3H, CH3-15), 1.27-1.21 (m, 2H), 0.95 (d, 3H, J ) 5.3
Hz, CH3-13), 0.87 (d, 3H, J ) 7.2 Hz, CH3-14), 0.84 (m, 1H).
13C NMR (CDCl3, 63 MHz): δ 177.3, 176.6, 175.1,174.7, 104.3,
89.0, 81.5, 76.9, 52.8, 52.1, 44.9, 37.6 36.8, 34.8, 34.5, 30.4,
27.1, 26.2, 25.1, 24.9, 21.0, 20.6, 13.7. IR (KBr): υmax 3346
(CO2H), 2942, 2877, 1728 (CdO), 1631 (CdO), 1539, 1453,
1381, 1202, 1051, 912, 880 (O-O), 732 cm-1. LCMS (ESI): m/z
492 ([M + Na]+). Anal. (C23H35NO9) C, H, N.
20
mg) in 91% yield as a white solid; [R]D ) +84.2° (c 0.44,
1
CHCl3); mp 98 °C. H NMR (CDCl3, 250 MHz): δ 5.30 (s, 2H,
H-5), 4.25-4.18 (m, 2H, H-12), 3.53-3.41 (m, 2H, H-2′), 3.05-
2.93 (m, 2H, H-2′), 2.79-2.71 (m, 2H), 2.36 (ddd, 2H, J )
3.2, 3.5, 4.1 Hz), 2.17-1.92 (m, 6H), 1.88-1.78 (m, 4H), 1.69-
1.49 (m, 8H), 1.39 (s, 6H, CH3-15), 0.97 (d, 6H, J ) 5.7 Hz,
CH3-13), 0.92 (d, 6H, J ) 7.6 Hz, CH3-14), 0.89 (m, 2H). 13C
NMR (CDCl3, 63 MHz): δ 134.1, 130.6, 130.1, 128.6, 103.6,
89.4, 81.4, 74.1, 52.5, 44.4, 36.8, 30.5, 26.4, 25.2, 22.4, 20.4,
13.2. IR (KBr): υmax 2928, 2876, 1723, 1575, 1449, 1380, 1280,
1123, 1052, 880 (O-O), 734 cm-1. HRMS (FAB): m/z 677.3335
([M + Na]+, obsd), 654.3438 (calcd for C34H64O10S). Anal.
(C34H64O10S) C, H, S.
P r ep a r a tion of Deoxoa r tem isin in Tr im er 17 fr om
N-[12-(â-Deoxoa r tem isin in )p r op ion yl]-L-glu ta m ic Dia cid
(16). A solution of N-[12-(â-deoxoartemisinin)propionyl]-L-
glutamic diacid (16) (22 mg, 0.047 mmol) in dry CH2Cl2 (2 mL)
was treated with HOBt (27 mg, 0.141 mmol) and EDC (31 mg,
0.141 mmol). The reaction mixture was stirred at room
temperature for 30 min, and then, 12-(2′-aminoethyl)deoxo-
artemisinin (9a ) (29 mg, 0.093 mmol) was added and further
stirred at room temperature for 19 h. The mixture was
extracted with ethyl acetate (30 mL × 3) and washed with
brine (20 mL × 2). The extract was dried over MgSO4 and
concentrated in vacuo to give crude product and was purified
by a silica gel column (hexane/ethyl acetate ) 1/2 as eluent)
to obtain trimer 17 (73.3 mg) in 74% yield as a colorless solid;
P r ep a r a tion of S,S′-[12-(2′-Eth yl)d eoxoa r tem isin in ]-
d isu lfon yl P r op a n e (19b) fr om Dim er 19a . This compound
was prepared from S,S′-[12-(2′-ethyl)deoxoartemisinin]dithio-
propane (19a ) (29 mg, 0.041 mmol) and m-CPBA (31.1 mg,
0.18 mmol) using the general procedure in section 1.4 to give
25
the dimer 19b (22.6 mg) in 72% yield as a white solid; [R]D
1
) +110.4° (c 0.47, CHCl3); mp 138 °C. H NMR (CDCl3, 250
MHz): δ 5.30 (s, 2H, H-5), 4.25-4.21 (m, 2H, H-12), 3.49-
3.43 (m, 2H), 3.26 (t, 2H, J ) 7.1 Hz), 3.04-2.92 (m, 2H), 2.74-
2.62 (m, 2H), 2.49-2.43 (m, 2H), 2.41-2.29 (m, 2H), 2.08-
1.94 (m, 8H), 1.89-1.75 (m, 4H), 1.69-1.59 (m, 8H), 1.39 (s,
6H, CH3-15), 1.34-1.27 (m, 4H), 0.97 (d, 6H, J ) 5.7 Hz, CH3-
13), 0.91 (d, 6H, J ) 7.6 Hz, CH3-14), 0.88 (m, 2H). 13C NMR
(CDCl3, 63 MHz): δ 134.2, 130.6, 130.1, 128.4, 103.6, 89.5,
81.4, 74.1, 52.5, 44.3, 37.7, 36.8, 34.7, 31.3, 30.5, 26.4, 25.2,
20.4, 13.5. IR (KBr): υmax 2926, 2875, 1720, 1584, 1495, 1387,
1310, 1130, 1052, 877 (O-O), 756, 465 cm-1. HRMS (FAB):
[R]D ) +102.7° (c 0.41, CHCl3); mp 138 °C. 1H NMR (CDCl3,
24
250 MHz): δ 7.13-7.04 (m, 2H, NH), 6.83-6.81 (m, 1H, NH),
5.32 (s, 2H, H-5), 5.29 (s, 1H. H-5), 4.39-4.34 (m, 3H, H-12),
4.29-4.26 (m, 1H), 3.55-3.48 (m, 2H), 3.32-3.27 (m, 2H),
2.65-2.63 (m, 3H), 2.36-2.31 (m, 7H), 2.17-1.93 (m, 11H),
1.91-1.51 (m, 17H), 1.39 (s, 9H, CH3-15), 1.33-1.21 (m, 7H),
0.95 (d, 9H, J ) 5.4 Hz, CH3-13), 0.88-0.83 (m, 9H, CH3-14),
0.82 (m, 3H). 13C NMR (CDCl3, 63 MHz): δ 174.4, 174.3, 173.2,
173.1, 103.5, 103.4, 89.9, 89.8, 81.5, 81.4, 76.8, 53.2, 53.1, 52.8,
52.6, 52.4, 37.7, 36.8, 34.7, 31.3, 30.8, 30.7, 30.0, 29.1, 26.4,
26.4, 25.1, 20.5, 20.4, 13.2, 13.1. IR (KBr): υmax 3308 (NH),
2933, 2875, 1667 (CdO), 1535, 1465, 1377, 1102, 1061, 1014,
938, 874 (O-O), 751 cm-1. HRMS (FAB): m/z 1056.6392 ([M
+ H]+, obsd), 1055.6294 (calcd for C57H89N3O15). Anal.
(C57H89N3O15) C, H, N.
m/z 783.3538 ([M + Na]+, obsd), 760.3526 (calcd for C37H60
12S2). Anal. (C37H60O12S2) C, H, S.
P r ep a r a tion of N-[12-(â-Deoxoa r tem isin in )p r op ion yl]-
-
O
L-glu t a m ic Diet h yl E st er (15) fr om 12-(Ca r boxyet h yl)-
d eoxoa r tem isin in (11). A solution of 12-(carboxylethyl)-
deoxoartemisinin (11) (32 mg, 0.086 mmol) in dry CH2Cl2 (3
mL) was treated with HOBt (38 mg, 0.256 mmol) and EDC
(47 mg, 0.256 mmol). The reaction mixture was stirred at room
temperature for 30 min, and after L-glutamic diethyl ester (36
mg, 0.171 mmol) was added, the solution was further stirred
at room temperature for 3 h. The mixture was extracted with
ethyl acetate (20 mL × 3) and washed with brine (10 mL ×
2). The extract was dried over MgSO4 and concentrated in
vacuo to give crude product and was purified by a silica gel
Biology. In Vitr o An titu m or Assa y. The in vitro cyto-
toxicity of deoxoartemisinin and its related trioxanes to the
murine and human cancer cells was defined by the micro-
culture tetrazolium assay as described by Carmichel et al.44
Adriamycin, mitomycin, and taxol were used as the reference
substances, exhibiting the activity with an IC50 (µg/mL) as
shown in Table 1 toward mouse and human cell lines.
Ack n ow led gm en t. This study was supported by a
research grant from the Ministry of Health and Welfare
(Project No. HMP-00-B-21500-00106), the Republic of
Korea.
column (hexane/ethyl acetate ) 1/2 as eluent) to obtain
25
compound 15 (37.9 mg) in 84% yield as a colorless oil; [R]D
)
+44.5° (c 0.47, CHCl3). 1H NMR (CDCl3, 250 MHz): δ 6.31 (d,
1H, J ) 7.5 Hz, NH), 5.29 (s, 1H, H-5), 4.63-4.56 (m, 1H),
4.23-4.08 (m, 5H), 2.75-2.71 (m, 1H), 2.50-2.18 (m, 7H),
2.04-1.65 (m, 9H), 1.40 (s, 3H, CH3-15), 1.31 (s, 3H), 1.28 (s,
3H), 1.22-1.15 (m, 2H), 0.96 (d, 3H, J ) 5.8 Hz, CH3-13), 0.88
(d, 3H, J ) 7.5 Hz, CH3-14), 0.85 (m, 1H). 13C NMR (CDCl3,
63 MHz): δ 173.2, 172.3, 103.7, 89.1, 81.5, 76.8, 76.3, 61.9,
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