Synthesis and cytotoxicity of artemisinin derivatives containing cyanoarylmethyl group

Article abstract of DOI:10.1016/S0223-5234(01)01240-5

A series of 12α-deoxoartemisinyl cyanoarylmethyl dicarboxylates (4a-4o), dicarboxylic acids 12α-deoxoartemisinyl ester cyanoarylmethyl amide (5a-5k), and dicarboxylic acids 12α-deoxoartemisinyl ester N-methylcyanoarylmethyl amide (6a-6l), showing moderate cytotoxicity against P388 and L1210 cells were prepared. They induced the significant accumulation of L1210 and P388 cells in the G1 phase of the cell cycle. This mechanism of action was quite different from that of the majority of cytotoxic compounds used in the chemotherapy of cancer. Compound 4b possessed better cytotoxicity than the other compounds.

Full text of DOI:10.1016/S0223-5234(01)01240-5

Eur. J. Med. Chem. 36 (2001) 469–479
´
© 2001 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved
PII: S0223-5234(01)01240-5/FLA
Short communication
Synthesis and cytotoxicity of artemisinin derivatives containing
cyanoarylmethyl group
Jin-Ming Wua, Feng Shana, Guang-Shao Wua, Ying Lia,*, Jian Dingb, Dong Xiaob,
Jia-Xian Hanb, Ghanem Atassic, Ste´phane Leoncec, Daniel-Henri Caignardd, Pierre Renardd
aDepartment of Synthetic Chemistry, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences,
Chinese Academy of Sciences, Shanghai 200031, China
bDepartment of Pharmacology, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences,
Chinese Academy of Sciences, Shanghai 200031, China
cInstitut de Recherche Servier, Suresnes, France
dADIR ET COMPAGNIE, Courbevoie, France
Received 18 January 2001; revised 23 April 2001; accepted 2 May 2001
Abstract – A series of 12a-deoxoartemisinyl cyanoarylmethyl dicarboxylates (4a–4o), dicarboxylic acids 12a-deoxoartemisinyl ester
cyanoarylmethyl amide (5a–5k), and dicarboxylic acids 12a-deoxoartemisinyl ester N-methylcyanoarylmethyl amide (6a–6l),
showing moderate cytotoxicity against P388 and L1210 cells were prepared. They induced the significant accumulation of L1210 and
P388 cells in the G1 phase of the cell cycle. This mechanism of action was quite different from that of the majority of cytotoxic
compounds used in the chemotherapy of cancer. Compound 4b possessed better cytotoxicity than the other compounds. © 2001
´
Editions scientifiques et me´dicales Elsevier SAS
artemisinin derivatives / cyanoarylmethyl group / cytotoxicity
1. Introduction
changing of some the substituents might lead to yet
another new type of antitumor agent. Thus, 12a-de-
oxoartemisinyl cyanoarylmethyl dicarboxylates (4a–
4o) dicarboxylic acid 12a-deoxoartemisinyl ester
cyanoarylmethyl amide (5a–5k) and N-methyl-
cyanoarylmethyl amide (6a–6l) were prepared. Some
of the new artemisinin derivatives showed moderate
cytotoxicity in vitro against L1210 and P388 cell lines
having a mechanism of action similar to compound
2a. Compound 4b was the best one in the series next
to compound 2a (figure 1).
Artemisinin (1a) and its derivatives (dihydro-
artemisinin (1b), artemether (1c), arteether (1d), and
artesunate (3a)) distinguished themselves as a new
generation of antimalarial drugs with low toxicity [1].
Some of them possess other bioactivities also [2]. In
our laboratory it was found that the new type of
artemisinin derivatives, cyano-4%-bromophenylmethyl
12b-deoxoartemisinyl ether (2a) was notably active in
vitro against P388 and A549 cell lines and block the
cell cycle progression of P388 murine leukemia cells in
the G1 phase [3]. Recently it was also reported that
artesunate showed antitumor activity both in vitro
and in vivo [4]. Based on these facts, a combination of
a-hydroxyarylacetonitrile with artesunate and by
2. Chemistry
Artemisinin (1a) was reduced by sodium borohy-
dride to give dihydroartemisinin (1b), which reacted
with succinic anhydride to yield artesunate (3a) ac-
cording to literature procedure [5, 6]. Other dicar-
boxylic acids mono-12a-deoxoartemisinyl ester
* Correspondence and reprints: 294 Taiyuan Road, Shanghai
200031, China.
E-mail address: yli@mail.shcnc.ac.cn (Y. Li).

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J.-M. Wu et al. / European Journal of Medicinal Chemistry 36 (2001) 469–479
Figure 1. Structures of compounds 1–6.
These esters and amides were purified using column
chromatography and some of them were recrystal-
lized from ethyl acetate–petroleum ether. However,
others exist as amorphous solid. All the products
tested were 12a-isomers as indicated by the large
coupling constants (J>9 Hz) between 11-H and 12-H
(3b–3d) was prepared by the condensation of dicar-
boxylic acid with dihydroartemisinin in the presence
of DCC and DMAP (figure 2). a-Hydroxyarylace-
tonitrile and a-aminoarylacetonitrile were obtained
from aromatic aldehyde by following the procedure
outlined in Refs. [7–9]. If ammonia solution was
replaced by methylamine solution during the prepara-
tion of a-aminoarylacetonitrile, then N-methyl-a-
aminoarylacetonitrile was obtained. The esters
(4a–4o) were prepared by the condensation of dicar-
boxylic acid mono-12a-deoxoartemisinyl ester (3a–
3d) with a-hydroxyarylacetonitrile in the presence of
DCC and DMAP. Similarly, the amides (5a–5k) were
produced from artesunate (3a) and a-aminoarylace-
tonitrile (figure 3). The amides (6a–6l) were prepared
by the condensation of 1b with dicarboxylic acid
mono-N-methyl-cyanoarylmethyl amide (7a–7l) pre-
pared by the reaction of dicarboxylic anhydride and
N-methyl-a-aminoarylacetonitrile in the presence of
triethylamine (figure 4).
1
in H NMR (the b-isomers, J:3–4 Hz). As a-hy-
droxyarylacetonitrile, a-aminoarylacetonitrile or N-
methyl-a-aminoarylacetonitrile possess
a
chiral
center, all esters and amides (4–6) possess a pair of
epimer that could not be discriminated on TLC and
were hence separated using column chromatography
(table I).
3. Pharmacology
3.1. Cell culture and cytotoxity
The murine L1210 and P388 leukemia and human
lung A549 carcinoma cell lines were cultivated in RPMI
1640 medium supplemented with 10% fetal calf serum, 2
Figure 2. Synthesis of compound 3.

J.-M. Wu et al. / European Journal of Medicinal Chemistry 36 (2001) 469–479
471
Figure 3. Synthesis of compounds 4 and 5.
Figure 4. Synthesis of compound 6.
mM
-glutamine, 100 units mL−1 penicillin, 100
L
bated for 30 min in PBS containing 100 mg mL−1
RNAse and 50 mg mL−1 propidium iodide (PI, Sigma).
For each sample, 104 cells were analyzed on an Epics
XL/MCL flow cytometer (Becgman counter, France).
Results are expressed as the percentage of cells in the G1
phase of the cell cycle and in the sub-G1 phase (apop-
totic cells). Apoptotic cells were also quantified by flow
cytometry using the annexin-V-FITC labeling. The re-
sults are shown in table II.
mg mL−1 streptomycin, and 10 mM HEPES buffer (pH
7.4). The in vitro cytotoxicity of these artemisinin
derivatives to the murine and human cancer cells was
defined by the microculture tetrazolium assay as de-
scribed in Ref. [10]. Briefly, L1210, P388 and A549 cells
were exposed to graded concentrations of the drug for
48 and 96 h, respectively (4 doubling times). Results
were expressed as IC50, the concentration that reduced
by 50% the optical density of the treated cells with
respect to the density of untreated cells. Vincristine
Sulfate (VCR) was used as a reference cytotoxic
compound.
4. Results and discussion
The cytotoxicity of these artemisinin derivatives are
listed in table II.
3.2. Cell cycle and apoptosis
The data in table II indicated that some of these
compounds had moderate cytotoxicity to L1210 and
P388 but less cytotoxicity to A549. Some of these
compounds 4–6 as well as compound 2a could block
L1210 and P388 cells (2.5×105 mL−1) were first incu-
bated for 21 h in various concentrations of the drugs
followed by cells being fixed in 70% ethanol and incu-

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J.-M. Wu et al. / European Journal of Medicinal Chemistry 36 (2001) 469–479
the cell cycle progression of P388 murine leukemia cells
in the G1 phase and induced apoptose. Some com-
pounds also acted on the L1210 cells in the same mode.
Of the compounds examined, the ester 4 showed po-
tent cytotoxicity against L1210 and P388 cells; com-
pound 4b was the best one; and the amide 6 appeared
to be better than amide 5 against P388 cells. We found
that a deoxoartemisinyl moiety was required. As 2a
showed good cytotoxity against P388 and A549, its de-
oxy analog 2b was inactive [3]. Compounds 4b and 4m,
4a and 4n, 4d and 4o having the same aryl moiety, re-
spectively, in spite of chain length (Y=C2 –C7),
showed a similar cytotoxicity. Similar results were also
observed in the case of amides 6j, 6k and 6l. Moreover,
the electronegativity and the bulk of the substituent
that attach to the aryl ring play an insignificant role in
cytotoxicity. Therefore, the relationship between cyto-
toxicity and chemical structure was not so clear. In
other words, compounds 4–6 derived from the inser-
tion of dicarboxylic acid radical between the
cyanoarylmethyl and deoxoartemisinyl groups showed
less cytotoxicity than that of compound 2a.
Table I. Physico-chemical data of compounds 4–6.
Compound
Ar
Y
X
M.p. (dec.) (°C)
Yield (%)
Molecular formula
4a
4b
4c
4d
4e
4f
4g
4h
4I
4j
C6H5
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)4
(CH2)5
(CH2)7
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
1,2-C6H4
CHꢀCH (cis)
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NMe
NMe
NMe
NMe
NMe
NMe
NMe
NMe
NMe
NMe
NMe
NMe
142–144
31
37
27
83
60
57
25
42
40
60
79
68
65
60
42
24
40
28
37
24
22
24
38
30
32
49
47
59
56
81
48
70
33
80
43
53
70
45
C27H33NO8
2-ClC6H4
4-ClC6H4
2-BrC6H4
4-BrC6H4
4-CNC6H4
4-NO2C6H4
4-OMeC6H4
2,4-(OMe)2C6H3
3,4-(OMe)2C6H3
3-OMe, 4-Obz C6H3
3,4-OCH2OC6H3
2-ClC6H4
C6H5
2-BrC6H4
C6H5
2-FC6H4
3-FC6H4
4-FC6H4
3-ClC6H4
4-ClC6H4
2-BrC6H4
3-BrC6H4
4-BrC6H4
4-NMe2C6H4
2-naphthyl
C6H5
amorphous
amorphous
amorphous
amorphous
amorphous
amorphous
amorphous
amorphous
amorphous
amorphous
amorphous
amorphous
amorphous
amorphous
153–154
161–162
146–148
158–160
154–156
164–165
156–159
153–156
165–167
C27H32ClNO8
C27H32ClNO8
C27H32BrNO8
C27H32BrNO8
C28H32N2O8
C27H32N2O10
C28H35NO9
C29H37NO10
C29H37NO10
C35H41NO10
C28H33NO10
C29H36ClNO8
C31H41NO8
C32H42BrNO8
C27H34N2O7
C27H33FN2O7
C27H33FN2O7
C27H33FN2O7
C27H33ClN2O7
C27H33ClN2O7
C27H33BrN2O7
C27H33BrN2O7
C27H33BrN2O7
C29H39N3O7
C31H36N2O7
C28H36N2O7
C28H35FN2O7
C28H35FN2O7
C28H35FN2O7
C28H35ClN2O7
C28H35ClN2O7
C28H35BrN2O7
C28H35BrN2O7
C30H40N2O7
C35H39F3N2O8
C32H36N2O7
C28H34N2O7
4k
4l
4m
4n
4o
5a
5b
5c
5d
5e
5f
5g
5h
5I
5j
5k
6a
6b
6c
6d
6e
6f
6g
6h
6I
6j
160–162
amorphous
amorphous
amorphous
amorphous
amorphous
amorphous
amorphous
amorphous
amorphous
amorphous
amorphous
amorphous
amorphous
2-FC6H4
3-FC6H4
4-FC6H4
2-ClC6H4
4-ClC6H4
2-BrC6H4
4-BrC6H4
2,4-Me2C6H3
3 (3-CF3C6H4)OC6H4
C6H5
6k
6l
C6H5

J.-M. Wu et al. / European Journal of Medicinal Chemistry 36 (2001) 469–479
Table II. Cytotoxicity of compounds 4–6.
473
No.
IC50 (nM)
L1210
4.8
Cell cycle effect L1210% G1 (nM)
Cell cycle apoptosis P388
A549
12.4
39
41 990
2400
845
\50 mM
497
P388
% G1
% Apoptose
nM
VCR
2a
2b
4a
4b
4c
4d
4e
4f
4g
4h
4I
4j
4k
4l
4m
4n
4o
5a
5b
5c
5d
5e
5f
1.81
11
24 200
178
57
63
51
25
120
38
89
141
396
101
109
88
87
107
68
92
79
63
72
65
58
48
54
51
44
500
200
500
500
370
418
406
360
517
414
373
474
324
446
401
265
258
500
500
600
700
500
600
600
1100
600
600
700
395
297
259
60(400)
71(400)
64(1000)
61(400)
60(600)
59(600)
67(400)
60(400)
67(400)
63(400)
59(500)
7130
\25 mM
6320
7135
8260
4864
\50 mM
60
60
68
65
58
59
58
32
62
65
75
77
76
76
77
76
76
75
75
76
77
41
38
50
42
33
50
33
44
48
41
31
32
41
39
42
41
40
41
38
30
34
500
500
500
500
500
500
500
500
500
197
50
4633
57(400)
500
4700
4300
4700
4600
3000
4300
4600
4800
4200
4400
5300
1000
1000
1000
2500
1000
1000
1000
1000
1000
1000
1000
5g
5h
5i
5j
5k
6a
6b
6c
6d
6e
6f
369
12 842
13 970
13 400
64(1000)
70
69
29
36
2000
2000
352
375
370
64(500)
6100
7343
16 100
5300
7660
2500
300
260
364
210
195
300
320
434
76
69
24
30
1000
2000
64(1000)
66(1000)
6g
6h
6i
6j
6k
6l
69
77
27
34
1000
500
450
10 900
19 200
66(1000)
70
27
2500
5. Experimental
Brucker AM-400. Elemental analyses were performed by
elementary vario EL and all the results were within 0.4%
of the theoretical values. All the reagents used were
commercially available.
5.1. Chemistry
All melting points (m.p.) were calculated in open
capillary using a BUCHI-510 melting point apparatus
and were uncorrected. The IR spectra were run on a
Perkin–Elmer 599B spectrophotometer. H NMR spec-
tra were determined in CDCl3 solution on a NMR
5.1.1. General procedure
5.1.1.1. Preparation of compounds 3
DCC (1.13 g, 5.5 mmol) and DMAP (30 mg) were
added to a solution of dihydroartemisinin (1.42 g, 5
1

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J.-M. Wu et al. / European Journal of Medicinal Chemistry 36 (2001) 469–479
mmol) and dicarboxylic acid (6 mmol) in 30 mL
CH2Cl2. The mixture was stirred at room temperature
(r.t.) until the reaction was completed. After the insolu-
ble DCCU was filtered off, the solvent was moved and
the residue was purified using column chromatography
(5:1 petroleum ether–ethyl acetate) to give 3. Yield:
45–55%.
5.1.1.7. 12h-Deoxoartemisinyl
cyano-2%-chlorophenylmethyl succinate (4b)
1H NMR (CDCl3, l ppm): 7.70 (m, 1H, ArꢁH); 7.41
(m, 3H, ArꢁH); 6.70 (s, 1H, Ha); 5.77 (d, 1H, 12-H,
[J=9.79 Hz]); 5.41 (s, 1H, 5-H); 2.77 (m, 4H, ꢁCO
CH2CH2COꢁ); 1.41 (s, 3H, 4-CH3); 0.94 (d, 3H, 11-
CH3, [J=5.91 Hz]); 0.82 (d, 3H, 10-CH3, [J=7.06 Hz]).
IR (KBr, cm−1): 1754.9, 1363.4, 1141.7, 1101.2,
1016.3.
5.1.1.2. Adipic acid mono-12h-deoxoartemisinyl ester
(3b)
5.1.1.8. 12h-Deoxoartemisinyl
1
Yield: 50%. H NMR (CDCl3, l ppm): 5.77 (d, 1H,
cyano-4%-chlorophenylmethyl succinate (4c)
1H NMR (CDCl3, l ppm): 7.43 (m, 4H, ArꢁH); 6.38
(s, 1H, Ha); 5.74 (d, 1H, 12-H, [J=9.70 Hz]); 5.41 (s,
1H, 5-H); 2.74 (m, 4H, ꢁCO CH2CH2COꢁ); 1.41 (s, 3H,
4-CH3); 0.94 (d, 3H, 11-CH3, [J=5.85 Hz]); 0, 79 (d,
3H, l5-CH3, [J=7.12 Hz]).
12-H, [J=9.79 Hz]); 5.47 (s, 1H, 5-H,); 2.34 (m, 4H,
ꢁCOCH2ꢁ); 1.41 (s, 3H, 4-CH3); 0.94 (d, 3H, 11-CH3,
[J=5.70 Hz]), 0.82 (3H, d, 10-CH3, [J=7.14 Hz]).
5.1.1.3. Pimelic acid mono-12h-deoxoartemisinyl ester
(3c)
IR (KBr, cm−1): 1754.9, 1494.6, 1143.6, 1097.3,
1016.3.
1
Yield: 55%. H NMR (CDCl3, l ppm): 5.75 (d, 1H,
12-H, [J=9.80 Hz]); 5.45 (s, 1H, 5-H); 2.40 (m, 4H,
ꢁCOCH2ꢁ); 1.41 (s, 3H, 4-CH3); 0.94 (d, 3H, 11-CH3,
[J=5.71 Hz]); 0.81 (d, 3H, 10-CH3, [J=7.11 Hz]).
5.1.1.9. 12h-Deoxoartemisinyl
cyano-2%-bromophenylmethyl succinate (4d)
1H NMR (CDCl3, l ppm): 7.71 (d, 1H, ArꢁH, [J=
7.70 Hz]); 7.62 (d, 1H, ArꢁH, [J=7.90 Hz]); 7.43 (t, 1H,
ArꢁH); 7.32 (t, 1H, ArꢁH); 6.71, 6.67 (s, s, 1H, Ha);
5.76 (d, 1H, 12-H, [J=9.90 Hz]); 5.41 (s, 1H, 5-H); 2.79
(m, 4H, ꢁCOCH2CH2COꢁ); 1.41 (s, 3H, 4-CH3); 0.94
(d, 3H, 11-CH3, [J=6.03 Hz]); 0.83 (d, 3H, 10-CH3,
[J=7.30 Hz]).
5.1.1.4. Azelaic acid mono-12h-deoxoartemisinyl ester
(3d)
1
Yield: 45%. H NMR (CDCl3, l ppm): 5.77 (d, 1H,
12-H, [J=9.79 Hz]); 5.44 (s, 1H, 5-H); 2.40 (m, 4H,
ꢁCOCH2ꢁ); 1.41 (s, 3H, 4-CH3); 0.94 (d, 3H, 11-CH3,
[J=5.74 Hz]); 0.81 (d, 3H, 10-CH3, [J=7.12 Hz]).
IR (KBr, cm−1): 1754.9, 1141.7, 1016.3.
5.1.1.5. Preparation of compounds 4 and 5
DCC (2.26 g, 11 mmol) and DMAP (50 mg) were
5.1.1.10. 12h-Deoxoartemisinyl
cyano-4%-bromophenylmethyl succinate (4e)
1H NMR (CDCl3, l ppm): 7.58 (d, 2H, ArꢁH, [J=
8.43 Hz]); 7.38 (d, 2H, ArꢁH, [J=8.39 Hz]); 6.37 (s, 1H,
Ha); 5.74 (d, 1H, 12-H, [J=9.72 Hz]); 5.49 (s, 1H, 5-H);
2.74 (m, 4H, ꢁCO CH2CH2COꢁ); 1.41 (s, 3H, 4-CH3);
0.95 (d, 3H, 11-CH3, [J=5.72 Hz]); 0.82, 0.77 (d, d, 3H,
10-CH3, [J=7.08, 7.16 Hz]).
added to
a
solution of dicarboxylic acid
monodeoxoartemisinyl ester (3) (10 mmol) and a-hy-
droxyarylacetonitrile (or a-aminoarylacetonitrile) (l2
mmol) in 50 mL CH2Cl2. The solution was stirred at r.t.
for 4 h. After filtrating the DCCU, the solvent was
removed and the residue was purified by column chro-
matography (10:1 petroleum ether–ethyl acetate) to give
compounds 4 or 5.
IR (KBr, cm−1): 1754.9, 1494.6, 1143.6, 1097.3,
1016.3.
5.1.1.6. 12h-Deoxoartemisinyl cyanophenylmethyl
succinate (4a)
5.1.1.11. 12h-Deoxoartemisinyl
cyano-4%-cyano-phenylmethyl succinate (4f)
1H NMR (CDCl3, l ppm): 7.46 (m, 5H, ArꢁH); 6.40
(s, 1H, Ha); 5.76 (d, 1H, 12-H, [J=9.92 Hz]); 5.42 (s,
1H, 5-H); 2.75 (m, 4H, ꢁCOCH2CH2COꢁ); 1.46 (s, 3H,
4-CH3); 0.94 (d, 3H, 11-CH3, [J=5.79 Hz]); 0.83 (d, 3H,
10-CH3, [J=7.10 Hz]).
1H NMR (CDCl3, l ppm): 7.75 (m, 2H, ArꢁH); 7.65
(m, 2H, ArꢁH); 6.47 (s, 1H, Ha); 5.73 (d, 1H, 12-H,
[J=8.92 Hz]); 5.41 (s, 1H, 5-H); 2.77 (m, 4H,
ꢁCOCH2CH2COꢁ); 1.41 (s, 3H, 4-CH3); 0.95 (d, 3H,
11-CH3, [J=5.68 Hz]); 0.80 (m, 3H, 10-CH3).
IR (KBr, cm−1): 2231.3, 1754.9, 1141.7, 1016.3.
IR (KBr, cm−1): 1753.0, 1452.2, 1151.3.

J.-M. Wu et al. / European Journal of Medicinal Chemistry 36 (2001) 469–479
475
5.1.1.12. 12h-Deoxoartemisinyl
cyano-4%-nitro-phenylmethyl succinate (4g)
5.16 (s, 2H, ArꢁCH2); 3.91 (s, 3H, ArꢁOCH3); 2.71 (m,
4H, ꢁCOCH2CH2COꢁ); 1.40 (s, 3H, 4-CH3); 0.94 (d,
3H, 11-CH3, [J=5.79 Hz]); 0.79 (m, 3H, 10-CH3).
IR (KBr, cm−1): 1751.1, 1702.9, 1616.1, 1510.0,
1211.1, 1143.2, 1016.3.
1H NMR (CDCl3, l ppm): 8.31 (m, 2H, ArꢁH); 7.72
(m, 2H, ArꢁH); 6.52 (s, 1H, Ha); 5.74 (d, 1H, 12-H,
[J=9.84 Hz]); 5.41 (s, 1H, 5-H); 2.76 (m, 4H,
ꢁCOCH2CH2COꢁ); 1.41 (s, 3H, 4-CH3); 0.94 (d, 3H,
11-CH3, [J=6.67 Hz]); 0.83 (m, 3H, 10-CH3).
IR (KBr, cm−1): 1753.0, 1702.9, 1658.5, 1600.7,
1209.2, 1132.2, 1016.3.
5.1.1.17. 12h-Deoxoartemisinyl
cyano-3%,4%-methylenedioxyphenylmethyl succinate (4l)
1H NMR (CDCl3, l ppm): 6.98 (d, 1H, ArꢁH, [J=
7.98 Hz]); 6.96 (s, 1H, ArꢁH); 6.82 (d, 1H, ArꢁH,
[J=7.95 Hz]); 6.30 (s, 1H, Ha); 6.00 (s, 2H, ꢁOCH2Oꢁ);
5.75 (d, 1H, 12-H, [J=9.97 Hz]); 5.41 (s, 1H, 5-H); 2.73
(m, 4H, ꢁCOCH2CH2COꢁ); 1.41 (s, 3H, 4-CH3); 0.94 (d,
3H, 11-CH3, [J=6.05 Hz]); 0.81 (m, 3H, 10-CH3).
IR (KBr, cm−1): 1751.1, 1490.7, 1448.3, 1249.7,
1143.6, 1037.5, 1016.3.
5.1.1.13. 12h-Deoxoartemisinyl
cyano-4%-methoxy-phenylmethyl succinate (4h)
1H NMR (CDCl3, l ppm): 7.42 (m, 2H, ArꢁH); 6.92
(m, 2H, ArꢁH); 6.34, 6.33 (s, s, 1H, Ha); 5.74 (d, 1H,
12-H, [J=9.84 Hz]); 5.40 (s, 1H, 5-H); 2.72 (m, 4H,
ꢁCOCH2CH2COꢁ); 1.40 (s, 3H, 4-CH3); 0.94 (d, 3H,
11-CH3, [J=5.83 Hz]); 0.82 (m, 3H, 10-CH3).
IR (KBr, cm−1): 1751.1, 1612.2, 1132.2, 1016.3.
5.1.1.18. 12h-Deoxoartemisinyl
cyano-2%-chlorophenylmethyl adipate (4m)
5.1.1.14. 12h-Deoxoartemisinyl
1H NMR (CDCl3, l ppm): 7.70 (m, 1H, ArꢁH); 7.40
(m, 3H, ArꢁH); 6.69 (1H, s, Ha); 5.76 (d, 1H, 12-H,
[J=9.89 Hz]); 5.41 (s, 1H, 5-H); 2.38 (m, 4H,
ꢁCOCH2ꢁ); 1.40 (s, 3H, 4-CH3); 0.94 (d, 3H, 11-CH3,
[J=5.86 Hz]); 0.82 (d, 3H, 10-CH3, [J=7.14 Hz]).
IR (cm−1): 1751.1, 1490.7, 1376.9, 1143.6, 1012.5,
875.5, 825.4.
cyano-2%,4%-dimethoxy-phenylmethyl succinate (4i)
1H NMR (CDCl3, l ppm): 7.45 (d, 1H, ArꢁH, [J=
8.47 Hz]); 6.61 (s, 1H, ArꢁH); 6.52 (d, 1H, ArꢁH,
[J=8.51 Hz]); 6.45 (s, 1H, Ha); 5.75 (d, 1H, 12-H,
[J=9.86 Hz]); 5.41 (s, 1H, 5-H); 3.82, 3.81 (s, s, 6H,
ArꢁOCH3); 2.74 (m, 4H, ꢁCOCH2CH2COꢁ); 1.41 (s,
3H, 4-CH3); 0.94 (d, 3H, 11-CH3, [J=5.68 Hz]); 0.81
(m, 3H, 10-CH3).
IR (KBr, cm−1): 1751.1, 1702.9, 1616.1, 1510.0,
1211.1, 1143.2, 1016.3.
5.1.1.19. 12h-Deoxoartemisinyl
cyanophenylmethylpimelate (4n)
1H NMR (CDCl3, l ppm): 7.48 (m, 5H, ArꢁH); 6.40
(1H, s, Ha); 5.75 (d, 1H, 12-H, [J=9.90 Hz]); 5.41 (s,
1H, 5-H); 2.71 (m, 4H, ꢁCOCH2CH2COꢁ); 1.41 (s, 3H,
4-CH3); 0.94 (d, 3H, 11-CH3, [J=5.91 Hz]); 0.81 (d, 3H,
10-CH3, [J=7.11 Hz]).
5.1.1.15. 12h-Deoxoartemisinyl
cyano-3%,4%-dimethoxy-phenylmethyl succinate (4j)
1H NMR (CDCl3, l ppm): 7.07 (d, 1H, ArꢁH, [J=
8.37 Hz]); 6.97 (s, 1H, ArꢁH); 6.87 (d, 1H, ArꢁH,
[J=8.36 Hz]); 6.36, 6.35 (s, s, 1H, Ha); 5.74 (d, 1H,
12-H, [J=9.91 Hz]); 5.39 (s, 1H, 5-H); 3.90, 3.88 (s, s,
6H, ArꢁOCH3); 2.74 (m, 4H, ꢁCOCH2CH2COꢁ); 1.40
(s, 3H, 4-CH3); 0.94 (d, 3H, 11-CH3, [J=5.96 Hz]);
0.82, 0.77 (d, d, 3H, 10-CH3, [J=7.10, 7.12 Hz]).
IR (KBr, cm−1): 2117.5, 1751.1, 1519.7, 1259.3,
1143.6, 1018.2.
IR (cm−1): 1751.1, 1490.7, 1376.9, 1143.6, 1012.5,
875.5, 825.4.
5.1.1.20. 12h-Deoxoartemisinyl
cyano-2%-bromophenylmethyl azelaate (4o)
1H NMR (CDCl3, l ppm): 7.71 (d, 1H, ArꢁH, [J=
7.71 Hz]); 7.62 (d, 1H, ArꢁH, [J=7.83 Hz]); 7.43 (t, 1H,
ArꢁH); 7.32 (t, 1H, ArꢁH); 6.65 (s, 1H, Ha); 5.77 (d,
1H, 12-H, [J=9.79 Hz]); 5.42 (s, 1H, 5-H); 2.71 (m, 4H,
ꢁCOCH2CH2COꢁ); 1.41 (s, 3H, 4-CH3); 0.94 (d, 3H,
11-CH3, [J=5.70 Hz]); 0.81 (d, 3H, 10-CH3, [J=7.11
Hz]).
5.1.1.16. 12h-Deoxoartemisinyl
cyano-3%-methoxy-4%-benzyloxyphenylmethyl succinate
(4k)
1H NMR (CDCl3, l ppm): 7.35 (m, 5H, ArꢁH); 6.99
(m, 2H, ArꢁH); 6.88 (m, 1H, ArꢁH); 6.35, 6.33 (s, s, 1H,
Ha); 5.74 (d, 1H, 12-H, [J=9.90 Hz]); 5.40 (s, 1H, 5-H);
IR (cm−1): 1751.1, 1490.7, 1376.9, 1143.6, 1012.5,
875.5, 825.4.

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J.-M. Wu et al. / European Journal of Medicinal Chemistry 36 (2001) 469–479
5.1.1.21. Succinic acid 12h-deoxoartemisinyl ester
cyanophenylmethyl amide (5a)
5.1.1.25. Succinic acid 12h-deoxoartemisinyl ester
cyano-3%-chlorophenylmethyl amide (5e)
1H NMR (CDCl3, l ppm): 7.45 (m, 2H, ArꢁH); 7.40
(m, 3H, ArꢁH); 6.58 (br d, 1H, NꢁH, [J=8.18 Hz]);
6.11, 6.07 (d, d, 1H, Ha, [J=8.20 Hz]); 5.74, 5.70 (d, d,
1H, 12-H, [J=9.75, 9.74 Hz]); 5.38, 5.28 (s, s, 1H, 5-H);
2.74 (m, 2H, ꢁCOCH2ꢁ); 2.55 (m, 2H, -COCH2ꢁ); 1.39,
1.38 (s, s, 3H, 4-CH3); 0.94 (d, 3H, 11-CH3, [J=5.02
Hz]); 0.81 (d, 3H, 10-CH3, [J=6.96 Hz]).
1H NMR (CDCl3, l ppm): 7.48 (s, 1H, ArꢁH); 7.36
(m, 3H, ArꢁH); 6.83 (br, 1H, NꢁH); 6.15, 6.09 (d, d, 1H,
Ha, [J=8.41, 8.38 Hz]); 5.75, 5.70 (d, d, 1H, 12-H,
[J=9.80, 9.79 Hz]); 5.38, 5.25 (s, s, 1H, 5-H); 2.76 (m,
2H, ꢁCOCH2ꢁ); 2.54 (m, 2H, ꢁCOCH2ꢁ); 1.39, 1.37 (s,
s, 3H, 4-CH3); 0.94 (d, 3H, 11-CH3, [J=5.30 Hz]); 0.81
(d, 3H, 10-CH3, [J=7.01 Hz]).
IR (KBr, cm−1): 3374.9, 1764.6, 1697.1, 1510.0,
1159.0, 1018.2.
IR (KBr, cm−1): 3370.0, 3334.4, 2250.6, 1762.6,
1731.8, 1695.1, 1670.1, 1376.9, 1161.0, 1016.3.
5.1.1.26. Succinic acid 12h-deoxoartemisinyl ester
cyano-4%-chlorophenylmethyl amide (5f)
5.1.1.22. Succinic acid 12h-deoxoartemisinyl ester
cyano-2%-fluorophenylmethyl amide (5b)
1H NMR (CDCl3, l ppm): 7.40 (m, 4H, ArꢁH); 6.73
(br d, 1H, NꢁH, [J=8.24 Hz]); 6.12, 6.08 (d, d, 1H, Ha,
[J=8.25, 8.28 Hz]); 5.73, 5.67 (d, d, 1H, 12-H, [J=9.76,
9.79 Hz]); 5.38, 5.23 (s, s, 1H, 5-H); 2.74 (m, 2H,
ꢁCOCH2ꢁ); 2.55 (m, 2H, ꢁCOCH2ꢁ); 1.38 (s, 3H, 4-
CH3); 0.94 (d, 3H, 11-CH3, [J=5.39 Hz]); 0.81 (d, 3H,
10-CH3, [J=6.97 Hz]).
1H NMR (CDCl3, l ppm): 7.48 (t, 1H, ArꢁH); 7.35
(m, 1H, ArꢁH); 7.19 (m, 1H, ArꢁH); 7.10 (m, 1H,
ArꢁH); 6.60, 6.52 (d, d, 1H, NꢁH, [J=8.25, 8.26 Hz]);
6.13 (d, 1H, Ha, [J=8.24 Hz]); 5.70, 5.66 (d, 1H, 12-H,
[J=9.89, 9.91 Hz]); 5.34, 5.31 (s, s, 1H, 5-H); 2.70 (m,
2H, ꢁCOCH2ꢁ); 2.47 (m, 2H, ꢁCOCH2ꢁ); 1.33 (s, 3H,
4-CH3); 0.89 (d, 3H, 11-CH3, [J=6.05 Hz]); 0.76, 0.74
(d, d, 3H, 10-CH3, [J=7.14, 7.14 Hz]).
IR (KBr, cm−1): 3332.4, 1764.6, 1693.2, 1515.8,
1157.1, 1016.3.
IR (KBr, cm−1): 3249.5, 1751.1, 1646.9, 1529.3,
1170.6, 1039.5, 1018.2.
5.1.1.27. Succinic acid 12h-deoxoartemisinyl ester
cyano-2%-bromophenylmethyl amide (5g)
5.1.1.23. Succinic acid 12h-deoxoartemisinyl ester
cyano-3%-fluorophenylmethyl amide (5c)
1H NMR (CDCl3, l ppm): 7.67 (d, 1H, ArꢁH, [J=
6.56 Hz]); 7.62 (d, 1H, ArꢁH, [J=7.82 Hz]); 7.41 (t, 1H,
ArꢁH); 7.28 (t, 1H, ArꢁH); 6.56 (br d, 1H, NꢁH,
[J=7.43 Hz]); 6.22 (d, 1H, Ha, [J=7.42 Hz]); 5.74 (d,
1H, 12-H, [J=9.88 Hz]); 5.39 (s, 1H, 5-H); 2.77 (m, 2H,
ꢁCOCH2ꢁ); 2.56 (m, 2H, ꢁCOCH2ꢁ); 1.40 (s, 3H, 4-
CH3); 0.94 (d, 3H, 11-CH3, [J=5.86 Hz]); 0.82 (d, 3H,
10-CH3, [J=7.01 Hz]).
1H NMR (CDCl3, l ppm): 7.39 (m, 1H, ArꢁH); 7.27
(d, 1H, ArꢁH, [J=6.09 Hz]); 7.19 (d, 1H, ArꢁH, [J=
9.19 Hz]); 7.09 (t, 1H, ArꢁH); 6.62 (br d, [J=8.40 Hz],
1H, NꢁH); 6.16 (d, [J=8.48 Hz], 1H, Ha); 5.71 (d,
[J=9.88 Hz], 1H, 12-H); 5.29 (s, 1H, 5-H), 2.83 (m, 2H,
ꢁCOCH2ꢁ); 2.59 (m, 2H, ꢁCOCH2ꢁ); 1.40 (s, 3H, 4-
CH3); 0.94 (d, 3H, 11-CH3, [J=5.30 Hz]); 0.82 (d, 3H,
10-CH3, [J=7.04 Hz]).
IR (cm−1): 3228.3, 1753.0, 1646.9, 1531.2, 1151.3,
1041.4, 1016.3.
IR (KBr, cm−1): 3361.4, 1729.9, 1666.2, 1500.4,
1164.8, 1018.2.
5.1.1.28. Succinic acid l2h-deoxoartemisinyl ester
cyano-3%-bromophenylmethyl amide (5h)
5.1.1.24. Succinic acid 12h-deoxoartemisinyl ester
cyano-4%-fluorophenylmethyl amide (5d)
1H NMR (CDCl3, l ppm): 7.63, 7.62 (s, s, 1H, ArꢁH);
7.51 (d, 1H, ArꢁH, [J=7.63 Hz]); 7.41 (d, 1H, ArꢁH,
[J=7.57 Hz]); 7.29 (t, 1H, ArꢁH); 6.85, 6.81 (d, d, 1H,
NꢁH, [J=8.45, 8.43 Hz]); 6.14, 6.08 (d, d, 1H, Ha,
[J=8.47, 8.45 Hz]); 5.74, 5.69 (d, d, 1H, 12-H, [J=9.90,
9.88 Hz]); 5.37, 5.22 (s, s, 1H, 5-H); 2.74 (m, 2H,
ꢁCOCH2ꢁ); 2.55 (m, 2H, ꢁCOCH2ꢁ); 1.38, 1.37 (s, s,
3H, 4-CH3); 0.94 (d, 3H, 11-CH3, [J=4.88 Hz]); 0.81 (d,
3H, 10-CH3, [J=7.02 Hz]).
1H NMR (CDCl3, l ppm): 7.46 (m, 2H, ArꢁH); 7.09
(m, 2H, ArꢁH); 6.72 (br d, 1H, NH, [J=8.20 Hz]); 6.10,
6.06 (d, d, 1H, Ha, [J=8.22 Hz]); 5.73, 5.68 (d, d, 1H,
12-H, [J=9.79, 9.81 Hz]); 5.37, 5.28 (s, s, 1H, 5-H), 2.80
(m, 2H, ꢁCOCH2ꢁ); 2.50 (m, 2H, ꢁCOCH2ꢁ); 1.38 (s,
3H, 4-CH3); 0.94 (d, 3H, 11-CH3, [J=5.09 Hz]); 0.81 (d,
3H, 10-CH3, [J=7.00 Hz]).
IR (KBr, cm−1): 3365.2, 1731.8, 1670.1, 1510.0,
1161.0, 1161.0, 1018.2.
IR (KBr, cm−1): 3372.9, 3338.2, 2250.6, 1760.7,
1731.8, 1697.1, 1670.1, 1376.9, 1161.0, 1029.8.

J.-M. Wu et al. / European Journal of Medicinal Chemistry 36 (2001) 469–479
477
5.1.1.29. Succinic acid 12h-deoxoartemisinyl ester
5.1.1.33. Succinic acid
cyano-4%-bromophenylmethyl amide (5i)
mono-N-methycyano-4%-bromophenylmethyl amide (7h)
1H NMR (CDCl3, l ppm): 7.53 (d, 2H, ArꢁH, [J=
8.36 Hz]); 7.27 (d, 2H, ArꢁH, [J=8.35 Hz]); 7.02 (s, 1H,
Ha); 2.91 (s, 3H, NꢁCH3); 2.70 (m, 4H,
ꢁCOCH2CH2COꢁ).
1H NMR (CDCl3, l ppm): 7.55, 7.53 (d, d, 2H, ArꢁH,
[J=8.22, 8.20 Hz]); 7.38, (d, 2H, ArꢁH, [J=8.21 Hz]);
6.81 (br d, 1H, NꢁH); 6.11, 6.06 (d, d, 1H, Ha, [J=8.41,
8.39 Hz]); 5.73, 5.66 (d, d, 1H, 12-H, [J=9.76, 9.77
Hz]); 5.37, 5.19 (s, s, 1H, 5-H); 2.74 (m, 2H, ꢁCOCH2ꢁ);
2.55 (m, 2H, ꢁCOCH2ꢁ); 1.38 (s, 3H, 4-CH3); 0.95 (d,
3H, 11-CH3, [J=5.70 Hz]); 0.81 (d, 3H, 10-CH3, [J=
7.05 Hz]).
IR (cm−1): 3050 (w); 1716.4; 1646.9; 1488.8; 1400.1;
1253.5; 1226.5; 1010.5.
5.1.1.34. Preparation of compound 6
IR (KBr, cm−1): 3357.5, 1764.6, 1731.8, 1696.2,
1664.3, 1159.0, 1016.3.
Compound 6 was prepared by the condensation of
compound 7 with dihydroartemisinin (1b) as in the
preparation of compound 4.
5.1.1.30. Succinic acid 12h-deoxoartemisinyl ester
cyano-4%-N,N-dimethylphenylmethyl amide (5j)
1H NMR (CDCl3, l ppm): 7.30 (d, 4H, ArꢁH, [J=
8.53 Hz]); 6.72 (br, 1H, NꢁH); 6.29 (d, 1H, Ha, [J=7.28
Hz]); 5.92, 5.78 (d, d, 1H, 12-H, [J=9.80, 9.79 Hz]);
5.40 (s, 1H, 5-H); 2.97 (s, 6H, NMe2); 2.78 (m, 2H,
ꢁCOCH2ꢁ); 2.55 (m, 2H, ꢁCOCH2ꢁ); 1.41 (s, 3H, 4-
CH3); 0.95 (d, 3H, 11-CH3, [J=5.60 Hz]); 0.84 (d, 3H,
10-CH3, [J=7.08 Hz]).
5.1.1.35. Succinic acid 12h-deoxoartemisinyl ester
N-methylcyanophenylmethyl amide (6a)
1H NMR (CDCl3, l ppm): 7.39 (s, 5H, ArꢁH); 7.07
(s, 1H, Ha); 5.79 (d, 1H, 12-H, [J=9.71 Hz]); 5.43 (s,
1H, 5-H); 2.90 (s, 3H, NꢁCH3); 2.80 (m, 4H,
ꢁCOCH2CH2COꢁ); 1.42 (s, 3H, 4-CH3); 0.95 (d, 3H,
11-CH3, [J=5.73 Hz]); 0.87 (d, 3H, 10-CH3, [J=7.03
Hz]).
IR (KBr, cm−1): 3365.2, 2242.8, 1731.8, 1666.2,
1525.4, 1161.0, 1027.9.
IR (KBr, cm−1): 2242.8, 1747.2, 1656.6, 1407.8,
1170.6, 1016.3.
5.1.1.31. Succinic acid 12h-deoxoartemisinyl ester
cyano-2%-naphylmethyl amide (5k)
5.1.1.36. Succinic acid 12h-deoxoartemisinyl ester
N-methylcyano-2%-fluorophenylmethyl amide (6b)
1H NMR (CDCl3, l ppm): 7.59 (t, 1H, ArꢁH); 7.39
(d, 1H, ArꢁH, [J=6.58 Hz]); 7.21 (d, 1H, ArꢁH, [J=
7.42 Hz]); 7.10 (t, 1H, ArꢁH); 7.10 (s, 1H, Ha); 5.79,
5.77 (d, d, 12-H, [J=9.72, 9.70 Hz]); 5.42 (s, 1H, 5-H);
2.93 (s, 3H, NꢁCH3); 2.80 (m, 4H, ꢁCOCH2CH2COꢁ);
1.41 (s, 3H, 4ꢁCH3); 0.94 (d, 3H, 11-CH3, [J=5.86 Hz]);
0.85 (d, 3H, 10-CH3, [J=7.04 Hz]).
1H NMR (CDCl3, l ppm): 8.03, 8.01 (s, s, 1H, ArꢁH);
7.88 (m, 2H, ArꢁH); 7.82 (m, 1H, ArꢁH); 7.50 (m, 3H,
ArꢁH); 6.86, 6.68 (d, d, 1H, NꢁH, [J=8.38, 8.34 Hz]);
6.32, 6.26 (d, d, 1H, Ha, [J=8.38, 8.35 Hz]); 5.72, 5.59
(d, d, 1H, 12-H, [J=9.96, 9.92 Hz]); 5.26, 4.78 (s, s,
1H, 5-H); 2.78 (m, 2H, ꢁCOCH2ꢁ); 2.55 (m, 2H,
ꢁCOCH2ꢁ); 1.39, 1.37 (s, s, 3H, 4-CH3); 0.83 (d, 3H,
11-CH3, [J=5.30 Hz]); 0.76 (d, 3H, 10-CH3, [J=7.05
Hz]).
IR (KBr, cm−1): 2244.8, 1751.1, 1666.2, 1492.7,
1164.8, 1101.2, 1018.2.
IR (KBr, cm−1): 3363.3, 2244.8, 1731.6, 1666.2,
1508.1, 1162.9, 1027.9.
5.1.1.37. Succinic acid 12h-deoxoartemisinyl ester
N-methylcyano-3%-fluorophenylmethyl amide (6c)
1H NMR (CDCl3, l ppm): 7.40 (m, 2H, ArꢁH); 7.21,
7.19 (s, s, 1H, ArꢁH); 7.08 (t, 1H, ArꢁH); 7.06, 7.04 (s,
s, 1H, Ha); 5.80, 5.79 (d, d, 12-H, [J=9.76, 9.80 Hz]);
5.43 (s, 1H, 5-H); 2.93 (s, 3H, NꢁCH3); 2.80 (m, 4H,
ꢁCOCH2CH2COꢁ); 1.41 (s, 3H, 4-CH3); 0.95 (d, 3H,
11-CH3, [J=5.67 Hz]); 0.86 (d, 3H, 10-CH3, [J=6.86
Hz]).
5.1.1.32. Preparation of compound 7
The solution of N-methyl-h-aminoarylacetonitrile (12
mmol), cyclic anhydride (10 mmol) and 1 mL triethy-
lamine in 50 mL CH2Cl2 was stirred at r.t. for 4 h. After
the completion of the reaction the solution was washed
by 5% HCl, saturated brine, and dried over MgSO4
successively. The solvent was evaporated under reduced
pressure. The residue, compound 7, could be used for
the next procedure without further purification.
IR (KBr, cm−1): 2244.8, 1751.1, 1446.4, 1164.8,
1016.3.

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J.-M. Wu et al. / European Journal of Medicinal Chemistry 36 (2001) 469–479
5.1.1.38. Succinic acid 12h-deoxoartemisinyl ester
N-methylcyano-4%-fluorophenylmethyl amide (6d)
1H NMR (CDCl3, l ppm): 7.38 (m, 2H, ArꢁH); 7.09
(m, 2H, ArꢁH); 7.04 (s, 1H, Ha); 5.78 (d, 12-H, [J=9.72
Hz]); 5.43 (s, 1H, 5-H); 2.90 (s, 3H, NꢁCH3); 2.80 (m,
4H, ꢁCOCH2CH2COꢁ); 1.42 (s, 3H, 4-CH3); 0.95 (d,
3H, 11-CH3, [J=5.54 Hz]); 0.86 (d, 3H, 10-CH3, [J=
6.93 Hz]).
(s, s, 1H, Ha); 5.80, 5.78 (d, d, 1H, 12-H, [J=9.79, 9.80
Hz]); 5.43 (s, 1H, 5-H); 2.92, 2.90 (s, s, 3H, NꢁCH3);
2.75 (m, 4H, ꢁCOCH2CH2COꢁ); 1.42 (s, 3H, 4-CH3);
0.95 (d, 3H, 11-CH3, [J=5.72 Hz]); 0.86 (d, 3H, 10-
CH3, [J=7.14 Hz]).
IR (cm−1): 2244.8, 1749.1, 1662.4, 1488.8, 1403.9,
1164.8, 1012.5, 877.5.
IR (KBr, cm−1): 2244.8, 1747.2, 1654.7, 1510.0,
1016.3.
5.1.1.43. Succinic acid 12h-deoxoartemisinyl ester
N-methylcyano-2%,3%-dimethyiphenylmethyl amide (6i)
1H NMR (CDC13, l ppm): 7.52 (d, 1H, ArꢁH, [J=
7.73 Hz]); 7.07 (d, 1H, ArꢁH, [J=7.70 Hz]); 7.01 (s, 1H,
ArꢁH); 6.93 (s, 1H, Ha); 5.79, 5.77 (d, d, 12-H, [J=
9.30, 9.28 Hz]); 5.42 (s, 1H, 5-H); 2.83, 2.81 (s, s, 3H,
NꢁCH3); 2.80 (m, 4H, ꢁCOCH2CH2COꢁ); 2.31 (s, 3H,
ArꢁCH3); 2.11, 2.09 (s, s, 3H, ArꢁCH3); 1.41 (s, 3H,
4-CH3); 0.95 (d, 3H, 11-CH3, [J=5.73 Hz]); 0.86 (d, 3H,
10-CH3, [J=6.87 Hz]).
5.1.1.39. Succinic acid 12h-deoxoartemisinyl ester
N-methylcyano-2%-chlorophenylmethyl amide (6e)
1H NMR (CDCl3, l ppm): 7.73 (t, 1H, ArꢁH); 7.39
(m, 3H, ArꢁH); 7.03 (s, 1H, Ha); 5.78 (d, 12-H, [J=9.89
Hz]); 5.42 (s, 1H, 5-H); 2.81 (s, 3H, NꢁCH3); 2.80 (m,
4H, ꢁCOCH2CH2COꢁ); 1.41 (s, 3H, 4-CH3); 0.94 (d,
3H, 11-CH3, [J=5.75 Hz]); 0.85 (d, 3H, 10-CH3, [J=
7.07 Hz]).
IR (KBr, cm−1): 2244.8, 1751.1, 1662.4, 1164.8,
1016.3.
IR (KBr, cm−1): 1747.2, 1662.4, 1170.6, 1099.2,
1012.5.
5.1.1.44. Succinic acid 12h-deoxoartemtsinyl ester
N-methylcyano-3%-(3-trifluoromethylphenyl)-
phenylmethyl amide (6j)
5.1.1.40. Succinic acid 12h-deoxoartemisinyl ester
N-methylcyano-4%-chlorophenylmethyl amide (6f)
1H NMR (CDCl3, l ppm): 7.38 (d, 2H, ArꢁH, [J=
8.25 Hz]); 7.33 (d, 2H, ArꢁH, [J=8.27 Hz]); 7.04 (s, 1H,
Ha); 5.78 (d, 12-H, [J=9.58 Hz]); 5.43 (s, 1H, 5-H);
2.90 (s, 3H, NꢁCH3); 2.80 (m, 4H, ꢁCOCH2CH2COꢁ);
1.41 (s, 3H, 4-CH3); 0.95 (d, 3H, 11-CH3, [J=5.56 Hz]);
0.86 (d, 3H, 10-CH3, [J=6.87 Hz]).
1H NMR (CDCl3, l ppm): 7.47–7.36 (m, 3H, ArꢁH);
7.21, 7.19 (s, s, 2H, ArꢁH); 7.15–7.06 (m, 3H, ArꢁH);
6.98, 6.97 (s, s, 1H, Ha); 5.79, 5.76 (d, d, 12-H, [J=
10.02, 10.00 Hz]); 5.42, 5.41 (s, s, 1H, 5-H); 2.94 (s, 3H,
NꢁCH3); 2.80 (m, 4H, ꢁCOCH2CH2COꢁ); 1.41 (s, 3H,
4-CH3); 0.94 (d, 3H, 11-CH3, [J=5.12 Hz]); 0.84 (d, 3H,
10-CH3, [J=7.01 Hz]).
IR (KBr, cm−1): 2244.8, 1747.2, 1654.7, 1492.7,
1407.8, 1099.2, 1016.3.
IR (KBr, cm−1): 2244.8, 1751.1, 1662.4, 1450.2,
1328.7, 1166.7, 1130.1, 1018.2.
5.1.1.41. Succinic acid 12h-deoxoartemisinyl ester
N-methylcyano-2%-bromophenylmethyl amide (6g)
1H NMR (CDCl3, l ppm): 7.75 (d, 1H, ArꢁH, [J=
7.78 Hz]); 7.62 (d, 1H, ArꢁH, [J=7.80 Hz]); 7.42 (t, 1H,
ArꢁH); 7.29 (t, 1H, ArꢁH); 6.91, 6.90 (s, 5, 1H, Ha);
5.79, 5.77 (d, d, 12-H, [J=9.80, 9.77 Hz]); 5.42 (s, 1H,
5-H); 2.82, 2.79 (s, s, 3H, NꢁCH3); 2.80 (m, 4H,
ꢁCOCH2CH2COꢁ); 1.41 (s, 3H, 4-CH3); 0.94 (d, 3H,
11-CH3, [J=5.86 Hz]); 0.85 (d, 3H, 10-CH3, [J=6.98
Hz]).
5.1.1.45. Phthalic acid 12h-deoxoartemisinyl ester
N-methylcyanophenylmethyl amide (6k)
1H NMR (CDCl3, d ppm): 8.21 (d, 1H, ArꢁH, [J=
7.98 Hz]); 7.63–7.29 (m, 8H, ArꢁH); 7.23 (s, 1H, Ha);
6.02 (d, 1H, 12-H, [J=9.72 Hz]); 5.50, 5.47 (s, s, 1H,
5-H); 2.63, 2.62 (s, 3H, NꢁCH3); 1.42, 1.39 (s, s, 3H,
4-CH3); 0.97 (d, 3H, 11-CH3, [J=6.00 Hz]); 0.84 (d, 3H,
10-CH3, [J=7.07 Hz]).
IR (KBr, cm−1): 1733.7, 1658.5, 1384.7, 1263.2,
1033.7, 1016.3.
IR (KBr, cm−1): 1751.1, 1666.2, 1471.4, 1376.9,
1018.2.
5.1.1.42. Succinic acid 12h-deoxoartemisinyl ester
N-methylcyano-4%-bromophenylmethyl amide (6h)
1H NMR (CDCl3, l ppm): 7.54 (d, 2H, ArꢁH, [J=
8.34 Hz]); 7.27 (d, 2H, ArꢁH, [J=8.33 Hz]); 7.02, 7.01
5.1.1.46. Maleic acid 12h-deoxoartemisinyl ester
N-methylcyanophenylmethyl amide (6l)
1H NMR (CDCI3, l ppm): 7.57 (d, 1H, ArꢁH, [J=
7.17 Hz]); 7.52 (d, 1H, ArꢁH, [J=7.14 Hz]); 7.43 (m,

J.-M. Wu et al. / European Journal of Medicinal Chemistry 36 (2001) 469–479
[2] Wu Y.-L., Li Y., Med. Chem. Res. 5 (1995) 569–586.
479
3H, ArꢁH); 7.07, 7.06 (s, s, 1H, Ha); 6.60, 6.57 (d, d,
1H, ꢀCꢁH, [J=9.45, 9.41 Hz]); 6.20, 6.17 (s, s, 111,
5-H); 5.85, 5.82 (d, d, 1H, ꢀCꢁH, [J=10.22, 10, 27 Hz]);
5.44 (d, 1H, 12-H, [J=6.18 Hz]); 2.83 (s, 3H, NꢁCH3);
1.41, 1.39 (s, s, 3H, 4-CH3); 0.95 (d, 3H, 11-CH3,
[J=5.87 Hz]); 0.85, 0.81 (d, d, 3H, 10-CH3, [J=7.08,
7.10 Hz]).
[3] Li Y., Shan F., Wu J.M., Wu G.S., Ding J., Xiao D., Yang
W.Y., Atassi G., Leonce S., Caignard D.H., Renard P., Bioorg.
Med. Chem. Lett. 11 (2001) 5–8.
[4] Yang X.-P., Pan Q.-C., Liang Y.-G., Zikang Y.-L., Cancer 16
(1997) 186–187 (in Chinese).
[5] Liu J.-M., Ni M.-Y., Fan Y.-E., Tu Y.-Y., Wu Z.-H., Wu
Y.-L., Chou W.-S., Acta Chim. Sinica 37 (1979) 129–141.
IR (KBr, cm−1): 1735.6, 1658.5, 1452.2, 1405.9,
1207.2, 1016.3.
[6] Liu X., Chin. Pharm. Bull. 15 (1980) 183–183.
[7] Corson B.B., Ruth A.D., Harris S.A., Yeaw J.S., Org. Synth.
Coll. 1 (1941) 336–340.
[8] Kendall E.C., McKenzie B.F., Org. Synth. Coll. 1 (1941)
21–25.
References
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