Syntheses of cytotoxic novel arctigenin derivatives bearing halogen and alkyl groups on aromatic rings

Article abstract of DOI:10.1016/j.bmcl.2017.06.070

The new lignano-9,9′-lactones (α,β-dibenzyl-γ-butyrolactone lignans), which showed the higher cytotoxicity than arctigenin, were synthesized. The well-known cytotoxic arctigenin showed activity against HL-60 cells (EC₅₀ = 12 μM), however, it was inactive against HeLa cells (EC₅₀ > 100 μM). The synthesized (3,4-dichloro, 2′-butoxy)-derivative 55 and (3,4-dichloro, 4′-butyl)-derivative 66 bearing the lignano-9,9′-lactone structures showed the EC₅₀ values of 10 μM and 9.4 μM against HL-60 cells, respectively. Against HeLa cells, the EC₅₀ value of the derivative 66 was 27 μM. By comparing the activities with the corresponding 9,9′-epoxy structure (tetrahydrofuran compounds), the importance of the lactone structure of 55 and 66 for the higher activities was shown. The substituents on the aromatic ring of the lignano-9,9′-lactones affected the cytotoxicity level, observing more than 10-fold difference.

Full text of DOI:10.1016/j.bmcl.2017.06.070

ꢀꢁꢁꢂꢃꢄꢂꢅꢆ ꢇꢈꢉꢊꢁꢋꢌꢃꢄ

Syntheses of cytotoxic novel arctigenin derivatives bearing halogen and alkyl groups on
aromatic rings
Satoshi Yamauchia,b*, Tuti Wukirsaria, Yoshiaki Ochi,a Hisashi Nishiwakia,
Kosuke Nishia, Takuya Sugahara,a,b Koichi Akiyama,c Taro Kishidaa,b
aGraduate School of Agriculture, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime
790-8566, Japan
bSouth Ehime Fisheries Research Center, 1289-1 Funakoshi, Ainan, Ehime 798-4292,
Japan
cAdvanced Research Support Center (ADRES), Ehime University, 3-5-7 Tarumi,
Matsuyama, Ehime 790-8566, Japan
*To whom correspondence should be addressed. Tel: +81-89-946-9846; Fax:
+81-89-977-4364; E-mail: syamauch@agr.ehime-u.ac.jp,
yamauchi.satoshi.mm@ehime-u.ac.jp
1

ABSTRACT
The new lignano-9,9'-lactones (α,β-dibenzyl-γ-butyrolactone lignans), which
showed the higher cytotoxicity than arctigenin, were synthesized. The well-known
cytotoxic arctigenin showed activity against HL-60 cells (EC50 = 12 µM), however, it
was inactive against HeLa cells (EC50 > 100 µM). The synthesized (3,4-dichloro,
2'-butoxy)-derivative 55 and (3,4-dichloro, 4'-butyl)-derivative 66 bearing the
lignano-9,9'-lactone structures showed the EC50 values of 10 µM and 9.4 µM against
HL-60 cells, respectively. Against HeLa cells, the EC50 value of the derivative 66 was
27 µM. By comparing the activities with the corresponding 9,9’-epoxy structure
(tetrahydrofuran compounds), the importance of the lactone structure of 55 and 66 for
the higher activities was shown. The substituents on the aromatic ring of the
lignano-9,9'-lactones affected the cytotoxicity level, observing more than 10-fold
difference.
Key words: lignan; arctigenin; matairesinol; γ-butyrolactone; lignano-9,9'-lactone;
α,β-dibenzyl-γ-butyrolactone
2

The naturally occurring (8R,8'R)-arctigenin (1) bearing a lignano-9,9'-lactone
was isolated from fruits of Arctium lappa and phagocytic activity on leulemia cells have
been reported.1 It was recently found that Jurinea mollis is a rich source of
(8R,8'R)-arctigenin (1).2 The mechanism of cytotoxicity,3,4 the activity against multidrug
resistant cancer cells,5 and attenuation of learning and memory deficits6 have been
examined. The research on the arctigenin derivatives have also been continued.7-9
Matairesinols (2, 3) bearing similar structure to arctigenin are dietary
lignano-9,9'-lactones and contained in vegetables (Figure 1).10 The IgE-suppressive
activity11 and immunomodulatory activity12 of (-)-matairesinol have been reported.
Figure 1. Structures of (8R,8'R)-arctigenin (1), both enantiomers of matairesinol (2, 3),
and (8R,8'R)-dihydroguaiaretic acid (4).
(8R,8'R)-Dihydroguaiaretic acid (4), which is a butane type lignan, is also a natural
cytotoxic lignan containing butane type structure. We previously clarified the structure
3

containing stereochemistry-activity relationship of dihydroguaiaretic acid, discovering
the compounds showing the higher activity than the natural compound 4 by preparing
the benzene ring derivatives.13 As a first stage for this project, the cytotoxicities of 1-3
were compared to evaluate the effect of the lignano-9,9'-lactone structure on the activity
using H-60 and HeLa cells. After this evaluation, the lignano-9,9'-lactones bearing
different kinds of substituents on the benzene ring were synthesized, and then the
structure-activity relationship was examined to develop the new lignano-9,9'-lactones
showing the higher activity than the natural lignano-9,9'-lactones 1-3 against HL-60 and
HeLa cells. The results of this project would contribute to the construction of
chemical library of lignan and develop a new medicine based on the lignan structure.
We can find the synthetic reports of the optically active arctigenin14-16 and
(R)-3-benzyl-4-butanolide,17,18 which is a synthetic intermediate for the derivatives 5-46
(Table 2). In this experiment, all derivatives were synthesized by employing the
previously described method19,20 with modification. The α-benzylation was applied to
(R)-3-benzyl-4-butanolide to prepare 5-46 and (R)-3-arylmethyl-4-butanolide to prepare
52-75 (Table 3). The synthesis of the racemic compound 5 was reported. The NMR
data of our synthetic (8R,8'R)-5 agreed with those in the literature.21,22 The 9,9'-lactone
structure were transformed to 9,9'-epoxy structure 76-99 (Table 3) by the previously
described method.19 The α,β-unsaturated butyrolactones 49 and 50 were prepared from
the corresponding aldol product from (R)-3-benzyl-4-butanolide by dehydration
employing KHSO4,23 followed by separation of E- and Z-form. The E- and Z-forms
were identified by 1H-NMR data.24 The differential NOE between 7-H and 8'-H
4

confirmed the E and Z structures. The benzyl ethers, which are the protective group
for the phenolic group in the synthetic process, were cleaved by BBr325 to obtain 52, 58,
62, 76, 82, 86 or BCl326 to obtain 68, 69, 92, 93. The hydrogenolysis using 5% Pd/C
and H2 was performed to get the other phenolic compounds. The synthetic method,
NMR, and MS data were descried in the supporting information.
Table 1. Cytotoxicities of 1-4
Compounds
EC50 (µM SD)
HL-60 cells
12 1.5
74 2.2
> 100
HeLa Cells
> 100
(8R,8'R)-arctigenin (1)
(8R,8'R)-matairesinol (2)
(8S,8'S)-matairesinol (3)
(8R,8'R)-dihydroguaiaretic acid (4)
> 100
> 100
26 0.9
22 4.1
The activities of (8R,8'R)-arctigenin (1), (8R,8'R)-matairesinol (2), and
(8S,8'S)-matairesinol (3) against HL-60 and HeLa cells were compared in Table 1.
Against HL-60 cells, (8R,8'R)-arctigenin (1) exhibited the highest activity to show the
EC50 value of 12 µM. In the case of matairesinol, (8R,8'R)-matairesinol (2), which
was 6-fold less potent than that of (8R,8'R)-arctigenin (1), exhibited the enantiospecific
activity. (8S,8'S)-Matairesinol (3) did not show the activity at 100 µM. The
cytotoxicities of all lignano-9,9'-lactones 1-3 against HeLa cells were not observed at
100 µM. However, (8R,8'R)-dihydroguaiaretic acid (4), which is a butane type of
lignan, was effective against both HL-60 and HeLa cells. It could be assumed that the
lignano-9,9'-lactone structure is disadvantageous for the cytotoxicity against HeLa cells.
We tried to improve the activity of the lignano-9,9'-lactone by syntheses of the
5

Table 2. Cytotoxicities of lignano-9,9'-lactone derivatives 5-46 bearing different kinds
of substituents on the 7-atomatic ring against HL-60 and HeLa cells (nt: not tested)
EC50 (µM SD)
No. R
No. R
EC50 (µM SD)
HL-60
77 2.7
83 1.8
79 6.6
39 1.6
76 7.3
HL-60
HeLa
5
H
28 4-OCF3
27 5.1
71 2.0
23 1.5
>100
nt
6
2-OH
29 4-OCH2OCH3
30 4- O(CH2)3CH3
31 4-O(CH2)6CH3
nt
7
2-OCH3
2-OCF3
2-OCH2OCH3
27 4.7
nt
8
17% inhibition
9
10
2-O(CH2)3CH3 20 1.1
32 4-CH3
33 4-CF3
44 1.1
22 1.0
57 2.6
36 1.7
93 5.2
35 3.5
nt
11 2-O(CH2)6CH3 75 9.3
29 4.5
12
13
14
15
16
2-CH3
2-CF3
2-F
57 3.0
37 1.3
72 1.8
37 0.8
>100
34 4-F
nt
nt
nt
nt
35 4-Cl
36 3-OCH3, 4-OH
37 3-O(CH2)3CH3
4-OH
2-Cl
3-OH
45% inhibition
66 3.8
34 3.7
80 9.4
38 3-OCH3, 4-OCH3 >100
nt
nt
38% inhibition
17
18
19
20
21
22
23
24
25
26
27
3-OCH3
3-OCF3
39 3-O(CH2)3CH3
4-O(CH2)3CH3
40 3-O(CH2)O-4
41 3-CH3, 4-CH3
42 3-F, 4-F
>100
29% inhibition
57 5.8
35 5.1
50 3.7
19 0.6
19 0.5
23 1.9
3-OCH2OCH3
3-O(CH2)3CH3 26 1.7
3-O(CH2)6CH3 81 0.4
nt
nt
3-CH3
3-CF3
3-F
53 8.3
34 1.9
75 3.4
36 1.9
88 4.1
67 6.0
nt
43 3-Cl, 4-Cl
44 2-Cl, 4-Cl
45 3-Cl, 5-Cl
26 3.8
23 3.8
17 3.5
nt
3-Cl
4-OH
4-OCH3
46 3-OCH3, 4-OCH3 >100
44% inhibition
5-OCH3
6

derivatives bearing many kinds of the substituents on the aromatic rings. Because of
the results of the activity tests of (8R,8'R)- and (8S,8'S)-matairesinol (2 and 3), we
decided to select the (8R,8'R)-configuration for the following derivatives.
The derivatives 5-46 bearing many kinds of the aromatic rings at the
7-position and the phenyl group without any substituent at the 7'-position were
synthesized and their cytotoxicities were examined (Table 2). The activity of the
derivative 5 against HL-60 cells, whose benzene rings do not have any substituent, was
similar to that of (8R,8'R)-matairesinol (2) in Table 1, suggesting that phenolic hydroxy
groups and methoxy groups of matairesinol are not necessary to show this level of
activity. The results of the tests of the 2-hydroxy 6, 4-hydroxy 26, 2-methoxy 7,
3-methoxy 17, and 4-methoxy 27 derivatives reflects this fact, showing the same level
of the EC50 values (66-88 µM) as the derivative 5. The introduction of a hydroxyl
group to the 3-position dramatically reduced the activity (16: EC50 > 100 µM, against
HL-60 cells). The electron-withdrawing trifluoromethoxy derivatives 8, 18, 28
showed 2-3-fold higher activities than the methoxy derivatives 7, 17, 27 to exhibit the
EC50 values of 23-40 µM. Though the activities of the methoxymethoxy derivatives 9,
19, 29 and heptoxy derivatives 11, 21, 31 were similar to those of the methoxy
derivatives 7, 17, 27, the butoxy derivatives 10, 20, 30 showed 2-4-fold more potent
activities than the methoxy derivatives 7, 17, 27, exhibiting the EC50 values of 20-26
µM. It is suggested that the suitable length of the alkoxy group for the higher activity
would be present. Thus, the derivatives bearing the methoxy group and heptoxy group
showing lower activities than the butoxy derivatives. Comparing the trifluoromethyl
7

derivatives 13, 23, 33 with the methyl derivatives 12, 22, 32, the derivatives bearing the
higher electron-withdrawing trifluoromethyl group, whose EC50 values were 22-37 µM,
were about 2-fold more potent than the methyl compounds. As for the comparison of
the halogen derivatives, the chloro-derivatives 15, 25, 35 were around 2-fold more
potent than the fluoro-derivatives 14, 24, 34 to show the EC50 values of 36-37 µM.
The activity levels of the fluoro-derivatives 14, 24, 34 (EC50 = 57-72 µM) were similar
to the phenyl derivative 5, suggesting that the activity is not affected by the density of
electron. The di-substituted derivatives were also tested. The activity of the
3-methoxy-4-hydroxy derivative 36 was almost similar to that of mono-hydroxy
derivatives, showing activity (EC50 = 93 µM). However, the activity of the phenolic
derivative was increased by the introduction of a longer alkoxy group at the 3-position.
The 3-butoxy-4-hydroxy derivative 37 (EC50 = 35 µM) was 3-fold more potent than the
3-methoxy-4-hydroxy derivative 36. Though the hydrophobicity seemed to be
important for the higher activity, the activities of the 3,4-dimethoxy derivative 38 and
3,4-dibutoxy derivative 39 were very weak (EC50 > 100 µM). On the other hand, the
EC50 value of the 3,4-methylenedioxy derivative 40 was 57 µM, which was almost
similar to that of the 3,4-difluoro derivative 42 (EC50 = 50 µM). The 3,4-dimethyl
derivative showed higher EC50 value of 35 µM than 40 and 42, suggesting that the
presence of the oxygen atoms is disadvantageous and some size of hydrophobic groups
is necessary for the higher activity. This assumption was confirmed by the tests using
the dihalogen derivatives. The dichloro derivatives 43-45 (EC50 = 19-23 µM) were
2-fold more potent than the 3,4-difluoro derivative 42. The 3,4,5-trimethoxy
8

derivative 46 was not effective. The activity level did not depend on the position of
the hydrophobic group on the 7-aromatic ring. Some effective derivatives were
applied to HeLa cells. The EC50 values of the 4-butoxy 30, 4-trifluoromethyl 33, and
dichloro derivatives 43-45 were 17-29 µM against HeLa cells, showing higher activities
than natural (8R,8'R)-arctigenin (1). These activities were similar to that of
(8R,8'R)-dihydroguaiaretic acid (4), which is a butane type of natural lignan, against
both HL-60 and HeLa cells.
Figure 2. Cytotoxicities of 9,9'-epoxy (47, 48), lign-7-eno-9,9'-lactone (49, 50), and
butane 51 type lignans against HL-60 cells
The effect of main lignan structure on the activity was also examined.
Figure 2 shows the cytotoxicities of 9,9'-epoxylignans 47, 48, lign-7-eno-9,9'-lactone 49,
50, and butane type lignan 51 bearing the 3,4-dichlorophenyl group or 4-butoxyphenyl
group at the 7-position against HL-60 cells. The activities of the 9,9'-epoxylignan 48
and butane type lignan 51 were similar to that of the corresponding lignano-9,9'-lactone
derivative bearing 3,4-dichlorophenyl or 4-butoxy group, however, the butoxy
9

derivative of 9,9'-epoxylignan 47 showed 2-fold more potent than corresponding
lignano-9,9'-lactone derivative 30. In this case, carbonyl group of lactone structure
does not play an important role. Comparing Z-form 49 with E-form 50, Z-form
showed the higher activity (EC50 = 58 µM), however, the corresponding
lignano-9,9'-lactone 30 was 2-fold more potent. It was suggested that the presence of
α,β-unsaturated double bond, which is found in the natural lignans,27 would be
disadvantageous. The higher activity of Z-form suggests that the same direction of
7-aryl group as the carbonyl group is favorable for the higher activity.
To evaluate the effect of the aromatic ring at the 7'-position, the
3,4-dichlorophenyl group was employed for the 7-position. Table 3 shows the results
of the cytotoxic assay. In the 2'-position, the alkoxy derivatives 53-55 (EC50 = 10-15
µM) were 2-3-fold more effective than the phenolic 52, methyl 56, and fluoro 57
derivatives against HL-60 cells. The 2'-butoxy derivative 55 was most effective
among the 2'-derivetives against HL-60 cells, showing the EC50 value of 10 µM.
Among the 3'-derivativs, the 3'-fluoro derivative 61 showed the highest activity against
HL-60 cells (EC50 = 14 µM). The 3'-hydroxy 58, 3'-methoxy 59, and 3'-methyl
derivative 60 showed the EC50 values of 22-48 µM. These facts suggest that the
smaller hydrophobic group would be important for the higher activity at the 3'-position.
In the case of the 4'-position, the 4'-methyl derivative 64 was around 2-fold more potent
than the 4'-hydroxy 62 and 4'-methoxy derivative 63 to show the EC50 value of 19 µM
against HL-60 cells. The disadvantage of the presence of the oxygen atom at the
4'-position was suggested. The test of the relationship between the length of the alkyl
10

Table 3. Cytotoxicities of 3,4-dichlorolignan-9,9'-lactone 52-69 and 9,9'-epoxy derivatives 76-93
(nt: not tested). Arctigenin (1): against HL-60 (EC50 = 12 µM), against HeLa (EC50 >100 µM)
R
No.
9,9'-lactone, EC50 (µM SD) No.
9,9'-epoxy, EC50 (µM SD)
HL-60
HL-60
33 3.6
14 4.3
15 4.1
10 2.8
22 4.9
28 4.8
48 8.4
34 1.0
22 4.3
14 2.4
37 4.2
37 3.4
19 7.8
16 2.7
HeLa
2'-OH
nt
34 2.7
55 12
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
2'-OCH3
24 4.0
2'-OCH2CH3
2'-O(CH2)3CH3
2'-CH3
31 6.7
29 9.6
20 6.9
21 9.5
51 7.7
31 4.2
73 9.0
28 5.7
20 2.5
31 3.9
39 6.8
21 3.3
26 7.9
23 8.6
43 6.1
21 4.1
33 4.3
16 3.1
22 3.7
38 9.1
36 6.3
18 2.1
16 7.3
>100
nt
2'-F
nt
3'-OH
nt
3’-OCH3
nt
3'-CH3
nt
3’-F
20 3.2
4'-OH
nt
nt
nt
nt
4'-OCH3
4'-CH3
4'-CH2CH3
4'-(CH2)3CH3
4'-F
9.4 2.3 27 3.3
14 2.7
36 5.6
32 8.7
24 8.7
51 7.8
28 12
16 4.5
25 6.3
20 4.9
19 1.3
3'-OCH3, 4'-OH
3'-OH, 4'-OCH3
3'-OCH3, 4'-OCH3
3'-O(CH2)O-4'
3'-O(CH2)2O-4’
3'-CH3, 4'-CH3
3'-F, 4'-F
nt
nt
nt
nt
nt
nt
nt
nt
3'-Cl, 4'-Cl
11

chain and the activity showed the 4'-butyl derivative 66 was more potent (EC50 =
9.4µM) than the methyl derivative 64. The 4'-fluoro derivative 67 showed almost
similar activity to the 4'-butyl derivative 66. It could be assumed that the longer
hydrophobic group is advantageous for the higher activity. To evaluate the effects of
two substituents, which are found in the natural compounds, activities of derivatives
68-72 were also examined. There is a possibility that the effect of one substituent is
increased and the bulky effects could be also evaluated. Among the 3',4'-disubstituted
derivatives, the 3',4'-dimethyl derivative 73 showed the highest activity, showing the
EC50 value of 16 µM. The derivatives 68-72 and 74 containing the phenolic and
alkoxy substituents or two fluorine atoms were 1.5-3-fold less potent than the
3',4'-dimethyl derivative 73. The activities of the dichloro-derivative 75 was almost
similar to that of the 3',4'-dimethyl derivative 73. Some size of the hydrophobic group
would be more potent in the case of the 3',4'-disubstituted derivatives. The almost
similar activities to arctigenin 1 were observed in the 2'-butoxy 55 and 4'-butyl
derivative 66 against HL-60 cells. The most less potent 9,9'-lactone structure against
HL-60 cells were the 3'-OH 58 and 3',4'-methylenedioxy 71 derivatives, which were
5-6-fold less potent than the 4'-butyl derivative 66. The derivatives 53-55, 61, 66, and
67 were applied to the tests against HeLa cells. Except for the 2'-butoxy derivative 55,
the EC50 values of 19-31 µM, which were higher than that of arctigenin 1, were shown.
Considering the inactive 2'-butoxy derivative 54 and active 4'-butyl derivative 66
against HeLa cells, the presence of oxygen atom would be disadvantageous for the
higher activity against HeLa cells in the case of the derivative bearing longer
12

hydrophobic group on the 7'-aromatic ring. Since natural arctigenin bearing two
methoxy groups on 7'-aromatic ring is inactive against HeLa cells, more hydrophobicity
would be effective against HeLa cells. The activities of the corresponding 9,9'-epoxy
derivatives 76-99 were also evaluated against HL-60 cells. The obvious advantage of
the 9,9'-lactone structure was shown in the 2'-methoxy derivative 53, which was 4-fold
more potent than the corresponding 9,9'-epoxy structure 77. The most effective
9,9'-epoxy structure was the 3',4'-dimethoxy 94 and 3',4'-dichloro derivative 99,
showing the EC50 values of 16 µM. However, the obvious advantage of the 9,9'-epoxy
structure than the 9,9'-lactone was not observed in most of the cases. The lowest
activity of the 9,9'-epoxy structure was shown in the 3'-methoxy derivative 83 (EC50 =
73 µM). The most effective 9,9'-epoxy lignan was 4-butoxy derivative 30 (Figure 2,
against HL-60 dells, EC50 = 11 µM), suggesting that the longer alkoxy substituent on
the 7-aryl group and phenyl group without substituent on the 7'-position is advantageous
in the case of 9,9'-epoxy structure.
In summary, the novel cytotoxic lignano-9,9'-lactones were developed. Two
chlorines on the 7-aromatic ring and 2'-butoxy/4'-butyl group on the 7'-aromatic ring
were effective to improve the activity level of arctigenin. In the previous study,7 the
alkoxy derivatives were synthesized and their activities were evaluated. In our
research, the chloro and alkyl derivatives were prepared and they showed almost similar
activity to arctigenin against HL-60 cells. On the other hand, their activities against
HeLa cells were dramatically improved comparing natural arctigenin. It could be
assumed that hydrophobic substituents on the aromatic ring are important for the
13

activity against HeLa sells. We have showed the effects of aromatic substituents in the
other lignan structure on the cytotoxicity by our previous study.13,28-30 It was clarified
that the substituents on the aromatic ring of the lignano-9,9'-lactone structure effects on
the activity in this study. Since many biological activities of lignano-9,9'-lactone have
been reported,31-35 there is a possibility that the new biological activities of these
compounds would be discovered.
Acknowledgements
Part of this study was performed at ADRES (Johoku station) of Ehime University. We
are grateful to MARUTOMO Co., LTD for financial support.
Supplementary data
Supplementary data associated with this article can be found in
the online version.
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