A concise synthesis and biological study of evodiamine and its analogues

Article abstract of DOI:10.1039/c9cc00434c

Efficient access to evodiamine and its analogues is presented via Lewis acid catalysis. In this reaction, three chemical bonds and two heterocyclic-fused rings are constructed in one step. The reaction shows good functional group tolerance and atom economy, and various heteroatom-containing evodiamine analogues are obtained in moderate to excellent yields even on a gram scale. An anti-tumor study in vitro demonstrates compound 2b possesses potent efficacy against hepatoma cell line (IC₅₀ = 5.7 μM).

Full text of DOI:10.1039/c9cc00434c

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc
first methanofullerene derivatives of Sc
3
N@C2n (2n
=
68 and 80). Synthesis of the
3
N@D5h-C80
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DOI: 10.1039/C9CC00434C
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A Concise Synthesis and Biological Study of Evodiamine and Its
Analogues
Received 00th January 20xx,
Accepted 00th January 20xx
a,b,d
a,d
a
a
a
c
Jie-Dan Deng,
Shuai Lei, Yi Jiang, Hong-Hua Zhang, Xiao-Ling Hu, Huai-Xiu Wen, Wen
a
a,b
Tan, * Zhen Wang *
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient access to Evodiamine and its analogues is presented synthesis and modification of which have aroused broad
via Lewis acid catalysis, in this reaction, three chemical bonds and interests in both synthetic and pharmaceutical industries
4
two heterocyclic-fused rings are constructed in one step. The because of its diverse biological activities. In last decades,
reaction shows good functional group tolerance and atom
economy, various heteroatom-contained Evodiamine analogues
are obtained in moderate to excellent yields even on gram scale.
Anti-tumor study in vitro demonstrates compound 2b possess
potent efficacy against hepatoma cell line (IC50=5.7 µM).
O
N
N
N
H
O
N
M1: three steps
M2: MeOTf, HMPA
ref. 10c,10d
O
X
O
O
N
O
N
M1: heat
-XO2
X=C, S
M2: EDCI
strong
acid
ref. 11
Me
or
NH2
N
O
O
Ar1
X
Ar2
X=N-R, O, S
Wu's work
O
N
N
N
Polycyclic heterocycles are crucial motifs widely exist in
Yref. 10a,10b
H
H
H
Me
two steps prepared
two steps prepared
limited to Nitrogen
1
XH
X=N-R, O, S
Y=Cl, OH
drugs and alkaloids, many of them have shown superior
BF3.Et2O
HC(OEt)3, DMF
bioactivity in anti-bacterials (Roquefortine C), anti-tumors
O
(
Camptothecin), cerebral vasodilatory (Vincoline) etc.
R1
HN
Our work
20 examples
0%-94%
2
Ar2
according to the known reports (Figure 1). Thus, making the
rapid construction of polycyclic heterocycle skeletons is always
the hotspot in synthetic chemistry. Among them, Evodiamine
N
HX
6
H
X=N-R, O, S




three C-X bonds formation
wider substrates scope
step concisely and high efficient
high functional group tolerance
3
Scheme 1. Approaches to Evodiamine and its analogues.
as one of the most typical polycyclic heterocycles, the
O
several groups have done elegant works in this domain, in
997, Chen firstly employed Evodiamine for anti-
H
N
NH
1
N
NH
N
N
H
5
inflammatory.
Subsequently,
Kamiya
demonstrated
H
H
NH H
O
OH
6
MeO
Evodiamine’s efficacy in anti-obesity in 2001. After that,
Zhang successfully applied Evodiamine in transgenic mouse
model for Alzheimer´s disease (AD) treatment. Through
NH
CO2Me
C2H5
O
N
Roquefortine C
anti-bacterial
Tabersonine
anti-tumor
Yohimbine
2 adrenergic
7
receptor antagonist
chemical decorations, Sheng etc. discovered several
Evodiamine analogues as potent anti-cancer drug candidates
in recent years. The structure−activity relationships of the
O
O
N
N
N
H
OH
O
H
8
N
O
N
H
H
N
HO
H
evodiamine derivatives has been reported previously, in which
C2H5
O
2
MeO C
O
OH
Me
H
R
1
and X follows the listed orders respectively. For R
1
: OH > I >
Camptothecin
anti-tumor drug
Nauclofficine
anti-tumor
Vincoline
cerebral vasodilatory
F > OMe > Br > Cl or Me; For X: 0, S > N-Me > CH > C=N.
Figure 1. Polycyclic heterocycle skeletons in drugs and natural products.
Meanwhile, when different positions of Ar
2
are substituted by
different groups, the activity also varies.8
b,8d
Despite
Evodiamine and its analogues having shown greatly potential
benefits for human health, the approaches to these
compounds are still limited. Conventional methods to such
a. School of Pharmacy, Lanzhou University, West Donggang Road. No. 199, Lanzhou
9
7
30000, China. E-mail: tanwen@lzu.edu.cn. E-mail: zhenw@lzu.edu.cn
b.
c.
Institution State Key Laboratory of Applied Organic Chemistry, College of
Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China.
Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau
Biology, Chinese Academy of Sciences, No. 23 Xining Road, Xining, P. R. China.
These authors contributed equally. E-mail: zhenw@lzu.edu.cn
kind of chemicals usually suffered from multi-step preparation
and an imine intermediate had to be synthesized stepwise,
along this process some toxic reagents as well as transition
d.
1
0
metals were also employed (Scheme 1). In this context, the
†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See methodologies on how to prepare Evodiamine and its
DOI: 10.1039/x0xx00000x
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analogues concisely are highly desired in synthetic chemistry. Whereas, this reaction was suppressed thoroughly at room
View Article Online
DOI: 10.1039/C9CC00434C
Recently, Wu and co-workers developed an elegant work on temperature (entry 16).
one-pot synthesis of Evodiamine and its analogues,
With the optimized conditions in hand, we investigated the
unfortunately, the substrates were merely constrained to N- scope of the reaction with regard to various substituents on
1
1
methylisatoic anhydride accordingly.
Therefore, related the indole rings as well as the ortho-position of benzamides,
works on one-step preparation of diversified heteroatom- and moderate to excellent yields were obtained in all the cases
contained Evodiamine analogues still remain blank. Herein, we (2a-2t, 60%-94%). Different electron-donating substituents on
report
a concise access to Evodiamine and various
O
O
BF3•Et2O (0.5 eq)
HC(OEt)3 (3.0 eq)
HN
HX
N
X
heteroatom-contained Evodiamine analogues via Lewis acid
catalysis, in this protocol, different fused heterocycles are
efficiently constructed within one step.
Ar1
Ar1
DMF, 5 h, 100 o
C
N
Ar2
N
Ar2
H
H
1
X=N-R, O, S
2
O
O
O
Me
MeO
N
N
N
O
O
Lewis acid
HC(OEt)3
sol., temp., 5 h
HN
HN
N
N
Ph
2a
N
H
N
N
H
N
N
N
Ar1
H
Ar1
Ar2
N
H
Ar2
N
H
2a, 92%
2b, 91%
2c, 93%
Ph
1a
O
O
O
Cl
N
N
N
N
N
HC(OEt)
3
Temp.
Yieldb
(%)
73
46
28
N.R.
81
70
45
33
93
91
75
trace
48
92
Entry
Solvent
DMF
Lewis acid
o
N
H
N
H
N
H
N
（
eq）
( C)
1
2
3
4
5
6
7
8
9
AlCl
AlCl
AlCl
AlCl
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
1
3
3
135
135
135
135
135
135
135
135
135
135
135
135
135
100
70
Me
Me
CH
3
CN
Me
2e, 94%
Cl
2
d, 71%
2f, 90%
Toluene
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
O
O
O
Me
N
N
O
N
O
N
N
Me
g, 92%
N
H
N
H
ZnCl
ZnBr
SnCl
TiCl
2
H
2
2h, 72%b
2i, 73%b
2
Evodiamine
O
O
O
O
O
MeO
Cl
4
N
N
N
4
N
O
N
O
N
O
H
H
H
BF
3
BF
3
BF
3
•Et
2
O
2
O
2
O
2
j, 75%b
2k, 60%b
2l, 71%b
0c
d
Me
1
•Et
•Et
/
O
O
O
N
O
N
N
O
1
1
1
2
N
N
O
N
Me
H
H
H
c
c
c
c
1
1
1
1
3
4
5
6
BF
3
BF
3
BF
3
BF
3
•Et
•Et
•Et
•Et
2
O
2
O
2
O
2
O
2m, 73%b
2n, 70%b
2o, 74%b
OMe
O
F
N
N
N
80
N.R.
N
H
O
Cl
N
O
N
S
3
25
H
H
2p, 60%b
2q, 76%b
2r, 76%c
a
a
Table 1. Optimization of reaction conditions. Reaction conditions: 1a (1 eq,
0
.10 mmol), HC(OEt)
3
(3 eq, 0.30 mmol), Lewis acid (1 eq, 0.10 mmol), solvent (1
O
O
b
c
Me
MeO
mL) under Ar atmosphere for 5h. Isolated yields. BF
3
•Et
2
O was used in 0.5 eq.
N
S
N
d
3 2
BF •Et O was used in 0.3 eq. N.R.=no result.
N
H
N
S
H
2
s, 75%c
2t, 81%c
We initiated this study with 1a as the model substrate, and
choosing HC(OEt) as the carbon source with Lewis acid AlCl
a
a
b
Scheme 2. Investigation of substrates scope. Standard conditions. Reaction
o
C
2 2
temperature was 135 C. CH Cl was used as the solvent, room temperature.
3
3
as the catalyst. After screening of various solvents, DMF was
confirmed to the optimal solvent and the desired product was
obtained in 73% yield (entry 1). Considering the curial role of
Lewis acid in this transformation, different catalysts were
checked subsequently (entry 5-9), delightedly, 2a was
the indole rings were well tolerant in this reaction (2b, 91%;
c, 93%), when electron-withdrawing group introduced the
yield was reduced slightly (2d, 71%). Meanwhile, various aryl-
substituted amidogens on the ortho-position of the
benzamides provided the desired products in excellent yields
2
generated in 93% when 1 equivalent BF
entry 9). Inspired by this delighting result, we tried to lower
the amount of BF •Et O, and no obviously decreased efficiency
was observed when 0.5 equivalent BF •Et O used (91%, entry
0). While the yield reduced sharply accompanying with
reduced amount of BF •Et O further (75%, entry 11), in the
absence of Lewis acid merely trace of 2a was detected (entry
2). Meanwhile, similar result was provided when we
regulated the amount of HC(OEt) (48%, entry 13) Lastly, we
preformed this reaction in different temperature gradients,
3 2
•Et O was employed
(2e, 94%; 2f, 90%). Noteworthily, Evodiamine 2g was directly
(
obtained within our protocol in 92% yield. Subsequently,
various ortho-hydroxyl substituted benzamides were checked
in this scenario (1h-1q), electron-donating substituents
showed no effects on the reaction while the electron-
withdrawing one gave a lower yield on the contrary (2i-2k,
3
2
3
2
1
3
2
6
0%-75%), which in accordance with the aforementioned
1
results. Unexpectedly, diversified substituents on the para-
position of ortho-hydroxyl substituted benzamides made no
difference on the yields (2l-2n, 70%-73%), no matter for the
electron-donating or -withdrawing ones. Likewise, as for the
meta-substituted substrates, the same phenomenon was
3
.
o
and excellent yield was provided at 100 C (92%, entry 14), and
o
no obvious effect was observed even at 70 C (entry 15).
2
| J. Name., 2012, 00, 1-3
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and uniform, and the nucleus was obviously regular, the
ellipsoid shape (Figure 3A). But when the cells were exposed to
SMMC
7721
View Article Online
DOI: 10.1039/C9CC00434C
Compds
CAL-27
A549
WI-38
-
2
2
2
a
b
c
>200
75.1±2.3
9.9±1.0
>200
>200
>200
14.6±2.9
13.4±0.9
>200
64.1±1.8
56.7±2.8
29.4±3.2
>200
12.6±5.7
5.7±4.5
12.9±2.1
16.8±2.2
43.3±2.3
9.2±1.9
>200
64.5±7.8
43.5±5.0
>200
58.7±2.0
42.8±5.7
27.4±2.1
84.0±3.6
10.2±2.2
compound 2b for 72 h, the nucleus were apparently damaged.
Most cells showed condensed and fragmented nuclei (arrows)
(Figure 3, B-C). It indicated that compound 2b could induce a
significant cell apoptosis in SMMC-7721 cells. All data
mentioned above data suggested these new compounds merit
further research for identifying the promising features as
antitumor candidates in the future.
2
2
d
e
2
f
2
q
>200
1.3±0.3
Vorinostat
3.1±0.5
3.6±0.5
O
O
Table 2. The cytotoxicity of the synthesized compounds on cancer cell lines and
Me
a a
normal cell line (IC50, µM). All values are the mean ± SEM (n =3).
BF Et O (0.5 eq)
HC(OEt)3 (3 eq)
DMF, 100 oC, 5 h
N
N
N
H
3
2
Me
N
HN
N
H
observed as the different electronical substituents on the
indole rings (2o, 74%; 2p, 60%). Lastly, three ortho-sulfydryl
benzamides were also tested in this reaction (1r-1t), since
stronger nucleophilicity of sulphur atom compared with
Nitrogen and Oxygen atom which enabled these reactions to
be performed under milder conditions. And different electron-
donating groups on the indole rings showed no effects on the
yields (2s, 75%; 2t, 81%).
H
1b (1.1 g, 3.0 mmol)
2b (0.89 g, 79%)
Scheme 3. Gram scale experiment.
To demonstrate the robust nature of this protocol, we
performed a gram scale reaction using 1b as the typical
substrate, and the corresponding product 2b was obtained in
good yield (0.89 g, 79%), which could ensure sufficient reagent
supplement in the following insightful bioactivity assessments.
In summary, we have developed an efficient access to
Evodiamine and various heteroatom-contained analogues, in
this transformation three chemical bonds and two fused rings
were constructed within one step. The reaction showed good
functional group tolerance, and all the expanded examples
were obtained in good to excellent yields even on gram scales.
Notably, the unreported Evodiamine analogue 2b synthesized
in our protocol exhibited potent efficacy against SMMC-7721
2
2
1
1
50
00
50
00
50
(
IC50=5.7 µM). The fluorescence photomicrograph results
0
showed compound 2b could particularly induce a significant
apoptosis in SMMC-7721 cells. More insightful bioactivity
assays and applications of the reaction are under progress in
our lab.
2
a
2b
WI-38
2c
2d
2e
2f
2q Vorinostat
CAL-27
A549
SMMC-7721
Figure 2. In Vitro Antitumor Activity of the new compounds (IC50, μM)
8
th
According to previous studies, since Evodiamine analogues
Dedicated to Lanzhou University for her 110 birthday. We
usually possess anti-tumor activity, these unreported thank Prof. Quan-Yi Zhao and Prof. Dian He for helpful
compounds synthesized by us were evaluated for their discussions. Financial support was provided by the
cytotoxicity using MTT method (table 2, figure 2). The results Recruitment Program of Global Experts (1000 Talents Plan).
data showed that the compound 2b exhibited higher activity
than other compounds in the field of inhibiting proliferation of
SMMC-7721 cells, and its IC50 value was 5.7 µM which were Conflicts of interest
close to IC50 of Vorinostat. Moreover, the selectivity of 2b on
both the tumor cell lines and normal cell line (WI-38) were also
better than that of Vorinostat.
The authors declare no competing financial interest.
Control
25M
100M
Notes and references
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Figure 3. Apoptosis of SMMC-7721 cells after compound 2b treatment (200×).
SMMC-7721 cells were incubated with compound 2b for 72 h, and the nuclei
were stained by DAPI.
1
634. For selected examples of polycyclic heterocycle’s
The induced apoptosis of compound 2b in SMMC-7721 cells
were further confirmed by DAPI fluorescence after a 72-h
treatment. Under the fluorescence microscope, the
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