Synthesis and glucose-stimulate insulin secretion (GSIS) evaluation of vindoline derivatives

Article abstract of DOI:10.1016/j.bmcl.2016.09.064

It is demonstrated that natural product vindoline can enhance the glucose-stimulated insulin secretion (GSIS) in MIN6 cells with the EC₅₀ value of 50.2?μM. In order to improve the activities, a series of vindoline derivatives are synthesized an

Full text of DOI:10.1016/j.bmcl.2016.09.064

Accepted Manuscript
Synthesis and glucose-stimulate insulin secretion (GSIS) evaluation of vindo-
line derivatives
Chengqian Xiao, Yunan Tian, Min Lei, Fanglei Chen, Xianwen Gan, Xingang
Yao, Jing Chen, Xu Shen, Lihong Hu
PII:
S0960-894X(16)31013-7
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.09.064
BMCL 24288
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
7 June 2016
6 September 2016
26 September 2016
Please cite this article as: Xiao, C., Tian, Y., Lei, M., Chen, F., Gan, X., Yao, X., Chen, J., Shen, X., Hu, L., Synthesis
and glucose-stimulate insulin secretion (GSIS) evaluation of vindoline derivatives, Bioorganic & Medicinal
Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.09.064
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Graphical Abstract
Synthesis and glucose-stimulate insulin
secretion (GSIS) evaluation of vindoline
derivatives
Leave this area blank for abstract info.
Chengqian Xiao, Yunan Tian, Min Lei, Fanglei Chen, Xianwen Gan, Xingang Yao, Jing Chen, Xu Shen,
Lihong Hu

Bioorganic & Medicinal Chemistry Letters
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Synthesis and glucose-stimulate insulin secretion (GSIS) evaluation of vindoline
derivatives
a,†
Chengqian Xiao , Yunan Tian , Min Lei ∗, Fanglei Chen , Xianwen Gan , Xingang Yao , Jing Chen ,
b,†
a,
a
a
b
b
b,
Xu Shen ∗ and Lihong Hu ∗
a,
a
State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Chinese Academy of Sciences,
Shanghai, P. R. of China.
b
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Chinese Academy of Sciences,
Shanghai, P. R. of China.
ARTICLE INFO
ABSTRACT
Article history:
Received
It is demonstrated that natural product vindoline can enhance the glucose-stimulated insulin
secretion (GSIS) in MIN6 cells with the EC50 value of 50.2 µM. In order to improve the
activities, a series of vindoline derivatives are synthesized and evaluated in MIN6 cells.
Compounds 4, 8, 17 and 24 show about 4.5 times more effective stimulation insulin secretion
ability (EC50: 10.4, 14.2, 11.0 and 12.7 µM , respectively) than vindoline.
Revised
Accepted
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Vindoline
Natural product
Glucose-stimulate insulin secretion (GSIS)
Structure-activity relationships (SARs)
Diabetes mellitus containing type 1 and type 2 is a complex
metabolic disordered disease worldwide with significant resulting
morbidity and mortality. It is estimated by International Diabetes
Federation that more than 415 million people have diabetes, 318
million have impaired glucose tolerance, and about 21 million
women develop gestational diabetes in worldwide in 2015. Type
Catharanthus roseus. It has been previously reported to possess
4
diverse pharmacological properties. Furthermore, vindoline is an
important chemical precursor to synthesis of antitumor drugs,
5
6
7
such as vinorelbine, vinflunine, and vindesine. Recently, we
reported vindoline could obviously enhanced the GSIS in MIN6
cells and primary mice pancreatic islets. Moreover, the assays on
type 2 diabetic animal models (db/db mice and STZ/HFD-
induced type 2 diabetic rats) demonstrated that vindoline
effectually decreased fasting plasma glucose, improved oral
2
diabetes mellitus (T2DM) is reported to ranged between 90%
and 95% of both types, which is primarily characterized by
insulin resistance and relative insulin deficiency that eventually
1
cause hyperglycemia. At present, insulin secretagogues
glucose tolerance, lowered serum glycated hemoglobin (HbA1c)
8
including sulfonylureas and glinides, which can promote
endogenous insulin release and further increase glucose uptake
and transformation in target tissues, are widely used clinically for
and triglyceride (TG) levels. Due to its obviously ant-T2DM
activities in vivo and vitro, vindoline is chosen as a drug lead for
further investigation.
2
the treatment of T2DM. However, these agents readily lead to
hypoglycemia. Therefore, the development of glucose-stimulated
insulin secretion (GSIS) agents without hypoglycemia has been
received a considerable attention.
In recent years, there has been a growing interest in anti-
3
diabetes agents from folk medicinal plants. Vindoline, as shown
in Figure 1, is a main ingredient of an anti–T2DM herb
Figure 1. The structure of vindoline (1).
—
——
These authors contributed equally to this work.
†
∗
∗
∗
Corresponding author. Tel.: +86-21-2023-1965; fax: +86-21-2023-1965; e-mail: mlei@simm.ac.cn
Corresponding author. Tel.: +86-21-5080-6031; fax: +86-21-5080-6031; e-mail: xshen@simm.ac.cn
Corresponding author. Tel.: +86-21-2023-1965; fax: +86-21-2023-1965; e-mail: lhhu@simm.ac.cn

To study its structure–activity relationships (SARs) further, a
series of vindoline derivatives were synthesized and their
biological activities of GSIS (EC50 values) were tested in MIN6
cells. According to the structural characteristic of vindoline, we
carried out the modification of vindoline on C-4, C-6, C-7 and C-
Hydrolysis of vindoline took place in the presence of MeONa as
base in MeOH to obtain C-4 deacetyl vindoline (2) in 93% yield.
Then, 2 reacted with acyl chloride to form 3–6 (62–66%).
Compounds 3 and 4 were hydrogenated on Pd/C to give 7 and 8,
respectively. As shown in Scheme 2, compound 9–12 were
synthesized from 2 by etherification in 15–30% yields.
22. Initially, to investigate the effect of C-4 ester group on GSIS
activities, compounds 2–6 were synthesized (Scheme 1).
N
N
N
O
O
O
O
O
a
OH
b
OH
c
OH
1
N
N
R1
N
R1
OH
O
O
H
O
H
O
H
O
O
O
O
3
-6
2
, 93%
7
, 8
1
3
: R = ethyl, 65%
d
1
7
: R = ethyl, 95%
1
4
: R = i-propyl, 62%
1
8
: R = i-propyl, 95%
1
5
:
R = cyclohexyl, 65%
N
1
O
6: R = phenyl, 66%
OH
R2
2
N
9: R = methyl, 30%
O
H
2
1
0: R = ethyl, 25%
O
O
2
1
1: R = n-propyl, 20%
2: R = n-butyl, 15%
2
1
9
-12
1
Scheme 1. Synthesis of 2–12: reagents and conditions: (a) MeONa, MeOH; (b) R COCl, Et
3
N, DCM; (c) 10% Pd/C, MeOH; (d)
2
I or R Br, NaH, THF.
CH
3
1
a
N
N
N
O
O
O
O
OH
O
OH
b, c
d, c
N
H
OH
O
N
R1
O
N
OH
H
H
O
O
R4
OH
1
3, 91%
O
R3
16-20
e
1
4-15
1
4
1
1
1
1
6: R = methyl, R = methyl, 45%
N
1
4
7: R = methyl, R = ethyl, 58%
3
1
4: R = ethyl, 55%
O
1
4
8: R = methyl, R = n-propyl, 62%
3
1
5: R = i-propyl, 58%
1
4
9: R = methyl, R = n-butyl, 64%
N
OH
1
4
H
O
20: R = i-propyl, R = ethyl, 53%
f, g
2
1, 80%
N
N
O
1
5
O
23: R = methyl, R = methyl, 72%
O
OH
h, c
1
5
2
4: R = methyl, R = ethyl, 70%
OH
N
R1
O
1
5
N
H
H
25: R = methyl, R = t-butyl, 63%
OH
1
5
NH
26: R = i-propyl, R = ethyl, 70%
NH2
R5
O
2
2, 75%
23-26
, THF; (b) BtCOR , NaH, THF; (c) Ac
d) NaOH, TBAI, MeI or R Br. (e) TsCl, TBAI, NaOH, THF; (f) NaN , NH Cl, MeOH/H O; (g) LiAlH
DCM.
3
1
O or R COCl, Py or Et
Scheme 2. Synthesis of 13–26: reagents and conditions: (a) LiAlH
4
2
3
N;
4
5
(
3
4
2
4
, THF; (h) R COCl, NaOAc,

In addition, the modification of C-22 of vindoline was also
carried out by a multi-step process (Scheme 2). Vindoline was
reducted by LiAlH in THF to afford 13 in 91% yield, then 13
were evaluated their GSIS activities on MIN6 cell line. The
1
results indicate that both ester group and size of R on C4 played
4
a key role to keep the activities. The reduction of double bond of
C-6 and C-7 led to the activity decreased. As for the ester and
was esterified to form 14 and 15, or etherified to form 16–20.
Furthermore, anino substituted derivatives were also synthesized
as shown in Scheme 4. Epoxy intermediate 21 was formed from
3
4
ether derivatives on C-22, the size of R or R also have a
significant impact on GSIS activities. In addition, the activities
are improved for those compound with amide substituted
derivatives on C-22. Among all compounds, 4, 8, 17 and 24 show
good GSIS activities, which were about 4.5-fold more potent
than vindoline.
1
3 in the presence of TsCl in THF in 80% yield. Then ring
opening reaction of 19 with NaN3 resulted in the formation of
the azide, which was reduced by LiAlH to give 20 in 75% yield.
Further acylation reaction of 22 was carried out to give 23–26
4
(
63–72%).
Then, we evaluated the GSIS activities of these compounds on
MIN6 cell line, and the results are presented in Table 1. The EC50
values of vindoline and C-4 deacetyl vindoline (2) were 50.2 µΜ
and >100 µΜ, respectively. This result clearly indicated that C-4
ester group was important to keep the activities. Therefore,
several C-4 ester group derivatives 3–6 were synthesized, and the
EC50 values of these compounds ranged from 10.4 to 80.5 µΜ.
Acknowledgments
This work was supported by the National Natural Science
Foundation of China (Grant: 81273397).
References and notes
1
1
The GSIS activities of 3 (R = ethyl) and 4 (R = i-propyl) were
increased greatly compared with vindoline. On the contrary, the
1. (a) Schwarz, P. E. H.; Gallein, G.; Ebermann, D.; Muller, A.;
Lindner, A.; Rothe, U.; Nebel, I. T.; Muller, G. Diabetes Res.
Clin. Pract. 2013, 100, 11; (b) Seo, W.-D.; Lee, J. H.; Jia, Y.; Wu,
C.; Lee, S.-J. Bioorg. Med. Chem. Lett. 2015, 25, 5237; (c)
Bloomgarden, Z. T. Diabetes Care 1996, 19, 295. (d) Wild, S.;
Roglic, G.; Green, A.; Sicree, R.; King, H. Diabetes Care 2004,
1
activities of 5 (R = cyclohexyl) and 6 (R = phenyl) were
1
1
decreased. These results revealed that increasing the group of R
properly was favorable for increased activities, however,
the large steric hindrance group was unfavorable.
27, 1047.
Porte, D. Jr. Diabetes Metab. Res. Rev. 2001, 17, 181.
2
3
.
.
Zareba G.; Serradell N.; Castaner R.; Davies S. L.; Prous J.;
Mealy N. Drug Future 2005, 30, 1253.
Table 1
GSIS activities of vindoline derivatives on MIN6 cell line.
4
.
(a) Passarella, D.; Giardini, A.; Peretto, B.; Fontana, G.; Sacchetti,
A.; Silvani, A.; Ronchi, C.; Cappelletti, G.; Cartelli, D. Borlake,
J.; Danielia, B. Bioorg. Med. Chem. 2008, 16, 6269; (b) Nammi,
S.; Boini, M. K.; Lodagala, S. D.; Behara, R. B. S. BMC Comp.
Altern. Med. 2003, 3, 4; (c) Rasineni, K.; Bellamkonda, R.;
Singareddy,S. R.; Desireddy, S. Pharmacogn. Res. 2010, 2, 195.
Mangeney, P.; Andriamialisoa, R. Z.; Langlois, N.; Langlois, Y.;
Potier, P. J. Org. Chem. 1979, 44, 3765.
Compound
EC50 (µΜ)
50.2 ± 3.4
>100
Compound
EC50 (µΜ)
51.0 ± 3.9
>100
vindoline
14
15
16
17
18
19
20
23
24
25
26
2
3
4
5
6
7
8
9
32.6 ± 2.6
10.4 ± 0.6
80.5 ± 9.2
62.2 ± 4.4
38.5 ± 2.5
14.2 ± 0.6
>100
41.0 ± 3.5
11.0 ± 1.0
41.5 ± 3.0
>100
5
6
.
.
(a) Etievant, C.; Barret, J.-M.; Krucznski, A.; Perrin, D.; Hill, B.
T. Invest. New Drug. 1998, 16, 3; (b) Langlois, N.; Gueritte, F.;
Langlois, Y.; Potier, P. Bioorg. Med. Chem. Lett. 2002, 12, 505.
(a) Fahy, J.; Duflos, A.; Ribet, J. P.; Jacquesy, J. C.; Berrier, C.;
Jouannetaud, M. P.; Zunino, F. J. Am. Chem. Soc. 1997, 118,
7
8
.
.
14.2 ± 1.1
19.3 ± 1.4
12.7 ± 0.7
21.0 ± 1.8
18.5 ± 2.0
8576; (b) Bellmunt, J.; Delgado, F.-M.; George, C. Semin. Oncol.
2008, 35, S34.
Yao, X.; Chen, F.; Li, P.; Quan, L.; Chen, J.; Yu, L.; Ding, H.; Li,
C.; Chen, L.; Gao, Z.; Wan, P.; Hu, L.; Jiang, H.; Shen, X. J.
Ethnopharmacol. 2013, 150, 285.
1
1
1
0
1
2
62.2 ± 4.6
64.3 ± 4.3
>100
Supplementary Material
Supplementary data (experimental procedures, spectral data
and biological assay methods) associated with this article can be
found, in the online version, at
Then, compounds 3 and 4 were chosen to investigate the
effect of C-6 and C-7 double bond on activity. The EC50 values
of 7 (38.5 µΜ) and 8 (14.2 µΜ) showed that the reduction of
double bond led to the activity decreased. Furthermore, C-4 ether
derivatives 9–12 were also synthesized, and activity test showed
low activities (EC50 > 62.2 µΜ).
In addition, several ester and ether derivatives on C-22 (14–20)
were synthesized. As shown in Table 1, 17 showed more potent
GSIS activities on MIN6 cell line with the EC50 value of 11.0 µM,
which was 4.5-fold more potent than vindoline. The EC50 values
of 14–20 demonstrated that the activities were decreased
3
4
significantly with the increase of group (R or R ). Furthermore,
amide substituted derivatives on C-22 (23–26) showed good
activities with the EC50 value of 19.3, 12.7, 21.0 and 18.5 µM,
respectively.
In conclusion, we have synthesized a series of vindoline
derivatives on C-4, C-6, C-7 and C-22. All of these compounds