Catalyst-free visible-light-induced condensation to synthesize bis(indolyl)methanes and biological activity evaluation of them as potent human carboxylesterase 2 inhibitors

Article abstract of DOI:10.1039/c9ra08593a

A mild strategy for visible-light-induced synthesis of bis(indolyl)methanes was developed using aromatic aldehydes and indole as substrates. This reaction could be performed at room temperature under catalyst- and additive-free conditions to synthesize a

Full text of DOI:10.1039/c9ra08593a

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PAPER
Catalyst-free visible-light-induced condensation to
synthesize bis(indolyl)methanes and biological
activity evaluation of them as potent human
carboxylesterase 2 inhibitors†
Cite this: RSC Adv., 2019, 9, 40168
Yi-Shu Zhao,‡a Hong-Li Ruan,‡b Xiu-Yang Wang,a Chen Chen,b Pei-Fang Song,a
b
a
*
*
Cheng-Wei Lu and Li-Wei Zou
¨
A mild strategy for visible-light-induced synthesis of bis(indolyl)methanes was developed using aromatic
aldehydes and indole as substrates. This reaction could be performed at room temperature under
catalyst- and additive-free conditions to synthesize a series of bis(indolyl)methanes in good to excellent
yields. In addition, all synthesized bis(indolyl)methanes together with b-substituted indole derivatives
synthesized according to our previous work, were evaluated for their inhibitory effect against human
carboxylesterase (CES1 and CES2). Primary structure–activity relationship analysis of all tested
compounds showed that the modifications of b-substituted indole at the b-site with another indolyl
group led to a significant enhancement of the inhibitory effect on CES2, and the bisindolyl structure is
essential for CES2 inhibition. These results demonstrated that these bis(indolyl)methanes are potent and
selective CES2 inhibitors, which might be helpful for medicinal chemists to design and develop more
potent and selective CES2 inhibitors for biomedical applications.
Received 21st October 2019
Accepted 25th November 2019
DOI: 10.1039/c9ra08593a
rsc.li/rsc-advances
well-known roles of CES2 in xenobiotic metabolism, the enzyme
also participates in endogenous metabolism12,13 More recently,
1. Introduction
CES2 has been reported with triacylglycerol and diacylglycerol
hydrolase activity, its expression and function in liver are
strongly related with several metabolic diseases, such as obesity
and non-alcoholic steatohepatitis.13,14 Thus, CES2 inhibitors
could be used as potential tools for exploring the biological
functions of CES2 in complex biological systems.
Indole derivatives are widely distributed in nature and
possess benecial biological activities, including anticancer,15,16
antifungal,17 anti-inammatory,18,19 and antimicrobial activi-
ties.20,21 Among them, bis(indolyl)methanes and b-substituted
indole are distinguished skeletons which are important inter-
mediates for chemical synthesis and important pharmaco-
phores.22 In view of this, there is already a considerable demand
in medicinal and organic chemistry for developing versatile
synthetic approaches to these two kinds of compounds and
careful study their biological activities.23–28 The interest for
developing mild and environment-friendly synthetic method of
indole derivatives is one thread in our group.29,30 Meanwhile, we
also focus on the further applications of heterocyclic
compounds synthesized in our laboratory.
Mammalian carboxylesterases (CES, E.C. 3.1.1.1) are key
members of the serine hydrolase superfamily, and play impor-
tant roles in the hydrolytic metabolism of ester-, thioester-,
amide-, and carbamate-bond containing endogenous and
xenobiotic compounds.1,2 In the human body, there are two
predominant carboxylesterases, human carboxylesterase
1
(CES1) and human carboxylesterase 2 (CES2).3,4 As the major
CES distributed in the human intestines and colon, CES2 is
mainly known as the enzyme involved in the metabolism of
some ester-containing drugs and environmental toxicants.5,6
For example, CPT-11, a carbamate prodrug prescribed for the
treatment of colorectal cancer, could trigger severe delayed
diarrhea due to the overproduction of SN-38 (the hydrolytic
product of CPT-11) in the small intestine.7–9 Therefore, it is
hypothesized that co-administration with potent CES2 inhibi-
tors may ameliorate CPT-11 caused severe diarrhea in patients
and thus improve the therapeutic effect.10,11 In addition to the
aInstitute of Interdisciplinary Integrative Medicine Research, Shanghai University of
Traditional Chinese Medicine, Shanghai 201203, People's Republic of China.
E-mail: chemzlw@shutcm.edu.cn
bSchool of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian
116029, People's Republic of China. E-mail: chengweilv@126.com
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra08593a
In recently years, biochemists have made signicant break-
through on the design and development of several highly
specic optical substrates for sensing the real activities of CES1
or CES2 in complex biological systems.31–37 These newly devel-
oped optical substrates have been successfully used for high
‡ These authors contributed equally to this work.
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throughput screening of natural or unnatural inhibitors against CES1.36 In brief, each compound (2 mL, different concentrations
CES.38–43 However, indole and its derivative inhibitors against according to the initial screening settings) and CES1 enzyme
CES2 with high potency and enhanced selectivity are rarely re- source (HLM, 2 mL, 0.02 mg mLꢁ1, initial concentration) were
ported.44,45 Based on the wide and benecial activity of bis(in- placed in phosphate buffer (94 mL, pH 6.5), add the positive
dolyl)methanes and b-substituted indole derivatives, we were inhibitor BNPP in parallel and incubate for 5 min in a 37 ꢀC
interested in whether these two kinds of compounds have incubator. The reaction was then initiated by the addition of
effects against human CES1 and CES2. We have developed some probe DME (2 mL, 0.15 mM, approximately equal to the Km value
environmentally benign synthetic methodologies for the prep- of CES1 hydrolyzed DME). Aer shaking the reaction for 10 min
aration of b-substituted indole derivatives.29,30 Herein, we in a 37 ꢀC incubator, 50 mL of the reaction solution was pipetted
provide a relatively simple and environmental friendly reaction and mixed with LDR (50 mL) to terminate the reaction. Detection
condition to synthesized bis(indolyl)methanes. More impor- was performed in
a
multi-mode microplate reader
tant, these two types of synthetic compounds have been (SpectraMax® iD3, Molecular Devices, Austria). All compounds
meticulously screened for inhibitory effects against human were formulated in chromatographic grade DMSO with a nal
CES1 and CES2.
volume ratio of DMSO of less than 1% (v/v).
2.3.2. Inhibition of indole derivatives on CES2-mediated
FD hydrolysis. The inhibitory effects toward CES2 were inves-
tigated with FD as the specic probe substrate. The reaction
procedure mainly includes the following parts: rstly, phos-
phate buffer (194 mL, pH 7.4), CES2 enzyme source (HLM, 2 mL,
0.2 mg mLꢁ1, initial concentration), indole derivatives (2 mL),
and add the positive inhibitor LPA in parallel. The mixture was
2. Experiment
2.1. Chemicals and reagents
Fluorescein diacetate (FD), Loperamide (LPA) and bis-p-nitro-
phenyl phosphate (BNPP) were purchased from TCI (Tokyo,
Japan) and their purity was greater than 98% by HPLC-UV
measurement. b-Substituted indole derivatives 1a–p were
synthesized according to our previous work.29,30 Compounds
1a–p, 4a–p, LPA and BNPP were prepared in DMSO (Tedia, USA)
ꢀ
mixed and placed in a 37 C incubator for 10 min, then added
with FD (2 mL, 0.2 mM, initial concentration) for 20 min, and an
equal volume of acetonitrile (chromatographic grade) was
added to the reaction solution to terminate the reaction. Then,
200 mL of the mixture was pipetted into the microtiter plate.
Place it in the microplate reader for testing. All compounds were
formulated in chromatographic grade DMSO with a nal
volume ratio of DMSO of less than 2% (v/v).
2.3.3. Statistical analysis. The half maximal inhibitory
concentration (IC50) of each compound was determined using
various inhibitor concentrations under the same incubation
conditions as mentioned above. All values obtained from
experiments were expressed as mean ꢂ SD. The IC50 values of
the compounds were evaluated using GraphPad Prism 7.0
(GraphPad Soware, Inc., La Jolla, USA) nonlinear regression.
ꢀ
to prepare a stock solution and stored in a refrigerator at 4 C
until use. The specic uorescent probes D-luciferin methyl
ester (DME) was synthesized in our laboratory.36 Ultrapure water
(Millipore, Bedford, USA). Human liver microsomes (HLM)
purchased from Research Institute for Liver Disease (Shanghai)
Co., Ltd. Luciferin detection reagent (LDR) was obtained from
Promega Biotech (Madison, USA). Phosphate buffer (PBS) is
prepared by ultrapure water and stored in a 4 C refrigerator,
divided into pH 6.5 and pH 7.4. All H NMR (500 MHz) were
recorded on a Bruker Avance spectrometer with chemical shis
reported as ppm (in DMSO-d6, TMS as the internal standard).
ꢀ
1
2.2. General procedure for the synthesis of indole derivatives
(4a–p)
Table 1 Optimization of the reaction conditions for the synthesis of 4a
A mixture of the appropriate aldehyde (0.5 mmol), 2-methyl-
indole (1.0 mmol) and 1.5 mL solvent (EtOH–H2O 1 : 1, v/v) were
added in a 10 mL Schlenk tube. This solution was stirred under
irradiation of blue LEDs (15 W LED light band was used). The
reaction was monitored by TLC. Aer completion, 1 mL EtOH
was added and vigorously stirred for 10 min to remove the
impurity. Corresponding puried product was obtained aer
ltered and washed with cold aqueous ethanol. If necessary,
product was puried by column chromatography using silica
gel (200–300 mesh). (Please note: low power blue LED light band
was used in the experiment. Exothermic effect was not obvious.)
The detailed structural characterization of indole derivatives
(4a–p) are described in the ESI.†
Entrya
Solvent
Vol./mL
Time/h
Yieldb/%
1
2
3
4
EtOH–H2O
EtOH–H2O
EtOH–H2O
EtOH–H2O
EtOH–H2O
EtOH–H2O
EtOH–H2O
0.75/0.75
0.9/0.6
0.5/1.0
0.75/0.75
0.75/0.75
0.75/0.75
0.75/0.75
4
4
4
5
3
4
4
98
93
95
98
94
90
96
5
6c
7d
2.3. Florescence-based CES inhibition assays
2.3.1. Inhibition of indole derivatives on CES1-mediated
DME hydrolysis. The inhibitory effects towards CES1 was
investigated with DME used as the specic probe substrates for
a
The reactions were carried out with 0.5 mmol benzaldehyde and
b
c
1.0 mmol indole. Isolated yield. At 45 ꢀC without irradiation of
blue LEDs. Irradiation of white LEDs.
d
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Table 2 Substrate scope for the synthesis of 4a
a
The reactions were carried out with 0.5 mmol benzaldehyde and 1.0 mmol indole in 1.5 mL EtOH–H2O (1 : 1) under irradiation of blue LEDs.
Isolated yield.
b
widely utilized to promote various organic synthetic trans-
3. Results and discussion
3.1. Design synthetic protocols and optimize reaction
formations.55–57 In this context, visible light assisted reactions
without catalyst meet the requirements of mild reaction
conditions and environmental friendliness, which should be
the best choice to implement the reaction of indole and alde-
hydes. Based on the references and our experiences, aqueous
ethanol was good solvent for the reaction containing indole and
aldehyde, therefore, it was used throughout our study. In view of
the inhibitory property of b-substituted indole derivatives 1l–p
toward CES2 in Section 3.3 and to realize our envisaged
protocol, model reaction of 2-methylindole with benzaldehyde
was performed with irradiation by blue light-emitting diodes
(LEDs; 15 W) at room temperature under catalyst-free
conditions
Over the years, a plethora of synthetic protocols has been
developed due to the wide range of applications in biomedicine
and agriculture of bis(indolyl)methanes (BIMs).46–48 Among
them, using indoles and aldehydes as substrates is one of the
most effective synthesis methods that received more atten-
tion.49–52 Therefore, the rst purpose of this study is to develop
facile pathway for the green synthesis of BIMs via the reaction of
indole with aldehydes. Recently, visible light as a rich, readily
available and renewable clean energy source,53,54 has been
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condition. Delightedly, the desired product 4a was obtained in
98% yield (Table 1, entry 1). The heat would generate due to the
use of LED band and the temperature was about 45 ꢀC.
Considered this, a control experiment without light irradiation
was conducted at 45 ꢀC, but not at room temperature. Based on
this result, visible light was proved essential for the reaction,
because in the absence it, the yield was reduced (entries 1 and
6). When replace blue LED with white LED, a slight lower score
is obtained, but still better than conventional heat method. The
solvent was also nely tuned by employing ethanol with water in
different volumes and proportions. Aer some experiments, we
found this conversion took place with maximum isolated yield
in the mixture of 0.75 mL ethanol and 0.75 mL water. Optimi-
zation result indicated that reacted 4 hours were adequate for
this reaction. Target molecule could form and isolate in 98%
yield aer ltration and washing with 50% ethanol.
Table 3 The IC50 values of indole derivatives toward CES2a
CES2 IC50 (mM)
CES2 IC50 (mM)
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
24.47 ꢂ 4.55
11.08 ꢂ 2.45
3.29 ꢂ 0.28
>100
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
0.64 ꢂ 0.13
0.56 ꢂ 0.16
0.34 ꢂ 0.091
0.28 ꢂ 0.027
0.20 ꢂ 0.044
1.28 ꢂ 0.24
0.15 ꢂ 0.032
0.57 ꢂ 0.086
1.23 ꢂ 0.37
0.84 ꢂ 0.23
0.35 ꢂ 0.091
3.17 ꢂ 0.81
1.21 ꢂ 0.28
0.19 ꢂ 0.045
0.35 ꢂ 0.11
1.22 ꢂ 0.20
>100
4.37 ꢂ 0.66
9.01 ꢂ 2.49
20.27 ꢂ 5.19
7.79 ꢂ 1.24
4.28 ꢂ 0.36
>100
2.98 ꢂ 0.53
2.64 ꢂ 0.35
2.89 ꢂ 0.30
4.12 ꢂ 0.84
7.47 ꢂ 0.77
3.2. Substrate scope
a
Using the optimized reaction conditions, we examined the
generality and scope of the protocol across a range of
All data presented are averages of at least three separate experiments.
Fig. 1 Chemical structures of tested b-substituted indole derivatives 1a–p.
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Table 4 The IC50 values of indole derivatives toward CES2 and CES1a
para positions of phenyl ring would decrease the yield (Table 2,
4n, 4p). However, increasing the electron withdrawing substit-
uents on aromatic ring at the 3-position of aromatic aldehyde
gave the desired products in good yields too. In other words,
nitro-group on aromatic ring in ortho or para positions, the
reactivity of carbonyl was further increased. The electron de-
cient benzaldehyde, which containing an overactive carbonyl
group was disadvantageous to the reaction under this condi-
tion. But satisfactory outputs could be furnished if they reacted
without irradiation of blue LED. Generally, the electronic effect
played a major role in governing the reactivity of the substrates
and steric effect was not the dominant factor in the product
formation.
CES2 IC50 (mM)
CES1 IC50 (mM)
4g
4n
0.15 ꢂ 0.032
0.19 ꢂ 0.045
1.72 ꢂ 0.28
5.66 ꢂ 0.62
2.90 ꢂ 0.24
3.68 ꢂ 0.43
>100
0.24 ꢂ 0.02
LPAb
BNPPc
a
All data presented are averages of at least three separate experiments.
Loperamide, a positive inhibitor against CES2. Bis-p-nitrophenyl
b
c
phosphate, a positive inhibitor against CES1.
benzaldehyde incorporating various substituents, such as Me,
MeO, Cl, Br, and NO2. These reactions worked well in most
cases, affording the corresponding products in moderate to
excellent yields (Table 2). Aromatic ring bearing a weak electron-
withdrawing group appeared to afford slightly higher yields
compared with benzaldehyde having an electron-donating
group. Introduction of strongly electron-withdrawing group on
benzene ring such as nitryl was disfavored to the yield of reac-
tion. The presence of substituents at various positions of
benzaldehyde appreciably affected the yields too. For instance,
methoxyl in meta-position on benzene ring had weak electron-
withdrawing inductive effect and no conjugation effect. So, it
afforded a better yield than other two methoxyl substituted
benzaldehyde (Table 2, 4e–4g). This outcome also showed that
introducing strongly electron-withdrawing group in ortho or
3.3. Evaluation of inhibitory activities against CES1 and
CES2
Following the establishment of these indole derivatives and
considering the pharmacophore characters of the indole,
a further investigation was carried out to evaluate whether these
indole compounds possess potential biological activities
against CES2 using FD as specic optical substrate. As shown in
Table 2, we rstly focused our attention on the variation of the
benzyl moiety of b-substituted indole derivatives 1a–q. The
benzyl unit with substitutes (Cl, Br, Me, MeO) at 2-position or 3-
position afforded increased inhibitory effect against CES2
compared with compound 1a. Compound 1h with 4-methyl on
Fig. 2 The dose-dependent inhibition of 4g and 4n against CES2 mediated FD hydrolysis and CES1 mediated DME hydrolysis. Left: the dose-
dependent inhibition curves of CES2. Right: the dose-dependent inhibition curves of CES1. All data represent the mean of triplicate
determinations.
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the benzyl unit exhibited similar trends in CES2 inhibition as
compound 1a, but the benzoyl unit with 4-methoxyl (1d), 4-
chlorine (1e) and 4-nitryl (1k) substitute displayed poor inhibi-
tion toward CES2. Further characterizations of compounds 1l–p
with the variation of indole unit demonstrated that these
compound with 2-methyl on indole unit is more benecial for
the inhibitory property of b-substituted indole derivatives
toward CES2.
Acknowledgements
We are grateful for nancial support from the Department of
Science and Technology of Liaoning Province (No. 2019-MS-215,
2019-ZD-0470), the NSF of China (21602219, 81703604,
81803489, and 81773810), the National Key Research and
Development Program of China (2017YFC1700200).
Following the good inhibitory effects of b-substituted indole
derivatives on CES2, a survey was next carried out to evaluate the
inhibitory effect against CES2 of these bis(indolyl)methanes 4a–
p. To our delight, all tested compounds 4a–p showed
a dramatically increase in the inhibitory effects against CES2
compared with compound 1 (Table 3). In addition, compounds
4g and 4n showed excellent inhibitory effect against CES2 with
much lower IC50 value of 0.15 mM and 0.19 mM, respectively.
Furthermore, the inhibitory effects of b-substituted indole
derivatives 1a–q and bis(indolyl)methanes 4a–p on CES1 were
routinely screened using one inhibitor concentrations (10 mM)
and using D-luciferin methyl ester (DME) as specic optical
substrate. As shown in ESI† Fig. 1, a majority of tested these
indole derivatives displayed weak inhibitory effects on CES1 at
the concentration (10 mM), only a few compounds showed
relative strong inhibition potentials on CES1-mediated DME
hydrolysis. As shown in Table 4, compounds 4g and 4n showed
reduced inhibitory effect toward CES1 (IC50 2.90 mM and 3.68
mM, respectively) in contrast to CES2. In addition, known
inhibitors loperamide (LPA) and bis-p-nitrophenyl phosphate
(BNPP) were tested under identical conditions as positive
control for CES2 and CES1, respectively. The result indicated
that LPA showed inferior inhibitory effects on CES2 in contrast
to compounds 4g and 4n (Fig. 2).
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promoted
three-component
cascade
approach
to
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