In vitro antiproliferative activity of glabridin derivatives and their in silico target identification

Article abstract of DOI:10.1080/14786419.2018.1530228

Novel Mannich base derivatives of glabridin were synthesized and their antiproliferative activity were performed along with our previously reported glabridin-chalcone hybrids molecules (GCHMs) against various human cell lines MDA-MB-231 (breast adenocarcinoma), HEK-293 (embryonic kidney cell line), K562 (leukemia), MCF-7 (breast adenocarcinoma), HeLa (cervix adenocarcinoma), HepG2 (hepatocellular carcinoma) and WRL-68 (hepatic carcinoma). The result showed that the glabridin significantly reduced cell proliferation with IC₅₀ ranges from 3.67 to 58.30 μM against all the tested cell lines. The remarkable reduction in antiproliferative activity 2’,4’-dimethoxyglabridin and GCHMs compounds with phenolic OH groups protected by methoxy (OCH₃) groups suggested that the free OH groups are essential factor for the antiproliferative activity of glabridin and its derivatives. The Mannich base derivatives of glabridin showed moderate activity IC₅₀ (2.20–>95.78 μM). Furthermore, in silico target identification analysis revealed that AKT1, DECR1 and NOS1 are the potential targets for glabridin and their derivatives.

Full text of DOI:10.1080/14786419.2018.1530228

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: http://www.tandfonline.com/loi/gnpl20
In vitro antiproliferative activity of glabridin
derivatives and their in silico target identification
Deepak Singh Kapkoti, Shilpi Singh, Sarfaraz Alam, Feroz Khan, Suaib
Luqman & Rajendra Singh Bhakuni
To cite this article: Deepak Singh Kapkoti, Shilpi Singh, Sarfaraz Alam, Feroz Khan,
Suaib Luqman & Rajendra Singh Bhakuni (2018): Inꢀvitro antiproliferative activity of
glabridin derivatives and their inꢀsilico target identification, Natural Product Research, DOI:
10.1080/14786419.2018.1530228
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2018.1530228
In vitro antiproliferative activity of glabridin derivatives
and their in silico target identification
Deepak Singh Kapkotia, Shilpi Singhb, Sarfaraz Alamc , Feroz Khanc,
Suaib Luqmanb and Rajendra Singh Bhakunia
aMedicinal Chemistry Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow,
b
India; Molecular Bioprospection Department, CSIR-Central Institute of Medicinal and Aromatic
c
Plants, Lucknow, India; Metabolic and Structural Biology Department, CSIR-Central Institute of
Medicinal and Aromatic Plants, Lucknow, India
ABSTRACT
ARTICLE HISTORY
Received 25 May 2018
Accepted 26 September 2018
Novel Mannich base derivatives of glabridin were synthesized and
their antiproliferative activity were performed along with our previ-
ously reported glabridin-chalcone hybrids molecules (GCHMs)
against various human cell lines MDA-MB-231 (breast adenocarcin-
oma), HEK-293 (embryonic kidney cell line), K562 (leukemia), MCF-7
(breast adenocarcinoma), HeLa (cervix adenocarcinoma), HepG2
(hepatocellular carcinoma) and WRL-68 (hepatic carcinoma). The
result showed that the glabridin significantly reduced cell prolifer-
ation with IC50 ranges from 3.67 to 58.30 mM against all the tested
cell lines. The remarkable reduction in antiproliferative activity 2’,4’-
dimethoxyglabridin and GCHMs compounds with phenolic OH
groups protected by methoxy (OCH3) groups suggested that the
free OH groups are essential factor for the antiproliferative activity of
glabridin and its derivatives. The Mannich base derivatives of glabri-
din showed moderate activity IC50 (2.20–>95.78 mM). Furthermore,
in silico target identification analysis revealed that AKT1, DECR1 and
NOS1 are the potential targets for glabridin and their derivatives.
KEYWORDS
Glabridin derivatives;
anticancer; in silico target
identification;
docking; ADME
CONTACT Rajendra Singh Bhakuni
bhakunirs2000@gmail.com; bhakunirs2000@yahoo.com
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2018.1530228
ß 2018 Informa UK Limited, trading as Taylor & Francis Group

2
D. S. KAPKOTI ET AL.
1. Introduction
Cancer is a group of diseases defined by the uncontrolled growth of the abnormal
cells, their invasion into healthy cells and metastasis. It is the second leading cause of
death worldwide after cardiovascular disease (GBD 2013 Mortality and Causes of
Death Collaborators 2015). Although significant progress has been achieved in the
field of anticancer chemotherapy but most of the drugs are in the market are toxic
and having various side effects. Natural products are always being good source of
lead molecules for anticancer drug discovery. It is estimated that during 1940s to
2012, out of the 175 small anticancer molecules, 131 or 74.8% are other than “S” (syn-
thetic), in which 85 or 48.6% are actually either natural products or directly derived
from them (Newman and Cragg 2012).
Glabridin is a major isoflavan isolated from the roots of Glycrrhiza glabra plant
possesses diverse biological activities including antioxidant, antimicrobial, anti-inflam-
matory, estrogenic, anticancer, anti-osteoporoticetc, anti-neuroprotective (Saitoh et al.
1976; Mitscher et al. 1980; Belinky et al. 1998; Tamir et al. 2000; Fukai et al. 2002;
Choi 2005; Kwon et al. 2008; Yu et al. 2008; Simmler et al. 2013). Previously glabridin
has been reported to inhibit lung and breast cancer metastasis by inhibiting the Focal
Adhesion Kinase (FAK)/rho signaling pathway (Hsu et al. 2011; Tsai et al. 2011).
Glabridin also significantly inhibits the migration and invasion by transcriptionally
inhibiting the matrix metalloproteinase 9 via the modulation of NF-jB and AP-1 activ-
ity in human liver cancer cells (Hsieh et al. 2014). Furthermore, it also mediates caspase
activation and induces apoptosis in human promyelocytic leukemia cells (Huang et al.
2014). Introduction of aminoalkyl group into molecules via Mannich reaction helps to
improve the solubility of the molecules hence aid to increase the bioavailability
of molecules. Therefore, the Mannich base derivatives of glabridin were synthesized and
evaluated for their in vitro antiproliferative activity. Furthermore the role of free phenolic
OH groups in antiproliferative activity, we have also screened our previously reported
glabridin-chalcones hybrids molecules along with 2’,4’-dimethoxyglabridin against the
different human cancer cell lines (Kapkoti et al. 2016). The in silico target identification,
molecular docking and ADMET studies have also been performed.
2. Results and discussion
Mannich reactions discovered by Carl Mannich, are the multicomponent, carbon-
carbon bond forming reactions. The classical Mannich reaction involves the condensa-
tion of enolisable carbonyl compounds (aldehyde and ketones) having a-CH acidic
proton/s, a primary or secondary amines and non enolisation aldehyde such as formal-
dehyde to form b-amino carbonyl compounds, commonly known as Mannich bases.
Compounds with activated aromatic systems such as phenols, aromatic amines and
electron rich heterocyclic compounds (pyrrol, furan and thiophene) also give the
Mannich reaction. The Classical variant of Mannich reaction has some drawback such
as formation of unwanted side-products, lack of regio- and stereo-selectivity, especially
in case of primary amines. The modern variant of Mannich reaction overcomes
these drawbacks by the use of preformed mannich reagents, enolates of carbonyl

NATURAL PRODUCT RESEARCH
3
Scheme 1. Reagents and conditions: (a) HCHO, secondary amines in methanol, reflux 4 hrs.
compounds, silyl enol ethers, enolizable imines and catalysts which provide the high
concentration of electrophile, activation of imines intermediate so the reaction
occurred under mild condition without forming side products (Arend et al. 1998).
The catalyst generally used are the lewis acids such as Zn, ZnO, InCl3, FeCl3, FePO4,
Bi(OTf)3.4H2O, Bi(NO3)3 Ag(OTF)3 etc. Enantioselective Mannich recation have been
performed in the presence of chiral organocatalsyts such as S-proline, chiral pyrrolidine
and cinchona alkaloids. Mannich reactions were also reported under both the
catalysis and solvent free environment. These reactions are also performed under
microwave and infrared irradiation and in ionic liquids (Filho et al. 2017).
Synthesis of mannich base derivatives of glabridin is depicted in Scheme 1.
Mannich bases were synthesized by the condensation of glabridin with formaldehyde
and secondary amines. The structures of final products were confirmed by their spec-
1
troscopic analysis (mass, H and 13C NMR). Synthesis of glabridin-chalcone hybrid mol-
ecules are outline in Scheme 2 (Kapkoti et al. 2016)]. The structures of synthesized
Mannich base derivatives of glabridin were assigned with the help of NMR and HRMS
spectroscopy. HRMS spectrum of compound 9a showed [M þ H]þ ion peak at
523.2806, suggested the molecular formula C30H38N2O6. Compound 9b and 9c showed
[M þ H]þ ion peak at 555.2357 and 519.3210 respectively, assigned the molecular for-
mula C30H38N2O4S2 for 9b and C32H42N2O for 9c. The glabridin framework of synthe-
sized derivatives showed similar NMR spectral value as reported for parent molecule,
glabridin (Jirawattanapong et al. 2009). The two benzylic methylene (CH2) groups gave
1
singlets at ꢀ3.9 ppm and ꢀ3.6 ppm in H NMR and showed peak at ꢀ61.0 ppm and
ꢀ53.0 ppm in 13C NMR which was confirmed as CH2’s by DEPT-135. The nitrogen het-
erocyclic ring of morpholine and thiomorphline showed eight methylene groups peak
1
and ten methylene groups peak for piperidine, confirmed by its H, 13C and DEPT-135
NMR spectra.
The antiproliferative activity of synthesized compounds were tested by MTT assay
against various cell lines MDA-MB-231 (human breast adenocarcinoma), HEK-293
(human embryonic kidney cell line), K562-(Human erythromyeloblastoid leukemia),
MCF-7 (human breast adenocarcinoma), HeLa (human cervix adenocarcinoma), HepG2
(human hepatocellular carcinoma) and WRL-68 (human hepatic carcinoma).

4
D. S. KAPKOTI ET AL.
Scheme 2. Reagents and conditions: (a) CH3I, K2CO3, acetone, reflux 4 hrs (b) DMF, POCl3 in aceto-
nitrile, rt, overnight (c) RCOCH3, KOH in MeOH, rt, 4–8 hrs.
Doxorubicin was used as reference compound. Compound 2, 2’,4’-dimethoxyglabridin
inhibited the proliferation of cancer cell lines up to 35.76% except hepatic and breast
cancer cell lines whereas their substituted formyl derivatives (Compound 3, 4 and 5)
inhibited the proliferation up to 48.04% excluding hepatic cell line. The glabridin-chal-
cone hybrid molecules were found to be moderately active with percent inhibition
ranged from 2.32 to 48.81%. Compound 8f showed maximum cytotoxicity (48.81%) at
the higher tested concentration (50 mg/mL) against HepG2 (Table S1). This might be
due to the absence of free OH groups, as parent molecule (glabridin) having free
phenolic OH groups, inhibited the proliferation of cancer cells with IC50 values from 3.
67 to 58.30 mM. The antiproliferative assay revealed that the Mannich bases of glabri-
din (9a–9c) inhibited the proliferation of the cancer cell lines. Among three com-
pounds, 9a and 9c inhibited the proliferation of the cancer cell lines with an IC50
ranged from 16.41 to >95.78 mM except cervical cell line non-significantly in compari-
son to doxorubicin (Figure S1, Table 1) whereas both the compounds also inhibited
the growth of normal kidney cell line (IC50 2.24 mM and 2.20 mM respectively) superior
to glabridin (IC50 13.88 mM) and doxorubicin (IC50 7.18mM). Compound 9b showed a
very weak antiproliferative activity with cytotoxicity ranges from 4.53 to 31.44% at
concentration of 50 mg/mL. In silico analysis was performed in order to understand the
molecular interaction of active compounds with targeted enzyme succinate dehydro-
genase (SDH), responsible for cell viability measurement. The outcomes of docking

NATURAL PRODUCT RESEARCH
5
Table 1. IC50 value (mM) of compounds in selected cancer cell lines.
Compound
WRL-68
MCF-7
HEK-293
2.24 1.74 >95.78 0.97 47.79 0.54
2.20 2.54 86.19 1.98 72.70 1.64
MDAMB-231
K562
HeLa
HepG2
9a
9c
81.16 1.28 73.67 0.80
70.40 1.64 55.34 1.49
24.90 1.88 58.30 1.15 13.88 0.74
4.84 0.43 10.73 0.32 7.18 1.80
–
–
16.41 1.89
47.50 3.97
7.22 1.32
2.22 0.52
Glabridin
Doxorubicin
42.31 1.46 36.51 0.62 3.67 0.73
5.13 0.91 12.00 1.62 6.81 0.79
experiment expressed that the compound 9a and 9c were found to be least
interactive with SDH with high binding energy (Table S2) whereas parent compound,
glabridin showed strong binding energy (ꢁ7.07 kcal/moL) and low ki (6.61mM) as com-
pared to malonate. Figure S2 depicted that parent compound; glabridin interacted
with the active site residues CYS163, ILE159, ALA 162 and CYS 161 as compared to
malonate. The interacting residues revealed the specific binding of glabridin towards
SDH while compounds 9a and 9c did not interact with the active site residues.
Therefore, it can be interrupted that inhibitory action of glabridin against SDH might
be responsible for its antiproliferative behavior.
2.1. Drug target selection
There were four possible targets identified namely, AKT1, ICAM1, DECR1, and NOS1
through the STITCH 4.0 program with confidence limits of 0.71 and above (Figure S3a)
which means strong association with glabridin (reference parent compound). Through
STITCH 4.0, the possible protein targets for the active derivatives were also analyzed
and it was found that AKT1, NOS1, ICAM1 interacted with score value 0.80, while
DECR1 interacted with score value 0.71. These interacted proteins are known anti-
cancer target. The score close to 1 was considered as a more appropriate target
(Table S3).
2.2. In silico molecular docking studies
To better understand the ligand protein interaction and prospects of binding pattern,
binding confirmations and interactive amino acid residues, the molecular docking
study was performed. For docking study the protein targets are used as identified in
Figure S3. Out of four different targets, docking study showed better score with three
targets i.e., AKT1, DECR1 and NOS1. The docking scores of studied compounds were
compared with control compound and presented in Figure S3b. The docking program
produces several poses with different orientations and confirmations within the
defined active site. All poses produce a different LibDock score. Higher the LibDock
docking scores indicates higher the chance of ligand protein interactions. The best
score was taken into account for further study. The docking results are shown in
Table S4. The analysis of the protein ligand docked complexes revealed binding site
residues, hydrogen bonds and docking scores. In Figure S4, best conformations and
superimpositions of candidate compounds were showed along with control com-
pound, in the binding site pocket of putative anticancer drug targets, i.e., NOS1 (A),
AKT1 (B), and DECR1 (C). The compounds are represented by different color such as
Compound-9a (blue color), compound-9c (red color), glabridin (green color) and

6
D. S. KAPKOTI ET AL.
control compound (yellow color). These results indicate that the compounds are
bound well within the binding site pocket of putative anticancer drug targets and
showed an almost similar binding pattern which are close to control compound.
2.3. In silico ADME and toxicity studies
The prediction of the human pharmacokinetics, bioavailabilty and toxicity screening of
new chemical entities is critical during early drug development stages to determine
the suitable dosing regimen. For this ADMET PredictorTM (Simulation Plus Inc., USA)
was used to predict the different ADMET risk parameters and to make a comparison
with the control compound glabridin. The ADMET risk was calculated for four major
properties .i.e., Absorption risk, Risk with Cytochrome P450 oxidation, Risk of mutage-
nicity and predicted toxicity. These different properties are collectively provided in
terms of risk and assessable in the form of a score with defined range limit. The candi-
date compound 9a and 9c has a molecular weight of 524.66 and 520.72, respectively,
and thus violates the Lipinski rule by single molecular property.
Result showed that both the compounds have a mild absorption rate due to their
size, hydrophilicity and charge, and also tend to show hepatotoxicity, and acute rat
toxicity. Compound 9c is more lipophilic in nature. Additionally compound 9a have
also the chance of mutagenicity when used for long period. The compound 9c found
to be the inhibitor of hERG which is generally considered as an anti-target. The
studied compounds showed predicted toxicity of serum glutamic oxaloacetic trans-
aminase (SGOT). High clearance rate as well as high tendency to cross the blood brain
barrier was observed for both the studied compounds. Both compounds are predicted
to be an inhibitor of P-glycoprotein (P-gp), a drug efflux pump and thus may not be
efflux out easily. The calculated volume of distribution for compound 9a and 9c was
1.42 and 1.92 L/Kg, respectively. The percent unbound to blood plasma was found to
be 5.41 and 5.73 for compound 9a and 9c, respectively. On the other hand, the blood
to plasma concentration was detected as 0.98 and 0.93 for compound 9a and 9c,
respectively. Finally studied compounds were found to be in the acceptable range
of ADMET risk (Table 6). Both compounds showed no sign of reproductive and skin
sensitization toxicity. The study of different enzymes, associated with human liver was
also carried out, so that to check the status of adverse effects caused by the studied
compounds. The results for different toxicity studies are summarized in Table S6.
2.4. Predicting drug metabolism and possible metabolites
Drug metabolism can produce metabolites with physicochemical and pharmacological
properties that differ substantially from those of the parent drug, and consequently
have important implications for both drug safety and efficacy. To tackle this, we here
predict the possible metabolites and their sites of metabolism. The different metabo-
lites as well as the sites of metabolism are provided in Figure S1. The cytochrome
enzymes involved in the metabolism were CYP 2D6 and CYP 3A4. A schematic
diagram which shows different metabolites are represented in Figure S5. Potency
to be a substrate of Uridine 5’-diphospho-glucuronosyl transferase has also been

NATURAL PRODUCT RESEARCH
7
identified for each of the compounds, which have the potential to transform the small
molecules to water soluble form.
3. Experimental
For general experimental procedures of extraction and isolation of glabridin,
preparation of Mannich base derivatives, antiproliferative activity, in silico, see
supplementary file.
4. Conclusions
In conclusion, we have prepared several derivatives of glabridin and evaluated their
anticancer activity against different human cancer cell lines. Drastic decrease in anti-
proliferative activity of GCHMs derivatives pointed out the importance of free phenolic
OH groups in their antiproliferative activity. Moderate activity of Mannich bases as
compared to parent molecule (glabridin) suggested that either the introduction of
aminoalkyl group on glabridin framework reduce its activity or there may be some
possibility of the intramolecular hydrogen bonding between the nitrogen atom of
amino group with hydrogen of phenolic OH group, so that phenolic groups are not
free in mannich base which might be essential for its antiproliferative activity. The
in silico studies revealed that AKT1, DECR1 and NOS1 are the potential targets for
glabridin and their derivatives. So, it can be concluded that the glabridin is promising
template for the development of potential leads for antiproliferative activity and can
be further exploited by the preparation of derivatives having free phenolic OH groups.
Conflict of interest
The authors confirm that this article content has no conflict of interest.
Acknowledgements
The authors are grateful to the Director, CSIR-CIMAP for providing necessary facilities for
this work. Financial support from the National Medicinal Plant Board (NMPB, GAP-208),
New Delhi, is duly acknowledged. D.S. Kapkoti is thankful to CSIR New Delhi for award of CSIR-
JRF & SRF fellowship.
ORCID
Sarfaraz Alam
http://orcid.org/0000-0002-7246-8687
Rajendra Singh Bhakuni
http://orcid.org/0000-0002-1423-8461
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