Molecular modeling based approach, synthesis, and cytotoxic activity of novel benzoin derivatives targeting phosphoinostide 3-kinase (PI3Kα)

Article abstract of DOI:10.1016/j.bmcl.2015.06.011

Abstract The oncogenic potential of phosphatidylinositol 3-kinase (PI3Kα) has made it an attractive target for anticancer drug design. In this work, we describe our efforts to optimize the lead PI3Kα inhibitor 2-hydroxy-1,2-diphenylethanone (benzoin). A s

Full text of DOI:10.1016/j.bmcl.2015.06.011

Bioorganic & Medicinal Chemistry Letters 25 (2015) 3120–3124
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Molecular modeling based approach, synthesis, and cytotoxic activity
of novel benzoin derivatives targeting phosphoinostide 3-kinase
(PI3Ka)
a
a
b
c
Dima A. Sabbah a, , Musaab Saada , Reema Abu Khalaf , Sanaa Bardaweel , Kamal Sweidan ,
⇑
Tariq Al-Qirim a, Amani Al-Zughier a, Heba Abdel Halim d, Ghassan Abu Sheikha a
a Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130, Amman 11733, Jordan
b Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman 11942, Jordan
c Department of Chemistry, The University of Jordan, Amman 11942, Jordan
d Faculty of Pharmacy and Medical Sciences, University of Petra, P.O. Box 961343, Amman, Jordan
a r t i c l e i n f o
a b s t r a c t
Article history:
The oncogenic potential of phosphatidylinositol 3-kinase (PI3K
anticancer drug design. In this work, we describe our efforts to optimize the lead PI3K
a
) has made it an attractive target for
inhibitor
2-hydroxy-1,2-diphenylethanone (benzoin). A series of 2-oxo-1,2-diphenylethyl benzoate analogs were
identified as potential PI3K inhibitors. Docking studies confirmed that the aromatic interaction is
Received 3 April 2015
Revised 24 May 2015
Accepted 2 June 2015
Available online 11 June 2015
a
a
mediating ligand/protein complex formation and identified Lys802 and Val851 as H-bonding key
residues. Our biological data in human colon carcinoma HCT116 showed that the structure analogs
inhibited cell proliferation and induced apoptosis.
Keywords:
PI3K
a
Ó 2015 Elsevier Ltd. All rights reserved.
Cancer
Docking
HCT116
Benzoin
Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that
Therefore, selective inhibitors targeting mutant PI3K
afford an effective therapeutic protocol.11,13
a might
phosphorylate phosphatidylinositol 4,5-biphosphate (PIP2) gener-
ating 3,4,5-triphosphate (PIP3).1 PI3Ks are negatively regulated by
the phosphatase and tensin homolog protein (PTEN), which
dephosphorylates PIP3.2,3 PIP3 is an important second messenger
that regulates the activities of PI3K downstream effector protein
kinase B (PKB), also known as AKT.4
The activation of PI3K/AKT signaling cascade induces cell prolif-
eration, growth, angiogenesis, and metastasis. Aberrant PI3K/AKT
pathway has been involved in a number of human cancers.4
PI3Ks are grouped into three classes based on their primary struc-
Due to the oncogenic potential of PI3K
a
and its negative regu-
lator PTEN, PI3K
a has emerged as an attractive target for anti-
cancer drug design.14,15
Several chemical scaffolds have been designed and synthesized
targeting PI3Ka16–30 and some of these have been investigated in
clinical trials.31–34 We previously reported the pharmacophore fea-
tures for PI3K
Novel N-Phenyl-4-hydroxy-2-quinolone-3-carboxamides were
synthesized as selective H1047R PI3K
inhibitors.36 Recruiting
ligand-based pharmacophore modeling for PI3K inhibitors and
a
inhibitors and identified potential inhibitors.35
a
ture and substrate specificity. Among them, class IA PI3K
a
(coding
a
gene PIK3CA) is amplified, overexpressed, and mutated in several
database searching against the National Cancer Institute (NCI)
compound database37 identified NSC 8082 (benzoin) (1) as a hit
(Fig. 1).35
human tumors.5–9 PIK3CA mutations and amplification have been
identified in an array of cancers. PI3Ka mutations have been
detected in colon, breast, brain, and endometrial tumors.10,11 Two
major classes of mutations are located in the helical (E542K and
E545K) and kinase (H1047R) domains. These ‘hot-spot’ mutations
Fortunately, benzoin (1) and its structure analog 4,40-
dimethoxybenzoin (p-anisoin) (2) are commercially available.
Both 1 and 2 fit the pharmacophore features of PI3K
a inhibitor
induce PI3K
a
in vitro kinase activity resulting in ‘gain-of-
as shown in Figure 2. Thus, we hypothesized that functionalization
of the backbones of 1 and 2 would generate promising inhibitors
function’.5,12
targeting PI3Ka. This work describes our efforts to functionalize
1 and 2 employing structure-based drug design and molecular
docking approach.
⇑
Corresponding author. Tel.: +962 64291511x296; fax: +962 64291432.
E-mail address: dima_sabbah@yahoo.com (D.A. Sabbah).
http://dx.doi.org/10.1016/j.bmcl.2015.06.011
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

D. A. Sabbah et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3120–3124
3121
R
O
O
Cl
O
O
O
a
+
2
OH
OH
R
3
R
4
R
(3a-f)
O
1
1, R = H
2, R = OCH3
4, R = H, 65%
7, R = (m-F), 3-F, 52%
8, R = (p-F), 4-F, 76%
9, R = (p-Cl), 4-Cl, 71%
5, R = (p-NO2), 4-NO2, 73%
6, R = (o-F), 2-F, 60%
Figure 1. Chemical structures of 1 and 2.
H3CO
O
Cl
OCH3
O
O
O
a
+
OH
H3CO
2
H3CO
O
F
F
(3e)
10, 66%
Scheme 1. Condition: (a) THF, Et3N, 50 °C, 24 h.
Table 1
Growth inhibition IC50 (mM) of HCT116 cell line after
24 h exposure time
Compounds
HCT-116
1
2
4
5
6
7
8
9
10
2.12
1.17
2.66
0.88
0.91
0.97
1.29
0.73
2.82
Figure 2. PI3K
a
pharmacophore model with 1 (C atoms in yellow) and 2 (C atoms
Standard deviation (SD) never exceeded 5%.
in blue). Aro stands for aromatic rings; Acc for H-bond acceptor; and Hyd for
hydrophobic groups. Picture made by MOE.38
harboring two methoxy groups at p-position is not preferred due
to steric clash as well as electron-donating effect. Surprisingly,
the parent compound 2 showed similar potency to that of 8. This
implies that the steric effect (size, shape, and volume) of the veri-
fied molecules determines their potency. Also, the activity of 1, 4,
and 10 confirms that both the steric and substituent effects should
be balanced to attain higher potency. The fact that HCT116 con-
The target products 4–9 were prepared by reacting benzoin (1)
with substituted benzoyl chlorides (3a–f), in a one pot reaction, in
a dry aprotic polar solvent (tetrahydrofuran) under heating condi-
tion via
a nucleophilic substitution mechanism (Scheme 1).
Triethylamine (Et3N) was added to the reaction mixture as a cata-
lyst and an acid scavenger; in a similar manner, 4-fluorobenzoyl
chloride (3e) was reacted with p-anisoin (2) to produce 10. The
chemical structure of the prepared compounds was determined
using spectroscopic approaches; FT-IR and NMR (1H and 13C).
In order to examine their antiproliferative activities, we
assessed the growth inhibition in the colon cancer cell line
(HCT-116) induced by 1, 2 and 4–10 (Table 1).
tains both alleles (wild-type and mutant H1047R PI3Ka) has hin-
dered our efforts to extrapolate more reasons for our results. Our
future research will aim to knockout either allele to harvest only
one specific gene in HCT116 cell line.
In order to determine possible pathways responsible for the
observed growth inhibition, caspase-3 enzyme activity was mea-
sured via the caspase-3 colorimetric assay. Activation of the cas-
HCT116 is a highly malignant colon carcinoma cell line harbor-
ing both wild-type and mutant (H1047R) PI3K
a
that was created
pase-3 pathway is a
hallmark of apoptosis40,41 and can be
from a primary tumor tissue culture.39
utilized in cellular assays to appraise activators and inhibitors of
the ‘death cascade’. To determine the apoptotic effects of the
examined compounds on HCT116 cells, cells were incubated with
The tested compounds inhibited PI3Ka activity in HCT-116 cell
line. Interestingly, 5, 6, 7, and 9 exerted a relatively high potency in
HCT116 cell line (IC50 <1 mM). Additionally, 2 and 8 with IC50s 1.17
and 1.29 mM showed comparable potency. A two-fold increase in
IC50s suggests a weak inhibitor such as 1, 4, and 10.
700 lM of each compound for either 24 or 48 h and changes in cas-
pase-3 enzyme activities were analyzed. The results demonstrate
that there is a significant increase in caspase-3 activity in response
to 24 h treatment for each compound. Indeed, lengthening of the
treatment period results in further increase in caspase-3 activity
relative to the untreated cells control (Fig. 3).
Interestingly, similar pattern of efficacy was exhibited in the
apoptosis assay for p- (5, 8, and 9) as well as o- and m-substituents
(6 and 7), and the parent structure 2. The consistency of the results
of both bioassays provides a clue for the significance of this scaffold
as a potential antitumor agent.
This result suggests that derivative with p-substituent is more
favored for –Cl and –NO2 functionalities. This might infer that
the size and electron-withdrawing effects of the p-substituent
are significant to attain potent inhibition. The size of –Cl and
–NO2 is bigger compared to that of –F (H isostere). The electron-
withdrawing effect of –NO2 and –F is higher than that of –Cl.
Substitution is favored for –F at o- or m-position. This implies that
the size and electron-withdrawing effects of substituents at
p-position should be considered to induce higher potency.
Compound 10 having p-methoxy groups on benzoin scaffold
showed to be the least potent compound. This indicates that
In order to investigate the structural basis of binding of the
verified inhibitors in the active domain of PI3K
a, we carried out
docking studies employing Glide42,43 dock approach against the

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D. A. Sabbah et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3120–3124
Table 2
Docking scores (kcal/mol) and H-bond interactions between compounds and PI3K
a
(PDB ID: 2RD0)
Compounds
Docking score (kcal/mol)
Binding residues
1
2
4
5
6
7
8
9
10
ꢀ4.71
ꢀ7.28
ꢀ6.25
ꢀ4.58
ꢀ5.82
ꢀ5.08
ꢀ6.13
ꢀ7.12
ꢀ6.48
NA
V851
K802
V851
NA
NA
K802
NA
K802, V851
Figure 3. Effects of compounds treatment on caspase-3 activity in HCT cells after
24 and 48 h. The results are the means of two independent experiments. P <0.05
was considered significant.
NA stands for not available.
wild-type PI3K
that these compounds occupy the kinase domain of PI3K
a
(PDB ID: 2RD0).7 Our Glide docking data show
(Fig. 4).
a
Most of these compounds tend to form H-bond with Lys802
(NH2 side chain) and Val851 (NH backbone) (Table 2). The
significance of these binding residues has been validated by other
computational35,36,44–46 and experimental studies.12
The low docking score of 5 might be due to ion-dipole or
ion-induced dipole interaction with Tyr836 (Fig. 5). Contrary to
structures having hydrophobic moiety attached on p-position
(2, 9, and 10) exhibited comparable good binding affinity.
Notably, 8 tailored with p-F substituent showed comparable
binding affinity to that of (2, 9, and 10). This might be contributed
Figure 5. Protein/ligand interactions with 5. Hydrophobic residues are colored
green, acidic residues are red, basic residues are purple, and polar residues are light
blue. Picture made by MAESTRO.
to the size of F (H isostere) and low hydrophobicity character of F
compared to that of Cl (higher atomic weight). This finding sug-
gests that p-substituent having hydrophobic and electron-with-
drawing properties are essential to elicit an activity. Additionally,
p-substituted derivatives adopt a planar pose in the binding
domain (Figs. 1S and 2S), which explains the o- and m-sub-
stituents’ corresponding binding affinity. Comparing the binding
affinity of 1 and 4 infers that the ligand’s size is critical to induce
an activity. All together, p-attachment and ligand’s size are both
required to attain favorable binding affinity. Figure 3S
(Supporting information) shows that the theoretical docking scores
(kcal/mol) are positively correlated (R2 = 0.76) with the experimen-
tally verified IC50s, rationalizing that docking scores could be
recruited to predict ligand binding affinities.
The aromatic (
found to drive the ligand/receptor complex formation (Fig. 5).
PI3K kinase domain is enclosed with hydrophobic and aromatic
p-stacking) and hydrophobic interactions were
a
residues; particularly Met772, Trp780, Ile800, Leu807, Tyr836,
Ile848, Val850, Val851, Met922, Phe930, Ile932, and Phe934.
To evaluate the performance of Glide dock program, we com-
pared the docked pose of 1LT in PI3Ka
(PDB ID: 4JPS)29 to its native
conformation in the crystal structure. Figure 6 shows the superpo-
sition of the Glide-generated 1LT pose and the native conformation
in 4JPS. The RMSD for heavy atoms of 1LT between Glide-generated
docked poses and the native poses was 0.55 Å. This indicates that
Glide dock is capable to identify the native poses in crystal
structures and can successfully predict the ligand binding
conformation. Moreover, the verified compounds satisfy the same
Fig. 4. Binding conformation of 8 (A) and 10 (B) in PI3K
domain. H-Bond is depicted in blue dotted line. H-atoms are hidden for clarity.
Picture made by PYMOL.
a (PDB ID: 2RD0) kinase

D. A. Sabbah et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3120–3124
3123
Interestingly, compounds with benzoin core nucleus were
previously reported as anticancer agent against Ehrlich ascites
carcinoma (EAC) xenograft model in mice.47,48 Attaching nitro at
o- or p-position or hydroxyl group at o-position enhances the
anticancer activity.47 Also, these derivatives revitalized blood cells
count toward normal, extended life-span, and decreased tumor
size effectively.47 Additionally, diversified derivatives of benzoin
showed pronounced broad spectrum antimicrobial,49–52 analgesic
and anti-inflammatory,53 and antidepressant activity in mice
model.54 Our future goal is to optimize this scaffold to enhance
the antitumor activity and selectivity against an array of kinases.
Acknowledgements
This work was fully supported by the Deanship of Scientific
Research and Graduate Studies at Al-Zaytoonah University of
Jordan. The authors acknowledge the Chemistry Department at
the University of Jordan for use of the NMR facility. We are grateful
to the College of Pharmacy at the University of Jordan for use of cell
culture laboratory and equipment. We thank Dr. Ma’mon Hatmal
at the Faculty of Allied Health Sciences in Hashemite University
for granting us the human colon carcinoma (HCT116) cell line.
Figure 6. Superposition of the Glide-docked 1LT pose and its native conformation
in 4JPS. The native coordinates are pink colored and the docked pose is grey colored.
Picture made by PYMOL.
Supplementary data
pharmacophoric features of PI3Ka inhibitors inferring that these
compounds occupy the kinase domain in a similar manner to those
of reported inhibitors (Fig. 7).
Supplementary data (detailed experimental methods, computa-
tional approaches, NMR and FT-IR characterization results, as well
as additional figures) associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2015.06.011.
In conclusion, PI3K
design. In our effort to develop novel PI3K
structure-based design and molecular docking to optimize the lead
PI3K inhibitor (NSC 8082) 2-hydroxy-1,2-diphenylethanone
(benzoin). We identified a series of 2-oxo-1,2-diphenylethyl ben-
zoate as potential PI3K inhibitors.
a
is a promising target for anticancer drug
a
inhibitors, we recruited
a
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