Synthesis, molecular docking and anticancer studies of peptides and iso-peptides

Article abstract of DOI:10.1016/j.bmcl.2015.05.020

Chiral peptides and iso-peptides were synthesized in excellent yield by using benzotriazole mediated solution phase synthesis. Benzotriazole acted both as activating and leaving group, eliminating frequent use of protection and subsequent deprotection. The procedure was based on the hypothesis that epimerization should be suppressed in solution due to a faster coupling rate than SPPS. All the synthesized peptides complied with Lipinski's Ro5 except for the rotatable bonds. Inhibition of cell proliferation of cancer cell lines is one of the most commonly used methods to study the effectiveness of any anticancer agents. Synthesized peptides and iso-peptides were tested against three cancer cell lines (MCF-7, MDA-MB 231) to determine their anti-proliferative potential. NFkB was also determined. Molecular docking studies were also carried out to complement the experimental results.

Full text of DOI:10.1016/j.bmcl.2015.05.020

Bioorganic & Medicinal Chemistry Letters 25 (2015) 2980–2984
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, molecular docking and anticancer studies of peptides
and iso-peptides
c
c
c
Farukh Jabeen a,b, Siva S. Panda a, , Tamara P. Kondratyuk , Eun-Jung Park , John M. Pezzuto ,
⇑
Ihsan-ul-haq d, C. Dennis Hall a, Alan R. Katritzky a,e,
a Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
b Department of Chemistry, Quaid-i-Azam University, Islamabad 44000, Pakistan
c College of Pharmacy, University of Hawii at Hilo, Hilo, HI, USA
d Department of Pharmacy, Quaid-i-Azam University, Islamabad 44000, Pakistan
e Chemistry Department, King Abdulaziz University, Jeddah 21589, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral peptides and iso-peptides were synthesized in excellent yield by using benzotriazole mediated
solution phase synthesis. Benzotriazole acted both as activating and leaving group, eliminating frequent
use of protection and subsequent deprotection. The procedure was based on the hypothesis that epimer-
ization should be suppressed in solution due to a faster coupling rate than SPPS. All the synthesized
peptides complied with Lipinski’s Ro5 except for the rotatable bonds. Inhibition of cell proliferation of
cancer cell lines is one of the most commonly used methods to study the effectiveness of any anticancer
agents. Synthesized peptides and iso-peptides were tested against three cancer cell lines (MCF-7, MDA-
MB 231) to determine their anti-proliferative potential. NFkB was also determined. Molecular docking
studies were also carried out to complement the experimental results.
Received 12 April 2015
Revised 8 May 2015
Accepted 12 May 2015
Available online 16 May 2015
Keywords:
Peptides
iso-Peptides
Anti-cancer
Benzotriazole
Molecular docking
Ó 2015 Elsevier Ltd. All rights reserved.
A diverse arsenal of peptide based drugs have been developed
for the treatment of cancer, viral infections, pain management,
and other diseases.1,2 The ubiquity of biologically active peptides
and peptide derivatives has attracted attention of the synthetic
community. In this context the 1923 Nobel Prize was awarded to
Banting and Macleod for the discovery and extraction of insulin.2
du Vigneaud, a Nobel laureate in chemistry, presented the first
total solution phase synthesis of a naturally occurring bioactive
octapeptide, oxytocin.3–5 Peptides are now routinely prepared by
chemical synthesis in solution or solid phase and are being used
as therapeutic agents such as leuprolide acetate (Lupron™), octre-
odide acetate (Sandostatin™) and goserelin acetate (Zoladex™).2,5
Peptides are intrinsically able to interact with biological sys-
tems and are therefore potent therapeutics,6–8 but their conforma-
tional flexibility, low ability to cross physiological barriers and
metabolic instability, represent major hurdles for the successful
development of peptide-based drugs.9
limitless sequence variations and well-defined homogeneity.10–12
New and improved strategies lead to more efficient synthesis of
complex peptide targets, opening avenues to both new drug candi-
dates and a deeper understanding of the intimate relation between
sequence, conformation and properties.
Despite recent progress and the arsenal of reagents available,
peptide synthesis remains challenging.
Benzotriazole emerged as a powerful synthetic tool in 1987.13–16
Since then tremendous progress has been achieved in this field.17
This solution phase benzotriazole mediated peptide coupling
avoids both epimerization and hydrolysis due to fast coupling rate.
Peptides containing iso-peptide bonds are called iso-peptides.
iso-Peptides are useful for the synthesis of large peptides and pro-
teins. The iso-peptide method led to the efficient preparation and
purification of large peptides, which are known to aggregate in
solution. Significantly, the combination of both techniques, peptide
and iso-peptide synthesis has advanced the frontiers of synthetic
peptide chemistry. ‘O-Acyl iso-peptides’ are more hydrophilic and
easier to purify by HPLC than the corresponding native peptides.18
This study reports the synthesis of chiral peptides and iso-pep-
tides by benzotriazole chemistry and their anticancer activity.
Molecular docking studies against kinases completes the study.
N-(Pg-Aminoacyl)-benzotriazoles 3a–d were readily prepared
from commercial N-protected-amino acids 1a–e following
Advantages for purely synthetic peptides include, large
scale preparation, incorporation of unnatural amino acid residues
to improve their absorption–distribution–metabolism profile,
⇑
Corresponding author. Tel.: +1 352 392 0554; fax: +1 352 870 9288.
E-mail address: sspanda12@gmail.com (S.S. Panda).
Deceased on February 10, 2014.
http://dx.doi.org/10.1016/j.bmcl.2015.05.020
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

F. Jabeen et al. / Bioorg. Med. Chem. Lett. 25 (2015) 2980–2984
2981
established procedures.19,20 N-Protected dipeptides 5a–h were
SOCl2, THF
or
DCC, DCM
R1
synthesized in 87–90% yields by peptide coupling reactions of N-
(Pg-aminoacyl)benzotriazoles 3a–b with free amino acid in the
presence of triethylamine in aqueous acetonitrile at 20 °C
(Scheme 1, Table 1).
Protected dipeptides 5a–b were treated with benzotriazole 2 in
the presence of thionyl chloride in DCM at ꢀ20 °C for 5 h to obtain
N-(Pg-dipeptidioyl)benzotriazoles 6a–b in good yields (Scheme 2,
Table 2).
R1
N
N
N
N
Pg
OH
+
N
Pg
N
H
N
H
2 h, 20 oC
N
H
O
O
1a-e
2
3a-d
R2
MeCN:H2O (7:3),
TEA, 20 oC, 2 h
OH
H2N
4
O
Isotripeptides 7a–e were synthesized by peptide coupling reac-
tions between protected dipeptides 5c–f and N-(Pg-aminoa-
cyl)benzotriazoles 3c–d in dry acetone in the presence of two
equivalents of triethylamine for one hour at ꢀ10 °C in 70–82%
yields (Scheme 3, Table 3).
R1
O
H
N
Pg
N
OH
H
O
R2
5a-h
Deprotection of the Cbz group of 7a–c with C/Pd in ethanol
under hydrogen gave unprotected isotripeptides 8a–c in good
yields (Scheme 4, Table 4).
Scheme 1. Synthesis of dipeptides 5a–h.
Peptides 5d, 7d and 8a showed QR1 greater than 2 (Table SI 1).
The cytotoxic potential of the synthesized peptides toward hor-
mone responsive breast cancer cell line MCF-7 ATCC (HTB-22),
and estrogen receptor negative breast cancer cell line MDA-MB-
231 (ATCC, HTB-26) was determined and the results are shown
in Table SI 1.
Inhibition of cell proliferation of cancer cell lines is one of the
most commonly used methods to study the effectiveness of any
anticancer agents. In the present study, three cancer cell lines
(MCF-7, MDA-MB 231) were used to determine antiproliferative
potential of selected samples. Both MDA-MB-231 and MCF-7 are
cytotoxicity assays performed on breast cancer cell line. All assays
Table 1
Preparation of dipeptides 5a–h
Entry
Compound 5
Yield (%)
Mp (°C)
Lit mp (°C)
1
2
Cbz-
Cbz-
L
-Phe-Bt, 3a
-Ala-Bt, 3b
98
95
94
94
89
88
90
89
80
87
89
88
150–152
109–110
69–70
151–15219
114–11519
68–6920
L
3
4
5
6
Boc-Gly-Bt, 3c
Boc- -Ala-Bt, 3d
Cbz- -Phe-Gly-OH, 5a
15-Cbz- -Ala- -Phe-OH, 5b
L
84–86
85–8620
L
164–165
142–144
140–141
146–148
192–194
191–193
200–202
203–204
163–16520
141–14320
140–14119
L
L
7
8
9
10
11
12
Cbz-
Cbz-
Cbz-
Cbz-
Cbz-
Cbz-
L
L
L
L
L
L
-Phe-
-Phe-
L
-Ser-OH, 5c
-Thr-OH, 5d
L
-Ala-
L
-Ser-OH, 5e
192-19419
-Phe-
D
-Ser-OH, 5f
-Ser-OH, 5g
-Thr-OH, 5h
were carried out at 20
better inhibition.
lg/mL. In case of NFkB 5d, and 6a showed
-Ala-
-Ala-
D
L
Nuclear factor kappa-B (NFkB) is an inducible transcription fac-
tor that plays an important role in the regulation of apoptosis, cell
differentiation, and cell migration. NFkB is commonly involved as a
regulator of genes that control cell proliferation and cell survival.
Many different types of human tumors have miss-regulated NFkB
that is constitutively active. Thus, inhibition of NFkB signaling
has a potential application for the prevention or treatment of
cancer.21,22 As NFkB is an important regulator in cell fate decisions,
such as programmed cell death, proliferation control, and cell inva-
sion, it is critical in tumor-genesis. Inhibition of NFkB signaling has
potential applications for the prevention or treatment of
cancer.22,23
R1
O
R1
O
H
N
H
N
Pg
N
N
N
SOCl2, DCM
6 h, -20 oC
Pg
N
H
N
N
N
H
OH
+
O
R2
N
H
O
R2
6a-b
2
5a-b
Scheme 2. Synthesis of N-(Pg-dipeptidioyl)benzotriazoles 6a–b.
Table 2
Preparation of N-(Pg-dipeptidioyl)benzotriazoles 6a–b
In the quinoline reductase (QRI) assay,24,25 after the initial test-
ing of 22 samples, 3 samples were selected to determine CD values
(concentration required to double the QRI activity). These samples
showed either an induction ratio (IR) > 2 or cytotoxic activity with
Entry
Compound 5
Yield (%)
Mp (°C)
Lit mp (°C)
165–16716
148–14919
1
2
Cbz-
Cbz-
L
L
-Phe-Gly-Bt, 6a
-Ala-
85
86
166–167
148–149
L
-Phe-Bt, 6b
cell survival 650% at 20
showed various levels of inhibition of NFkB. Among them, the most
l
g/mL.24–26 In this study, 22 peptides
R1
O
R3
N
N
H
potent 5d and 6a had 650% inhibition at 20 lg/mL. Results are tab-
N
Pg
N
ulated in Table SI 2.
N
H
OH
Boc
+
N
H
According to Lipinski’s Ro5,27 most drug like molecules have
O
R2 OH
O
molecular weight 6500, logarithm of the octanol/water partition
3c-d
0
5c-f
coefficient (logP) 6 5, total polar surface area (TPSA) < 140 ÅA2,
number of hydrogen bond donors (HBD) 6 5 and hydrogen bond
acceptor (HBA) 6 10.27 Further modifications in the Ro5 were
made by Veber et al. who suggested the number of rotatable bond
(NOR) of a drug like molecule must be fewer or equal to 10.28
Molecules violating more than one of these rules may have less
bioavailability. These molecular descriptors were calculated for
all the synthesized peptides, iso peptides and benzotriazolides by
the ligand property calculation function of MOE (Table SI 3) and
all of them were found to obey Lipinski’s Ro5 cut-off limits, with
the exception of number of rotatable bonds, revealing potent
druglike compounds.
KHCO3, dry Acetone
3 h, -10 oC
R1
O
H
N
Pg
N
OH
H
O
R2
O
R3
O
HN
Boc
7a-e
Scheme 3. Synthesis of iso-peptides 7a–e.

2982
F. Jabeen et al. / Bioorg. Med. Chem. Lett. 25 (2015) 2980–2984
Table 3
Preparation of isopeptides 7a–e
Entry
Compound 5
Yield (%)
Mp (°C)
1
2
3
4
5
Cbz-
Cbz-
Cbz-
Cbz-
Cbz-
L
L
L
L
L
-Phe-
-Phe-
-Phe-
L
-Ser(Boc-Gly)-OH, 7a
-Thr(Boc-Gly)-OH, 7b
80
82
80
70
79
86–87
65–66
67–68
92–94
90–91
L
D
-Ser(Boc-Gly)-OH, 7c
-Ser(Boc- -Ala)-OH, 7d
-Ser(Boc-Gly)-OH, 7e
-Ala-
-Ala-
L
L
L
Having studied chemo-preventive activities of peptides, molec-
ular docking studies were carried out in search of a rationale for
the lab results.
The receptor was cleaned of water molecules, 3D of the proto-
nated and energy minimized by MMFF9429 by making using MOE
suite. The crystal structure of Kinases
protein data bank (PDB code: 3BRT and 3BRV rec). Both IKK
a
and b were obtained from
, (PDB
a
code: 3BRT) and IKKb, (PDB code: 3BRV) comprise of four chains
each as shown in Figure SI 2a and b. Ribbon and surface structure
of both the IKKa, (PDB code: 3BRT) and IKKb, (PDB code: 3BRV) are
shown in Figure SI 1.
Since the 3BRT (1KK
a) is devoid of a co-crystalized ligand so
active site was indicated with the help of site finder module of
MOE software by the creation of an alpha center followed by dum-
mies as shown in Figure SI 2a and b. The active site isolated by
selecting the longest of the four chains turned to be a deep cleft lined
with key residues such as Gly730, Gly732, Phe734, Gly86, Glu89,
Lys90, and Leu93. Alpha spheres were created inside the cleft in
the form of a compact cluster, similarly dummy atoms were created
at the site of alpha sphere to carry out docking on the dummy atoms
as the receptor was devoid of its co-crystallized ligand.
3D structures of ligand molecules following the stereochemistry
of the peptides by using builder module of the MOE program were
drawn and energy minimized. Ligands were 3D protonated. Ligand
preparation was by a comprehensive collection of tools, including
3D protonation and energy minimization by using MMFF94 with
0.001 iteration criterion.29 This exercise generated lower energy,
stable and accurate minimized 3D model with correct chiralities.
Detailed results of molecular docking are exhibited in Table 4.
All the docked ligands clustered inside the pocket where the
dummies were created as shown in Figure 1.
Figures 1 and SI 3 show overlaying of ligands inside active site,
Figure SI 3 also exhibits the position of active site in heliacal struc-
ture of 3BRT. The dipeptide 5d with binding energy (London dG
ꢀ9.0400 kcal/mol) established three deterministic hydrogen bonds
with Met734 and Lys90 inside the active site which might be a
reason for its good activity. Moreover it also exhibited hydrophobic
and polar interaction with key residues. Peptide 6a also showed a
couple of polar interactions and hydrophobic interactions with key
residues inside the pocket and showed a binding energy (London
dG ꢀ8.8484 kcal/mol) Both the active peptides 5d and 6a exhibited
good binding score, mentioned in Table SI 5 of the Supporting
information. Multiple polar and nonpolar interaction coupled with
good binding energy could be the possible reason for peptide 5d
Figure 1. Overlaying of ligands inside cleft of 3BRT.
The protein is a 4-helix bundle of NEMO and IKKb domains each
consisting of two chains B, D and A, C respectively as shown in
Figure SI 1. NEMO density extends from residues 49–109 in chain
B and from 49–109 in chain D. The IKK peptide density extends
from residues 705–743 in chain A and from residues 701–744 in
chain C. N and C termini of NEMO chains B and D form dimeriza-
tion. Three regions are assigned within the IKKb peptide, desig-
nated as helical (705–731), linker (732–736), and the NEMO
Binding Domain (NBD) (737–742). Residues 85–101 of dimeric
NEMO forms a flat slit paving the way to two broad and extensive
IKK binding pockets; each pocket being occupied by the IKK pep-
tide linker and the NBD. The IKK peptide forms intermolecular
hydrogen-bond interactions (Ser85:Q730 and Glu89:S733) with
NEMO in the NEMO’s specificity pocket. Three large IKK side chains
inside the NEMO pocket which form consolidated intermolecular
hydrophobic interactions (Leu93:F734, Phe92:T735, Met94: F734,
Phe97:W739, Ala100:W741, and Arg101:W741) are responsible
for formation of NEMO–IKKb complex.
The active site isolated by selecting the longest chain of the
entire four chains turnout to be a deep cleft lined with the key resi-
dues such as Gly730, Gly732, Phe734, Gly86, Glu89, Lys90, and
Leu93. Alpha spheres were created inside the cleft in the form of
a compact cluster, similarly dummy atoms were created at the site
of alpha sphere to carry out docking around the dummy atoms as
receptor was devoid of having its co-crystallized ligand. Both
Figures SI 4a and b show the alpha center and dummies at the
pocket of 3BRV (1KKb) respectively.
All the ligand cluster compactly at the same position where
dummies were created by site finder module of MOE suite in active
site cleft of 3BRV (1KKb), however ligand 8a was found to be off set
compared to all other ligands, some of its part seemed to be off
lying and this could be a basis for its high binding energy which
and 6a to exhibit activity against 1KK
a
(Fig. 2 and Fig. 3).
R1
O
O
R1
O
O
H
N
H
N
Pg
N
H
OH
R3
H2N
OH
R3
Table 4
Pd/C, EtOH, H2
Preparation of unprotected isotripeptides 8a–c
O
O
R2
R2
Entry
Compound 5
Yield (%)
Mp (°C)
O
O
1
2
3
H-L
H-L
H-L
-Phe-
-Phe-
L
-Ser(Boc-Gly)-OH, 8a
-Thr(Boc-Gly)-OH, 8b
85
87
85
170 (dec.)
203–204
189–190
HN
HN
7a-c
8a-c
Boc
Boc
L
-Ala-L-Ser(Boc-Gly)-OH, 8c
Scheme 4. Synthesis of unprotected isotripeptides 8a–c.

F. Jabeen et al. / Bioorg. Med. Chem. Lett. 25 (2015) 2980–2984
2983
Figure 4. Docking pose of 5d inside active site of 3BRV. 2D interactions of 5d
(dotted lines represents hydrogen bonding).
Figure 2. 2D interactions of 5d with residues in active site (3BRT), dotted lines
represents hydrogen bonding, purple in case of 3D and black in case of 2D
interaction.
Figure 3. 3BRV (1KKb), superimposition of ligands (cyan) inside active site cleft.
is ꢀ1.774 kcal/mol and quite high London dG (4.7566 kcal/mol). In
addition to this ligand, both tri-peptides 7d and 7e also showed lit-
tle higher binding score but they positioned inside the cleft during
docking however not squashed as compared to other ligands. It is
interesting to note that these compounds were found inactive in
wet lab investigations against chemo-preventive assays hence the-
oretical results complement the experimental data.
Binding mode of ligands inside the active site cleft of 3BRV
(1KKb) was analyzed after docking simulation calculations was
investigated. The top ranked docking pose being lowest energy
conformation was selected for further analysis. Tremendous strong
hydrogen bonding interactions were noticed between the NH
groups of ligand 5d and amino acid residues such as Gly730, Ser
85 and Gly 86 as evidenced from Figures 4 and 5.
Figure 5. Docking pose of 5d inside active site of 3BRV. 2D interactions of 5d
(dotted lines represents hydrogen bonding).
All these interactions were indication of strong binding of
ligand 10 inside the active side cleft and in turn could be reason
for its activity. Ligand 5d showed low binding energy such as
ꢀ8.6 kcal/mol (London dG), polar interactions and hydrogen bond-
ing with key residues as shown in Figure SI 4, which might be the
possible reason of its activity. Peptide 6a established hydrogen
bonding and also polar interaction with key residues which pro-
claimed to be possible reason for its activity. Table SI 5 depicts
the detailed analysis of molecular docking of active triazoles with
3BRV.

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F. Jabeen et al. / Bioorg. Med. Chem. Lett. 25 (2015) 2980–2984
3. du Vigneaud, V.; Ressler, C.; Swan, J. M.; Roberts, C. W.; Katsoyannis, P. G. J. Am.
Figure SI 5 shows the position of active site in the helical struc-
Chem. Soc. 1954, 76, 3115.
4. Frackenpohl, J.; Arvidsson, P. I.; Schreiber, J. V.; Seebach, D. Chem. Biol. Chem.
ture of 1kkb and it also shows that all docked ligands clustered
inside the pocket. Figures 4 and 5 exhibited the 3D and 2D interac-
tion of 5d with key residues in active site inside the active site.
These results demonstrated the in silico molecular docking
studies of peptides with 1KK
possess the potential to disturb hydrophobic and H-bond interac-
tions thereby affecting the stability of attachment of 1KK and
1KKb chains, and may be effective for other cancer cell lines.
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a
In conclusion, we have synthesized various protected and
unprotected dipeptides and iso-peptides using benzotriazole
chemistry. Some of the dipeptides and iso-peptides show promis-
ing preliminary anticancer properties. The obtained results were
justified by computational studies. These compounds could be
used as precursor for developing potential anticancer agents.
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Acknowledgments
We thank the Higher Education Commission of Pakistan,
University of Florida, USA and the Kenan Foundation for financial
support.
22. Ihsan-ul-Haq; Mirza, B.; Kondratyuk, T. P.; Park, E.-J.; Burns, B. E.; Marler, L. E.;
Pezzuto, J. M. Pharm. Biol. 2012, 5, 1.
Supplementary data
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Supplementary data (biological data, synthetic procedure, anal-
ysis data, anticancer and molecular docking studies) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.bmcl.2015.05.020.
References and notes
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