Synthesis, docking and anticancer activity studies of D-proline- incorporated wainunuamide

Article abstract of DOI:10.1007/s12039-012-0301-x

D-proline-incorporated wainunuamide - a cyclic octapeptide was synthesized and characterized by FTIR, ¹H and ¹³C NMR and Mass spectral analysis. Molecular docking studies were carried out for the designed cyclic octapeptide and the results showed greater affinity for HPV18-2IOI receptor (HeLa cancer cell line). The synthesized cyclic octapeptide exhibited potent anticancer activity against HeLa cancer cells. Indian Academy of Sciences.

Full text of DOI:10.1007/s12039-012-0301-x

c
J. Chem. Sci. Vol. 124, No. 5, September 2012, pp. 1049–1055. ꢀ Indian Academy of Sciences.
Synthesis, docking and anticancer activity studies
of D-proline-incorporated wainunuamide
M HIMAJAa,∗, A RANJITHAa and SUNIL V MALIb
aSchool of Advanced Sciences, Pharmaceutical Chemistry Division, VIT University, Vellore 632 014, India
bMedicinal Chemistry Division, Piramal Life Science Ltd., Mumbai 400 060, India
e-mail: dr_himaja@yahoo.com; jranji16@yahoo.com
MS received 17 February 2011; revised 25 July 2011; accepted 23 August 2011
Abstract. D-proline-incorporated wainunuamide — a cyclic octapeptide was synthesized and characterized
1
by FTIR, H and 13C NMR and Mass spectral analysis. Molecular docking studies were carried out for the
designed cyclic octapeptide and the results showed greater affinity for HPV18-2IOI receptor (HeLa cancer cell
line). The synthesized cyclic octapeptide exhibited potent anticancer activity against HeLa cancer cells.
Keywords. Cyclic octapeptide; molecular docking; solution phase synthesis; anticancer activity.
1. Introduction
moderate cytotoxic activity.9 The synthetic wain-
unuamide also exhibited moderate anticancer activity
towards HeLa cancer cell lines.10 Literature review
on cytotoxic cyclic peptides revealed that phakellis-
tatins11 and theonellamides12 containing D- and/ (or)
L- proline units were reported to show potent anti-
cancer activity towards various cancer cells. Based
on these results, in order to further enhance the anti-
cancer activity of wainunuamide, a D-proline unit was
incorporated into the ring structure of wainunuamide.
The cyclic octapeptide Cyclo-D-Pro-(L-Phe-Pro-His-
Pro-Pro-Gly-Leu) was synthesized by solution phase
peptide technique using TBTU [O-(Benzotriazol-1-yl)-
N,N,Nꢁ,Nꢁ-tetramethyluronium tetrafluoroborate] as the
coupling reagent and triethylamine as the base.
Various active anticancer agents are derived from
marine sponges, plants and terrestrial microorganisms.
They are rich sources of bioactive cyclic peptides
and depsipeptides with unique structures involving a
wide variety of unusual amino acids and other build-
ing blocks.1–4 Many cyclic peptides, isolated from
marine sponges, exhibited interesting biological pro-
perties including a reverse of multi-drug resistance
in tumour cells,5 HIV inhibition,6,7 and nematocidal
activity.8
A cyclic heptapeptide, wainunuamide Cyclo-L-[Phe-
Pro-His-Pro-Pro-Gly-Leu], was isolated from a Fijian
marine sponge of Stylotella aurantium which showed
O
O
O
N
N
N
O
N
N
N
O
HN
NH
HN
O
O
O
HN
HN
HN
O
O
O
N
O
NH
HN
H
N
N
HN
N
O
O
O
Wainunuamide
D-Proline incorporated wainunuamide
∗For correspondence
1049

1050
M Himaja et al.
of ester group), 1681 (>CO Stretch), 1570 (-NH Bend),
2. Experimental
1461 (-CH bend). 1H NMR (500 MHz, CDCl3): δ 8.0–
7.5 (m, 7H, Ar-H), 7.2 (s, 1H, -NH of imidazole), 7.0
(s, 1H, -NH of Phe), 4.8 (t, 2H, α-CH of Phe and His),
4.2 (t, 2H, N-CH of Pro), 4.0 (d, 2H, -CH2 of Phe and
His), 3.8 (s, 3H, -OCH3), 3.2–2.4 (m, 8H, -CH2 of Pro),
3.4–3.3 (t, 4H, N-CH2 of Pro), 0.9 (s, 9H, -CH3 of Boc
group). HRMS (EI) m/z: 610.61 (M+). Anal. Calcd.
for C31H42N6O7: C 60.97, H 6.93, N 13.76. Found:
C 60.89, H 6.80, N 13.66.
All the reactions requiring anhydrous condition were
conducted in flame dried apparatus. Solvents and
reagents were purified by standard methods. Organic
extracts were dried over anhydrous sodium sul-
phate. All amino acids and other chemicals were
obtained from Spectrochem Private Limited (Mum-
bai, India). Boc-amino acids and Amino acid methyl
ester hydrochlorides were prepared using standard pro-
cedures.13 Purity of the compounds was checked by
pre-coated TLC plate. IR spectra were recorded on
Thermo Nicolet FTIR 330 spectrometer using a thin-
film supported on KBr pellets. 1H and 13C NMR spec-
tra were recorded on Bruker AC NMR spectrometer
using CDCl3 as solvent. HRMS Mass spectra were
recorded on a Jeol GC Mate. Elemental analysis (C, H
and N) was carried out using a PERKIN-ELMER 2400
elemental analyzer.
2.3 Preparation of Boc-Pro-Gly-Leu-OMe
The above tripeptide was prepared from the dipeptide
Boc-Pro-Gly-OMe and Leu-OMe units after appropri-
ate deprotection14 at the required functional groups.
The deprotected dipeptide and Leu-OMe units were
coupled using TBTU, Et3N to get the protected tripep-
tide using the procedure similar to that of the dipeptide.
2.1 Preparation of dipeptides
2.3a Tripeptide: Boc-Pro-Gly-Leu-OMe: Pale Yel-
lowish sticky semisolid mass, Molecular weight: 399,
Molecular Formula: C19H33N3O6, Yield 77%; UV
(100% MeOH) λmax 232; FTIR (KBr γ cm−1): 3221
(-NH Stretch), 2979 and 2960 (-CH Stretch), 1746
(>CO of ester group), 1680 (>CO Stretch), 1576 (-NH
Bend), 1466 (-CH bend). 1H NMR (500 MHz CDCl3):
δ 7.5–7.7 (s, 2H, -NH), 4.1 (t, 1H, N-CH of Pro), 3.9
(t, 1H, -CH of Leu), 3.6 (s, 3H, -OCH3 of Leu), 3.4–
3.2 (m, 2H, -CH2 of Pro), 3.5–3.0 (t, 2H, N-CH2 of
Pro), 2.9–2.5 (m, 2H, -CH2 of Pro), 1.8 (d, 2H, -CH2
of Leu), 1.7 (m, 1H, -CH of Leu), 1.4 (s, 2H, -CH2 of
Gly), 1.0 (s, 6H, -CH3 of Leu), 0.9 (s, 9H, -CH3 of Boc
group). HRMS (EI) m/z: 399.00 (M+). Anal. Calcd. for
C19H33N3O6: C 57.12, H 8.33, N 10.52. Found: C 57.04,
H 8.25, N 10.42.
Amino acid methyl ester hydrochloride (10 mmol) was
dissolved in chloroform (20 ml). To this, triethylamine
(4 ml, 28.7 mmol) was added at 0◦C and the reac-
tion mixture was stirred for 15 min. Boc-amino acid
(10 mmol) in CHCl3 (20 ml) and TBTU (10 mmol) were
added and the reaction mixture was stirred for half an
hour. After 30 min, the reaction mixture was filtered
and the residue was washed with CHCl3 (30 ml) and
the washings were added to the filtrate. The filtrate was
washed with 5% HCl (20 ml), 5% NaHCO3 (20 ml) and
saturated NaCl (20 ml) solutions. The organic layer was
filtered, dried over anhydrous Na2SO4 and evaporated
in vacuo to get the synthesized product. The completion
of the reaction was monitored by TLC. Boc-Phe-Pro-
OMe, Boc-His-Pro-OMe and Boc-Pro-Gly-OMe were
prepared in the similar manner.
2.4 Preparation of Boc-D-Pro-Phe-Pro-His-Pro-OMe
2.2 Preparation of Boc-Phe-Pro-His-Pro-OMe
The above pentapeptide was prepared from the
tetrapeptide Boc-Phe-Pro-His-Pro-OMe and Boc-D-
Proline units after appropriate deprotection14 at the
required functional groups. The deprotected tetrapep-
tide and Boc-D-Proline units were coupled using
TBTU, Et3N to get the protected pentapeptide using the
procedure similar to that of dipeptide.
The above tetrapeptide was prepared from the dipeptide
Boc-Phe-Pro-OMe and Boc-His-Pro-OMe units after
appropriate deprotection14 at the required functional
groups. The deprotected dipeptide units were coupled
using TBTU, Et3N to get the protected tetrapeptide
using the procedure similar to that of the dipeptide.
2.2a Tetrapeptide:
Boc-Phe-Pro-His-Pro-OMe:
2.5 Preparation of linear octapeptide -
Brown sticky semisolid mass, Molecular weight: 610,
Molecular Formula: C31H42N6O7, Yield 79%; UV
(100% MeOH) λmax 249; FTIR (KBr γ cm−1): 3227
(-NH Stretch), 2982 and 2964 (-CH Stretch), 1749 (>CO
Boc-D-Pro-L-(Phe-Pro-His-Pro-Pro-Gly-Leu-OMe)
The Boc-group of the tripeptide (Boc-Pro-Gly-
Leu-OMe) was removed and the ester group of the

Anticancer activity of D-proline-incorporated wainunuamide
1051
pentapeptide (Boc-D-Pro-Phe-Pro-His-Pro-OMe) was of Gly), 171.3 (>CO of His), 172.1 (>CO of Pro),
deprotected. Both the deprotected units were cou- 173.8 (>CO of Leu), 174.7 (>CO of Pro), 175.2 (>CO
pled to get the linear octapeptide- Cyclo D-Pro-L- of Pro), δ 119.2, 127.4, 128.4, 130.3, 130.5, 134.9,
(Phe-Pro-His-Pro-Pro-Gly-Leu).
138.7, (Ar-C of Phe and His), δ 60.6 (Pro α-CH2), 61.4
(Pro α-CH2), 62.6 (Pro α-CH2), 64.3s (Pro α-CH2),
δ 53.5 (His α-CH), δ 50.7 (α -CH of Phe), 44.8 (Gly
α-CH2), δ 41.5 (Leu -CH2), δ 45.1 (Pro δ-CH), 46.7
(Pro δ-CH), 46.9 (Pro δ-CH), 47.2 (Pro δ-CH), δ 37.7
(α-CH2 of Phe), 28.7 (Pro β-CH2), δ 29.1 (Pro β-
CH2), 32.4 (Pro β-CH2), 32.7 (Pro β-CH2), δ 28.7 (His
β-CH2) δ 22.7 (Pro γ -CH2), 24.3 (Pro γ -CH2), 24.8
(Pro γ -CH2), 25.2 (Pro γ -CH2), δ 20.5 and 20.8 (Leu
α 2-CH3). HRMS (EI) m/z: 843.17 (M+). Anal. Calcd.
for C43H58O8N10: C 61.27, H 6.93, N 16.62. Found:
C 61.19, H 6.79, N 16.52.
2.6 Preparation of Cyclo-D-Pro-L-(Phe-Pro-His-
Pro-Pro-Gly-Leu)
The cyclisation of the linear octapeptide unit was car-
ried out by p-nitrophenyl ester method of Bodanszky15
with certain modifications. The ester group of the linear
segment was removed with LiOH and the p-nitrophenyl
ester group was introduced using the following
procedure:
To the solution of 2.2 mmol of Boc-peptide car-
boxylic acid in 15 ml of CHCl3 was added and 0.31 ml
(2.2 mmol) of triethylamine. After cooling in an ice
bath, 0.44 g (2.2 mmol) of p-nitrophenol16 was added
and stirred for 12 h at room temperature. The reac-
tion mixture was filtered and the filtrate was washed
with 10% NaHCO3 (5 ml) solution until excess of
p-nitrophenol was removed and finally washed with 5%
HCl (5 ml) to get Boc-Peptide-pnp-ester.
To the above Boc-peptide-pnp-ester (2 mmol) in
CHCl3 (10 ml), CF3COOH (2 mmol) was added,
stirred for 1 h at room temperature and washed
with 10% NaHCO3 solution. The organic layer was
dried over anhydrous Na2SO4. To the Boc-deprotected
peptide-pnp-ester (1.5 mmol) in CHCl3 (10 ml), TBTU
(1.5 mmol), triethyl amine (1.5 mmol) was added
and stirred for half an hour. The reaction mixture
was washed with 10% NaHCO3 until the byproduct
p-nitrophenol was removed completely and finally
washed with 5% HCl (5 ml) dried and evaporated
in vacuo to get the cyclised product Cyclo-D-Pro-L-
(Phe-Pro-His-Pro-Pro-Gly-Leu).
2.7 Molecular docking
We have used the following bioinformatics tools; bio-
logical databases like PDB (Protein Data Bank),17,18
Swiss-PDB Viewer Version19 3.7 and docking soft-
ware - Hex Version20 5.1 ACD ChemSketch (ACD/
Labs, www.acdlabs.com. The Protein Data Bank (PDB)
is the single worldwide archive of structural data of
biological macromolecules, established in Brookhaven
National Laboratories.21 Computer aided drug design
methods are heavily dependent on bioinformatics tools,
applications and databases.22 The structure of 2IOI
(HPV - human papillomavirus) receptor molecule
(figure 1) was retrieved from protein data bank (PDB
Code: 2IOI).
Using ChemSketch the structure of the cyclic
octapeptide was sketched. The docking analysis of the
cyclic octapeptide with 2IOI was carried by HEX dock-
ing software. Docking allows the scientist to virtu-
ally screen a database of compounds and predict the
strongest binders based on the various scoring func-
tions. It explores ways in which two molecules, such
as ligand and 2IOI receptor fit together and dock to
each other. The cyclic octapeptide molecules bind-
ing to a 2IOI receptor, inhibit its function, and thus
act as an anticancer drug. The collection of drug and
receptor complex was identified via docking and their
relative stabilities were evaluated using molecular
dynamics and their binding affinities, using free energy
simulations. Based on the total energy values, the anti-
cancer activity of the compound was identified.
2.6a Cyclic octapeptide: Cyclo-D-Pro-L-(Phe-Pro-
His-Pro-Pro-Gly-Leu): Yellowish semisolid mass,
Molecular weight: 843, Molecular Formula:
C43H58O8N10, Yield 75%; UV (100% MeOH) λmax
300; FTIR (KBr γ cm−1): 3331 (-NH Stretch), 2989
and 2964 (-CH Stretch), 1716 (CO Stretch), 1569 (-NH
Bend), 1458 (-CH bend). 1H NMR (500 MHz CDCl3):
δ 7.8–7.1 (m, 7H, Ar-H), 7.3 (s, 1H, -NH of imidazole),
7.2–6.8 (s, 3H, -NH), 4.7 (t, 2H, -CH of Phe and His),
4.3 (t, 4H, N-CH of Pro), 4.0 (d, 4H, -CH2 of Phe and
His), 3.0–2.7 (t, 8H, N-CH2 of Pro), 3.8 (t, 1H, -CH
of Leu), 3.5–3.2 (m, 16H, -CH2 of Pro), 1.8 (d, 2H,
2.8 Anticancer activity
-CH2 of Leu), 1.7 (m, 1H, -CH of Leu), 1.4 (s, 2H, MTT [3-(4, 5-Dimethylthiazole-2-yl)-2,5diphenyltet-
-CH2 of Gly), 1.0 (s, 6H, -CH3 of Leu). 13C NMR razoliumbromide] assay23,24 - (Human breast adeno-
(125 MHz CDCl3): δ 168.9 (>CO of Phe), 170.5 (>CO carcinoma cell line) were obtained from ATCC and

1052
M Himaja et al.
Figure 1. Structure of HPV18-2IOI receptor.
Boc-Pro-OH +H-Gly-OMe
Boc-His-OH + H-Pro-OMe
Boc-Phe-OH + H-Pro-OMe
a
a
a
Boc-Pro-Gly-OMe
Boc-Phe-Pro-OMe
Boc-His-Pro-OMe
c, b
b
b
Boc-Pro-Gly- OH + H-Leu-OMe
H-His-Pro-OMe
+
Boc-Phe-Pro-OH
a
a
Boc-Pro-Gly-Leu-OMe
Boc-Phe-Pro-His-Pro-OMe
c
c
H-Pro-Gly-Leu-OMe
+
Boc-Phe-Pro-His-Pro-OH
a
+
N
O
Boc-D-Pro-Phe-Pro-His-Pro-Pro-Gly-Leu-OMe
O
HO
b, d
O
Boc-D-Proline
Boc-D-Pro-Phe-Pro-His-Pro-Pro-Gly-Leu-OPnp
c,e
O
O
N
N
N
O
NO2
Where PNP =
HN
NH
HN
O
a = CHCl3,TBTU, Et3N, 1/2hr, RT,
b = THF: H2O (1:1), LiOH, 1h, RT,
c = CF3COOH/CHCl3, 1h, RT
O
N
O
NH
d = p-nitrophenol, CHCl3, 12h, RT
e = CHCl3, Et3N ,TBTU, 1/2hr, RT
HN
N
O
TBTU = 2-(1H-benzotriazole-1-yl)-1, 1, 3, 3 tetramethyluronium
tetrafluoroborate
O
Cyclic octapeptide
Reaction Scheme-1
Scheme 1. Cyclic octapeptide reaction.

Anticancer activity of D-proline-incorporated wainunuamide
1053
units, Boc-Pro-Gly-Leu-OMe and Boc-Phe-Pro-His-
Pro-OMe. Both tripeptide and tetrapeptide units were
synthesized by standard method using TBTU as cou-
pling reagent.25 The synthesized tetrapeptide was
treated with Boc-D-Proline to get pentapeptide unit.
The tripeptide and pentapeptide units containing Boc-
and ester groups were properly deprotected and coupled
together to get the linear octapeptide. Finally the li-
near octapeptide was cyclised using p-nitrophenyl ester
method (scheme 1).
Table 1. Docking results of cyclic octapeptide with diffe-
rent anticancer receptors.
Cyclic octapeptide
E total (kJ/mol)
S. No
(PDB Code)
1
2
3
4
5
1ZZF
1JLM
1IDO
1R8P
2IOI
−119.14
−108.96
−73.14
−68.17
−160.11
Standard anticancer drug
(kJ/mol).
—
Camptothecin −141.65
FTIR spectrum of cyclic octapeptide showed char-
acteristic medium to strong bands corresponding to
the carbonyl stretching at 1716 cm−1 and NH bending
at 1569 cm−1, confirmed the coupling reaction of the
maintained in DMEM (Hi-Media Laboratories Pvt.
Ltd, Mumbai, India) supplemented with 10% heat-
inactivated FBS (v/v), streptomycin (100 μg/ml) and
penicillin (100 μg/ml). The cell line was maintained
at 37◦C with 5% carbon dioxide in CO2 incubator.
The MTT cell proliferation assay was used to evaluate
the anticancer activity of D-Proline incorporated wain-
unuamide using the Cell Quantification MTT cell via-
bility assay kit (Bioassay Systems). The optical density
was measured at 570 nm for each well on the
absorbance plate reader. Trypan blue dye exclusion
assay was also used to count the number of viable
and nonviable HeLa cancer cells in the culture medium
after drug treatment. Treatment with 5-FU at the same
concentration served as positive control.
1
cyclic octapeptide. H and 13C NMR spectrum of the
synthesized cyclic octapeptide showed a peak corre-
sponds to the peptide clearly confirm the coupling of
amino acids and peptides. The mass spectral data con-
firm a stable molecular ion peak [843.17 - M+] for the
synthesized compound. Based on the above mentioned
spectral datas, the structure of the cyclic octapeptide
was confirmed. The spectral data values for the synthe-
sized cyclic octapeptide are shown in the experimental
section.
Docking studies have been carried out using Hex
software tool. The designed cyclic octapeptide were
docked with different target cancer receptors collected
from protein database bank, out of all receptors HPV18-
2IOI receptor had shown good binding interaction with
the (ligand) cyclic octapeptide. The results were shown
in table 1.
3. Results and discussion
The D-Proline incorporated wainunuamide had
shown good docking score [−160.11 kJ/mol] (figure 2)
with HPV18-2IOI proteins. The docking result was
In order to carry out the synthesis, the wainunuamide
was disconnected into one tripeptide and tetrapeptide
Figure 2. Interaction and binding energy of cyclic octapeptide with 2IOI receptor.

1054
M Himaja et al.
Figure 3. Interaction and binding energy of camptothecin with 2IOI receptor.
(a)
(b)
Control
Treated
Figure 4. Representative phase micrograph of Hela cancer cell lines of control group
and of those treated with the one studied preparations (a) Control cells, untreated Hela
cells, (100% viability); (b) Hela cells treated with cyclic octapeptide (1) at 50 μg/ml (27%
viability).
compared with that of standard anticancer drug of D-Proline-incorporated wainunuamide were com-
Camptothecin [−141.65 kJ/mol] (figure 3). Based on pared with synthetic wainunuamide. The D-proline
the docking score, the synthesized compound was unit containing wainunuamide showed potent anti-
evaluated for the anticancer activity towards Hela can- cancer activity than that of synthetic wainunuamide.
cer cell line.
The IC50 values were calculated to be 31.75 μg/ml for
The effects of D-Proline incorporated cyclic octapep- D-Proline incorporated wainunuamide and 20.58 μg/ml
tide on the growth of HeLa cancer cells were tested for synthetic wainunuamide. After 96 h, D-Proline-
under in vitro conditions using different concentrations incorporated wainunuamide (50 μg/ml) exhibited potent
(5, 15, 25 and 50 μg/ml) and the cell survival after 48 h anticancer activity 27% (73% cell death) on HeLa can-
was shown in the figure 4. The D-Proline incorporated cer cells, but the synthetic wainunuamide had shown
wainunuamide inhibited the growth of HeLa cancer 53% cell viability (47% cell death) on HeLa cancer
cells and the results are shown in the table 2. The results cells.

Anticancer activity of D-proline-incorporated wainunuamide
1055
4. Aoki S, Cao L, Matsui K, Rachmat R, Akiyama S,
Kobayashi M 2004 Tetrahedron 60 7053
Table 2. Effect of cyclic octapeptide on HeLa cancer cell
line.
5. Oku N, Gustafson K R, Cartner L K, Wilson J A,
Shigematsu N, Hess S, Pannell L K, Boyd M R,
McMahon J B 2004 J. Nat. Prod. 67 1407
6. Mitchell S S, Faulkner D J, Rubins K, Bushman F D
2000 J. Nat. Prod. 63 279
7. Capon R J, Ford J, Lacey E, Gill J H, Heiland K,
Friedel T 2002 J. Nat. Prod. 65 58
8. He Y b, Huang Z, Raynor K, Reisine T, Goodman M
1993 J. Am. Chem. Soc. 115 8066
9. Jioji Tabudravu, Linda A Morris, J Jantina Kettenes-van
den Bosch and Marcel Jaspars 2001 Tetrahedron Lett. 42
9273
Anticancer activity of D-Proline incorporated
cyclic heptapeptide (wainunuamide) on HeLa cell
lines after 48 h treatmenta
Compound
Percentage of viable cells
Control
100
Treated
27
Cyclic octapeptide
aValues are mean of the three experiments. The viable HeLa
cells were calculated after 48 h of cyclic octapeptide treat-
ment and strained with trypan blue dye exclusion test
10. Himaja M, Ranjitha J, and Mali S V 2009 Indian Drugs
9 682
11. Pettit G R, Cichacz Z, Barkoczy J, Dorsaz A C,
Herald D, Williams M D, Doubek D L, Schmidt J M,
Tackett L P and Brune D C 1993 J. Nat. Prod. 56 260
12. Matsunaga S, Fusetani N, Hashimoto K, Walchli M,
1989 J. Am. Chem. Soc. 111 2582
13. Bodanszky M, Bodanszky A 1984 Practice of peptide
synthesis. 1st Ed. (New York: Springer-Verlag) vol. 143,
p. 91
14. Belagali S L, Harish Kumar K, Poojary B, Himaja M
1998 Acta Chim. Turcica. 26 59
15. Bodanszky M, Bodanszky A 1984 Practice of peptide
synthesis. 1st Ed. (New York: Springer-Verlag) vol. 131,
p. 91
16. Paul Gagnon, Xicai Huang, Eric Therrien and Jeffrey W
Keillor 2002 Tetrahedron Lett. 43 7717
4. Conclusion
In conclusion, TBTU was found to be effective cou-
pling reagent giving high yields and reduced reac-
tion time (30 min) as compared to DCC (24 h) and
EDC (12 h). Molecular docking studies concluded that
the designed cyclic octapeptide showed greater affi-
nity towards HPV18-2IOI target protein for cancer.
Based on the docking results, the synthesized cyclic
octapeptide was evaluated for the anticancer activity
and the compound showed potent anticancer activity as
compared to that of the parent cyclic heptapeptide —
wainunuamide.
17. Berman HM 2008 Acta Crystallographica 64 88
18. Duhovny D S, Inbar Y, Nussinov R, Wolfson H J 2005
Nucleic Acids Res. 33 363
19. Guex N and Peitsch MC 1997 Electrophoresis 18 2714
20. Fei Liu and Bai-Shan Fang 2007 Chinese J. Biotechnol.
23(1) 133
21. Berman H M, Westbrook J, Feng Z, Gilliland G, Bhat
T N, Weissig H, Shindyalov I N and Bourne P E 2000
Nucleic Acids Res. 28 235
Acknowledgements
The authors are thankful to Vellore Institute of Tech-
nology (VIT) University for providing the chemi-
cals and laboratory facilities. The authors are thank-
ful to Indian Institute of Technology (IIT) Madras for
providing the spectral data.
22. Ambesi-Impiombato A, Bernardo D 2006 Curr. Bioin-
format. 1 3
23. Carnichael J, DeGraff W G, Gazdar A F Minna J D,
Mitchell J B 1987 Cancer Res. 47 936
24. Mosmann T 1983 J. Immunol. Meth. 65 55
25. Andrey S Ivanov, Anna A Zhalnina, Sergey V Shishkov
2009 Tetrahedron 65(34) 7105
References
1. Faulkner D 2002 J. Nat. Prod. Rep. 19 1
2. Schemjakin M M 1960 Angew. Chem. 72 342
3. Hill R A 2005 Annu. Rep. Prog. Chem. Sect. B 101 124