Synthesis and study of modified polyvinyl alcohol containing amino acid moieties as anticancer agent

Article abstract of DOI:10.13005/ojc/340131

A series of new phthalimides compounds[3-7]_a-i were synthesized from reaction of Malic anhydride, phthalic anhydride, nitro phthalic anhydride, 2-phenyl-4H-benzo[d][1,3]oxazin-4-one, 2-(4-nitrophenyl)-4H-benzo[d][1,3]oxazin-4-one with different amino acids as glycine, alanine, valine, leucine, isoleucine, serine, threonine, tyrosine and Phenyl alanine [1]_a-i under fusion conditions. Compounds [3-7]_a-i react with SOCl₂ in the presence of benzene to produce compounds [8-12]_a-i. Chemical modification of Poly(vinyl alcohol)were obtained by reaction of PVA with compounds [8-12]_a-i using the dimethyl formamide to give compounds [13-17]_a-i. The structure of the synthesized compounds was characterized by their analytical and spectral data as, IR spectra, ¹H, ¹³C-NMR, Elemental analysis (CHN), UV-Vis Spectroscopy, Scanning electron microscopy (SEM), Antibacterial activity were screened via two kinds of bacteria. Also, anticancer activity were examined for most of the modified polyvinyl alcohol.

Full text of DOI:10.13005/ojc/340131

ISSN: 0970-020 X
CODEN: OJCHEG
2018, Vol. 34, No.(1):
Pg. 286-294
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
www.orientjchem.org
Synthesis and Study of Modified Polyvinyl Alcohol Containing
Amino Acid Moieties as Anticancer Agent
ALI H. SAMIR, RUWAIDAH S. SAEED* and FADHEL S. MATTY
Department of Chemistry, College of Education for Pure Science (Ibn Al-Haitham) / University of
Baghdad, Iraq.
*Corresponding author E-mail: dr.mohammd08@gmail.com
http://dx.doi.org/10.13005/ojc/340131
(Received: July 23, 2017; Accepted: November 03, 2017)
ABSTRACT
A series of new phthalimides compounds[ 3-7]a-i were synthesized from reaction of Malic
anhydride, phthalic anhydride, nitro phthalic anhydride, 2-phenyl-4H-benzo[d][1,3]oxazin-4-one,
2-(4-nitrophenyl)-4H-benzo[d][1,3]oxazin-4-one with different amino acids as glycine, alanine,
valine, leucine, isoleucine, serine, threonine, tyrosine and Phenyl alanine [1]a-i under fusion conditions.
Compounds [3-7]a-i react with SOCl2 in the presence of benzene to produce compounds [8-12]a-i.
Chemical modification of Poly(vinyl alcohol)were obtained by reaction of PVA with compounds [8-
12]a-i using the dimethyl formamide to give compounds [13-17]a-i. The structure of the synthesized
compounds was characterized by their analytical and spectral data as, IR spectra, 1H, 13C-NMR,
Elemental analysis (CHN), UV-Vis Spectroscopy, Scanning electron microscopy (SEM),
Antibacterial activity were screened via two kinds of bacteria. Also, anticancer activity were
examined for most of the modified polyvinyl alcohol.
Keywords: Phthalimide, Polyvinyl alcohol, antibacterial and anticancer activities.
INTRODUCTION
conduction blocking5, hypotensive6, muscle
relaxant7, antitumor8 antitubercular agents9 and
antinociceptive agents , Also, these compounds
interest as reactants for polymer synthesis10.
Cyclic imides and their derivatives brought
much attention to chemist and pharmacist in the
field of research and development1, These
compounds play an important role in medicinal
chemistry in drug development and drug
discovery2. They Researches used these
compounds as antibacterial3, analgesic4, nerve
In addition compounds containing
phthalimide moiety are distinguished with
antimicrobial11-13, anti-inflammatory, anxiolytic,
antiviral, antibacterial and antitumor properties14,15
.
This is an
Open Access article licensed under a Creative Commons Attribution-NonCommercial-ShareAlike
4.0 International License (https://creativecommons.org/licenses/by-nc-sa/4.0/ ), which permits unrestricted
NonCommercial use, distribution and reproduction in any medium, provided the original work is properly cited.

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S.SAEED et al., Orient. J. Chem., Vol. 34(1), 286-294 (2018)
Polyvinyl alcohol (PVA)is a water-soluble 2-aminobenzoic acid (0.01 mole) in (30 ml.)
polyhydroxy polymer, non-halogenated aliphatic pyridine. The mixture was shaken for 5 min. and
polymers, that has
a
two dimensional
then kept in room temperature with shaking for
25 min. Mixture was reacted with 15 ml. 10%
NaHCO3, filtered, washed with water, dried and the
crude product was recrystalized from absolute
ethanol. The yield of compound[2]a was 81% , m.p.
(126) and [2]b was 77% , m.p (144).
hydrogen-bonded network sheet structure16.
PVA is a semi-crystalline polymer
containing crystalline and amorphous phase17
which is used in biomedical and pharmaceutical
applications18 and in industries due to the excellent
chemical and physical properties, non-toxicity, good
chemical resistance, good film formation capacity.19
General procedure for Preparation of compounds
22
[3-7]a-i
.
A mixture of equimolar amounts (0.001 mole)
It has been applied in production of many
end products, as lacquers, resins, surgical threads , and
food packaging materials20.
of commercially available malic anhydride,
phthalic anhydride, nitro phthalic anhydride,
2-phenyl-4H-benzo[d][1,3]oxazin-4-one,
2-(4-nitrophenyl)-4H-benzo[d] [1,3] oxazin-4-one
were treated with corresponding amino acids[ 1]a-
i in glacial acetic acid (15 ml.).
Encouraged by these observation, the
present study to synthesize new series of imide
compounds containing amino acids with different
heterocycles they may be have more activity and
less toxicity as anticancer agents.
Mixture was refluxed for (5 h) . A liquot of
25 ml. of ice distilled water was added to the
reaction. The compounds was filtered, dried and
recrystallized from ethanol .The nomenclature and
physical properties for prepared compounds
Aim of the present work is directed toward
modification of polyvinyl alcohol containing active
moiety with screened of antibacterial and anticancer
activities.
[3-7] a-i. were shown in Table. (1)
EXPERIMENTAL
Elemental analysis of compound[3]c
Calcd: C%=54.82
Found: C%= 54.69
H%= 5.58
H%= 5.42
N% =7.10
N% = 6.21
A-Materials
All the chemical used in the synthesis
were supplied from BDH and Sigma-Aldrich.
Elemental analysis of compound[5]i
Calcd: C%=60
Found: C%=58.7
H%= 3.52
H%= 4.62
N% =8.23
N% = 7.71
B – Instrumentation
Melting points were recorded using
electro thermal melting point apparatus and are
uncorrected.
23
Synthesis of compounds [8-12]a-i
.
A mixture of compound [3-7]a-i (0.01mole)
and thionyl chloride (0.01mole) placed in dry
benzene (10 ml.) and refluxed for 7 hours. The
excess of thionyl chloride and benzene were
removed under vacuum after cooling .
Infrared spectra were recorded as KBr disc
on SHIMADZU-FT-IR-8400 spectrometer.1H,
13C-NMR spectra was recorded on Bruker 500 MHz
instrument using DMSO-d6 as a solvent and TMS
as internal reference, measurement were made at
Central lab, Tahran University (Iran). the progress
of the reaction was monitored by TLC using
aluminum silica gel plates .
24
Synthesis of polymers [13-17] a-i
(1mole) of PVA and (1mole) of compounds
[8-12]a-i were placed in 20 ml DMF.The mixture was
frequent shaking for 3hr. then refluxed for 2 h product
was poured into the water , washed with a little
sodium bicarbonate, washed with water , then with
ethanol. The product purified by DMSO and
21
Synthesis of compounds [2]a,b
.
Benzoyl chloride or 4-nitrobenzoyl chloride
(0.02 mole) was added to a solution of reprecipitating from ethanol.

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S.SAEED et al., Orient. J. Chem., Vol. 34(1), 286-294 (2018)
(DMSO) followed by incubation in 37 °C for 15 min.
Biological Activity
Antibacterial activity
with shaking. The absorbance was measured on a
microplate reader at 620 nm .The rate of inhibition
of cell growth was calculated according to27 follow
equation.
Some of synthesized compounds have
been screend for antibacterial activities against
(Bacillus cereus and Esherichia coli) using
cup-plate agar diffusion method25. The zone
of inhibition measured in mm. Pencilin was
(50 µg /ml) were used as a standard drug for
antibacterial activity to compare with the activity of
the synthesized compounds.
Inhibition rate = mean of control-mean of treatment x 100 (1.1)
mean of control
RESULTS AND DISCUSSION
Scheme (1) summarized the performed
reactions in this work. The structure of compounds
[2]a,b were confirmed from its correct analytical and
spectral data . FT-IR spectrum of compound [2]b,
Fig. (3.1), showed21 appearance band at (1766) cm-1
due to the carbonyl group of cyclic ester, (1666,
1614) cm-1 due to the C=N group and (1585) cm-1
Cytotoxicity Assay
Preparation of Cell Lines for Cytotoxicity Assay26
Fifteen modified PVA compound with
different sizes and concentrations were screened
for their anticancer activity and cytotoxicity by using
cultured cells in microtiter plate (96 wells).The assay
was applied by the following steps:
1
due to the C=C group. The H-NMR spectrum of
compound [2 ]b , Fig. (3.2) display the following
characteristic chemical shifts , (DMSO) ppm : the
aromatic ring protons of compound [2]b appeared
as multiple at δ (6.41-8.64) ppm .
A-Seeding: When cells in the incubated
falcon became monolayer, the confluent monolayer
was trypsinzed to get single cell suspension. A
liquot 200 µl/104-105 cells/well from single cell
suspension then were added to all the 96 wells of
the microtiter plates, which covered by plate lids
and sealed with adhesive parafilm. The plate was
shaked gently and returned to the incubator.
N-phthaloyl amino acid derivative [3-7]a-i
using economical experimental conditions via
reaction Malic anhydride , phthalic anhydride , nitro
phthalic anhydride, 2-phenyl-4H-benzo[d] [1,3]
oxazin-4-one, 2-(4-nitrophenyl)-4H-benzo[d] [1,3]
oxazin-4-one and different amino acids namely[1]a-i,
glycine, alanine, valine , leucine , isoleucine, serine,
threonine, tyrosine and Phenyl alanine in (15 ml.)
of glacial acetic acid , then mixture was refluxed for
(5 h) . The mechanism28. involves nucleophilic
addition reaction, as follows scheme (3.1).
B-Incubation: Microtiter Plates were then
incubated in humidified chamber at 37 °C, 5% CO2
until the cells reached confluence (i.e., vary
according to the type of cell line). The plate was
checked out for contamination , after cells
attachment
C- Exposure: When the cells are in full of
its activity, they were expose.d to three
concentrations of the fifteen modified of PVA µg/ml
for cell line . Aliquot of 200 µl of each concentration
were pipette into each well, while 200 µl of
maintenance medium were added to each well of
control group, then plates were sealed with
adhesive parrafilm and returned to the incubator.
Evaluation of cytotoxicity was carried out after
48hours.The photo picture were taken after 24 hours.
D- Staining: Cell viability was measured
after 48 h of exposure by removing the medium,
adding 20 µl/well solution of MTT and incubating
for 4 h at 37 °C. The crystals remaining in the wells
were solubilized by the addition of 200 µl/well of
Fig. 1. The mechanism of preparing compound (3-7)a-i

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S.SAEED et al., Orient. J. Chem., Vol. 34(1), 286-294 (2018)
The structure of compounds [3-7]a-i was
confirmed from its correct analytical and spectral
data, FT-IR spectra of compounds [5]a,i,
Fig. [(3.3),(3.4)], showed22 bands at (3300-2400)
cm-1 for (OH) of carboxylic acids, (1780,1735) cm-1
due to two (N-C=O), (1699) cm-1 for (C=O) of
carboxylic acid .While1H-NMR spectrum of
compound [5]a, Fig. (3.5) , showed characteristic
chemical shifts (DMSO-d6) ppm as follow: the
aromatic ring protons appeared as multiple at
δ (7.69-8.32) ppm and appearance singlet at δ (4.31)
ppm due to CH2 proton and singlet in the region of
δ 10.50 due to COOH proton.
N-phthaloyl amino acid chloride derivatives
[8-12]a-i through h the reaction of N- phthaloyl amino
acids [3-7]a-i with thionyl chloride in dry benzene
was refluxed for (7 h). A mechanism29 for this reaction
may be outlined as followed in scheme (3.2) .
O
O
O
Cl
S
O
Cl
Cl
O
S
O
N
O
H
N
O
H
Cl
O
O
O
O
Cl
Cl
O
O
S
S
N
O
O
N
O
H
O
H
Cl
O
O
Cl
The 1H-NMR spectrum of compound [5]i ,
Fig. (3.6) , display characteristic chemical shifts
(DMSO-d6) ppm as follow: the aromatic ring protons
appeared as multiple at δ (7.14-7.97) ppm and
appearance doublet signal at δ (3.14) ppm related
to CH2 proton and triplate signal at δ (3.99) due to
CH proton.
O
O
HCl +SO2
N
Cl
O
Fig. 2. The mechanism of preparing compound (8-12)a-i
Compound [10]b was characterized by
melting point and FT-IR spectrum . FT-IR spectrum
of compound [10]b , Fig. (3.10) , showed23 the
absence of absorption band at (1695) cm-1 and
(3392) cm-1due to (carbonyl , hydroxyl) group of
carboxylic acid and presence of band at (1761) cm-1
related to acyl chloride .
The FT-IR spectrum of compounds[7]c,
Fig. (3.7) showed disappearance of due to the
carbonyl group of cyclic ester at (1766) cm-1 and
appearance band at (1685) cm-1 due to carbonyl
group of carboxylic acid. Also, absorption bands at
(1643) cm-1, (1608) cm-1 and (1587) cm-1 due to
(C=O) of amide, (C=N) and (C=C) respectively .
The 1H-NMR spectrum of compound [7]c, Fig. (3.8),
showed characteristic chemical shifts (DMSO-d6)
ppm as follow: a singlet signal at δ (12.36) ppm for
proton COOH group, Many signals in the region
δ (7.19-8.73) ppm that could be attributed to
Chemical modification of Poly(vinyl
alcohol)[13-17 ]a-i was obtained by reaction of PVA
with compounds [8-12]a-i using the dimethyl
formamide.
aromatic protons. Also appearance doublet signal
The compounds [13-17 ]a-i were identified
by FT-IR spectrum . FT-IR spectrum of compound
[15]a , Fig. (3.11) illustrated the presence of a large
peak at 3390 cm−1 this peak is related to the
stretching of O–H from the intramolecular and
intermolecular hydrogen bonds, which seen at
2908 cm−1 and 2943 cm−1 respectively due to the
symmetric and asymmetric stretching vibrational of
C–H from alkyl groups 30, showed the disappearance
of absorption band at (1761) cm-1 due to acyl chloride
and appearance of absorption band at (1724) cm-1
due to carbonyl group of ester31 and appearance of
absorption bands at (C=O) of cyclic imide at
(1710-1778) cm-1.
at δ (4.13) ppm for proton CH-N group and many
signals in the region δ (1.88) ppm that could be
attributed to proton of CH in CH(CH3)2 and doublet
signal at δ (0.96) ppm is due to (CH3)2 group. Where
as 13C-NMR spectrum of compound [7]c, Fig. (3.9),
showed: a signal at δ (172.91) ppm could be
attributed to COOH group,while signal at δ (171.72) ppm
is due to carbon of C=O amide group. Signal atδ (164.45)
due to carbon of ph-C=N group. Many signal a δ (120-
140) ppm could be attributed to carbon of benzene ring.
Also signal at δ (59.1) ppm related to N-CH group. Signal
appeared at δ (58.2) ppm is related to carbon of CH in
CH(CH3)2. Two signal at δ (19.05-29.55)ppm could be
attributed to(CH3)2.

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The 1H-NMR spectrum of compound [13]a,
The UV-Vis spectrum of compound
[14]f, Fig. (3.14) shows the absorption peaks at
(332-402 ) may attributed to(π- π*) and (n-π*).
Fig. (3.12), showed32,33 the following characteristic
chemical shifts (DMSO-d ) ppm showed the
following signals: signal at δ 6(6.63) ppm for proton
(CH=CH) group, singlet peak at δ (4.48) ppm for
proton of (N-CH2)group, triplet peak at δ (4.24) ppm
for (CH)group and doublet peak at δ (1.37) ppm for
Biological Activity
Antibacterial activity
All the newly synthesized derivatives were
screened for their in vitro antimicrobial activity
against Escherichia coli , Bacillus cereus by
measuring the zone of inhibition in mm . Result
showed that compounds[6]f and [16]f exhibit some
antibacterial activity with penciline against E .coli
while compounds [15]f and [17]f showed
antibacterial activity closed to penciline against
Bacillus cereus . Resalts of all compounds all
compounds and their antibacterial activities listed
in Table. (3.4).
proton (CH2) group.
The 1H-NMR spectrum of compound [15]f,
Fig. (3.13), showed32,33 the following characteristic
chemical shifts (DMSO-d6) ppm showed the
following signals: many signals at δ (8.30-8.32)
ppm for proton aromatic protons.triplet peak at
δ (4.32-4.77) ppm for proton of (N-CH)group, doublet
peak at δ (3.99) ppm for protonCH2 in (CH2-OH), singelt
peak at δ (3.45) ppm for proton (OH) group, triplet peak at
δ (3.05) ppm for (CH-CH2) group and doublet peak at
δ (1.54) ppm for proton (CH2-CH) group .
Table. 1: FT-IR data of compounds[3-5]a-i
(C-H) arom. cm-1(C-H) aliph. cm-1 (C=O) imide. cm-1 (C=O) carboxlic
Com. No.
(O-H) cm-1
[3]a
[3]b
[3]c
[3]d
[3]e
[3]f
[3]g
[3]h
[3]i
[4]a
[4]b
[4]c
[4]d
[4]e
[4]f
3400-2400
3473
3053
3072
3066
3055
3075
3084
3093
3051
3086
3049
3080
3049
3109
3090
3089
3084
3088
3045
3089
3041
3115
3064
3024
3097
3026
2968-2879
2987-2873
2970-2890
2965-2877
2939-2855
2939-2872
2920-2850
2985-2939
2972-2926
2989-2883
2990-2951
2966-2890
3018-2990
2933-2877
2947-2885
2939-2872
2962-2893
2980-2943
2995-2941
2970-2881
2960-2860
2926-2854
2990-2889
3039-2926
2929-2856
1732-1770
1722-1784
1743-1782
1728-1770
1716—1774
1749-1772
1745-1774
1718-1735
1722-1780
1734-1780
1755-1786
1712-1761
1712-1764
1710-1772
1735-1776
1749-1772
1716-1772
1710-1770
1724-1784
1726-1784
1732-1782
1716-1780
1732-1776
1716-1780
1716-1734
1681
1691
1680
1690
1691
1697
1693
1685
1680
1683
1697
1691
1701
1696
1697
1697
1685
1662
1695
1690
1683
1683
1681
1690
1701
3392
3400-2400
3464
3462
3442
3400-2600
3400-2400
3344
3400-2400
3300-2400
3400-2600
3396
3394
[4]g
[4]h
[4]i
3462
3435
3392
[5]b
[5]c
[5]d
[5]e
[5]f
3392
3408
3400-2400
3400-2400
3398
[5]g
[5]h
3408
3400-2600

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S.SAEED et al., Orient. J. Chem., Vol. 34(1), 286-294 (2018)
Table. 2: FT-IR data of compounds[6,7]a-i
Com. No.
(O-H) cm-1
(C-H) arom. cm-1 (C-H) aliph. cm-1 (C=O) carboxlic (C=O) amid. cm-1
[6]
3442
3400-2400
3442
3049
3043
3061
3024
3064
3062
3064
3051
3062
3078
3082
3059
3057
3080
3061
3007
3061
2943-2895
2989-2933
2966-2879
2968-2889
2966-2877
3030-2951
2960-2883
2960-2887
2926-2858
2965-2879
2985-2858
2999-2854
2962-2875
2924-2850
2985-2856
2929-2827
2929—2856
1685
1683
1680
1697
1683
1683
1685
1685
1690
1681
1693
1689
1681
1689
1681
1690
1681
1643
1643
1645
1676
1645
1668
1643
1643
1654
1645
1655
1645
1640
1655
1647
1666
1668
[6]a
[6]b
[6]c
[6]d
[6]e
[6]f
[6]g
[6]h
[7]i
[7]a
[7]b
[7]d
[7]e
[7]f
[7]gh
[7]i
3433
3305
3400-2600
3400-2400
3300-2600
3400-2600
3502
3400-2400
3400-2600
3508
3498
3508
3300-2400
3508
Table. 3 :The inhibition zone of some
synthesized compounds
Compound
E .coli
(mm)
Bacillus cereus
mm
Peinciline
DMSO
[3]h
[13]h
[4]h
[14]h
[5]f
[15]f
[6]f
16
Nil
10
15
10
10
15
15
16
16
14
14
22
Nil
10
16
10
21
16
23
13
21
18
25
[16]f
[7]f
[17]f
Table. 4 :The inhibition zone of some
synthesized compounds
Compound
E .coli
mm
Bacillus cereus
mm
Penciline
DMSO
[3]h
[13]h
[4]h
[14]h
[5]f
[15]f
[6]f
16
Nil
10
15
10
10
15
15
16
16
14
14
22
Nil
10
16
10
21
16
23
13
21
18
25
[16]f
[7]f
[17]f
Fig. 3. Antibacterial activities of compounds
against E.coli

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S.SAEED et al., Orient. J. Chem., Vol. 34(1), 286-294 (2018)
Fig. 4. Antibacterial activities of compounds against Bacillus cereus
Fig. 6. Image of well after
Staining
Fig. 5. Image of before well
Staining
Fig.8. Image of plate after
Staining
Fig. 7. Image of plate before
Staining

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S.SAEED et al., Orient. J. Chem., Vol. 34(1), 286-294 (2018)
Fig. 10. SEM of compound[9]f
Fig. 9. SEM of compound[9]f
Anticancer activity
Chemical modification of Poly(vinyl alcohol) were
obtained by reaction of PVA with compounds using
the dimethyl formamide to give compounds. The
structure of the synthesized compounds was
characterized by their analytical and spectral data
as, IR spectra, 1H, 13C-NMR, Elemental analysis
(CHN), UV-Vis Spectroscopy, Scanning electron
microscopy (SEM), Antibacterial activity were
screened via two kinds of bacteria. Also, anticancer
activity were examined for most of the modified
polyvinyl alcohol.
Fifteen compounds modified polyvinyl
alcohol were selected for examend their anticancer
activity in Bio-technology research center,
Al-Nahrain University, Baghdad, Iraq. Two cell lines
were used (mice intestines carcinoma cell line L20b
and human pelvic rhabdomyosarcoma (RD).
according to the method described by Freshney26
Results are expressed in percentage. All
compounds except [17]b and [17]d showed more
than 50% inhibition for mice intestines carcinoma
cell line, while these compounds[17]b and [17]d
exhibit inhibition more than 50% inhibition for
human pelvic rhabdomyosarcoma.
ACKNOWLEDGMENTS
I would like to thank the University of
Baghdad- Faculty of Education (Ibn-Al-Haitham)
Department of Chemistry to help me for complete
this article.
CONCLUSION
Compounds react with SOCl2 in the
presence of benzene to produce compounds.
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