Research Article

Cytotoxic Activity of Flavone Analogues

Afroze Alam1, U Farooq2, Kamlesh Kumar Naik3, Rashmi Singh4, Vachaspati
Dubey5, Monika Verma6, BD Tripathi7, Vinod Kumar8
Abstract
The flavonoids are polyphenolic compounds and universally present as constituents of flowering plants,
particularly of food plants. The flavonoids are phenyl substituted chroman (benzopyran derivatives) consisting
of a 15-carbon basic skeleton (C6-C3-C6), composed of a chroman (C6-C3) nucleus (the benzo ring A and
the heterocyclic ring C), also shared by the tocopherols, with a phenyl (the aromatic ring B), substitution
usually at the 2-position. Different substitutions can typically occur in the rings, A and B. Several plants
and spices containing flavonoid derivatives have found application as disease preventive and therapeutic
agents in traditional medicine in Asia for thousands of years. Various analogues of 3-methylflavones
were synthesised, purified and characterised by UV, IR, 1HNMR and mass spectrometry .All the synthesised
compounds were evaluated for their cytotoxic activity by MTT assay against HeLa cell line. Most of the
compounds show moderate activity, whereas the compounds like FA-04.FA-20,FA-10 and FA-13 have
shown good activity having IC50 value 22.00,25.49.26.24 and 26.35 µg/ml respectively, in comparison
to standard molecule Cisplastin had IC50 value 6- 12.5 µg/ml . Thus it appears the presence of 3- methyl
group in the flavone nucleus significantly influences the log ‘P’ value of all the twenty test compounds.

The prominent activity the of above compounds is probably because of 3-methyl and N, N-dimethyl amino
substitution on 4’- position of flavonoid nucleus.

Keywords: Benzopyrone, Cytotoxic activity, Flavonoids, HeLa cell line, log ‘P’ value, MTT assay

Success in the drug discovery is dependent on the ability to identity novel, patentable compounds collectively called
as New Chemical Entities (NCEs) that have potential to treat a disease in a safe and efficacious manner1

Benzopyrone class of compounds occurs in nature as flavones, isoflavones, neoflavones, coumarins, etc. Depending
upon type of lactone ring, benzopyrone are available as α-benzopyrone, β-benzopyrone and γ-benzopyrone. Among
them α-benzopyrone (coumarines) and γ- benzopyrone (flavones, isoflavones, and neoflavones) occurs widely in nature.

Introduction
Compounds having Chromones (γ-benzopyrone) moiety are associated with interesting physiological activities such
as antibacterial antiviral, anticancer ,antioxidant, antifungal, anticholestermic, anti- diabetics, anti-allergic diuretics
etc2. Flavonoids, the derivatives of chromones are polyhydroxylated compounds, and they are capable of selectively
reacting with free radicals or system related to the induction of inflammatory process. Quercetin (3, 3’, 4’, 5’, and
7- pentahydroxy flavones) and related flavonoids are known to inhibit the growth of tumor cell and potentiates the
cytotoxicity of DNA demanding anti - cancer drugs such as cis-plastin3. Very few reports are available on the influence
of lipophilic substitution on the antioxidants or anti-inflammatory activities of this class of natural products 4. Flavones
inhibit CYPIA-mediated 7-ethoxy resurufin o-dethylase activity in rat and human liver5 microsomes. Certain bromoflavones
are found to significantly induce quinine reductase activity, which is an important mechanism of chemoprevention6.On
study of an inhibitor from the class of xanthone, chromone and flavone reports are available in the literature to bear
aromatase7 inhibition properties. Cancer is the cause of more than six million deaths each year in the world. In 2001,

Narayan Institute of Pharmacy, Jamuhar, Sasaram (ROHTAS) 821305, Bihar, India.

1,4,5,7,8

2
Faculty of Dentistry, Taif University, Taif, Kingdom of Saudi Arabia.
3
Nandha College of Pharmacy, Perundurai Main Road, Erode, Tamil Nadu-638052, India.
6
Department of Paediatrics, Advance Paediatrics Centre, PGIMER, Chandigarh, Punjab-160012.

Correspondence: Afroze Alam, Narayan Institute of Pharmacy, Jamuhar, Sasaram (ROHTAS) 821305, Bihar India.

E-mail Id: afrozepharma@gmail.com

How to cite this article: Alam A, Farooq U, Naik KK et al. Cytotoxic Activity of Flavone Analogues. J Durg Dis Dev 2017; 1(1): 13-21.

© ADR Journals 2017. All Rights Reserved.

Alam A et al.
about 1,268,000 new cancer cases and 553,400 deaths
were reported in the United States8 .For a long time, plants
are being used in the treatment of cancer.9 According to
an estimate, 50% of breast cancer and 37% of prostate
cancer patients use herbal products.10
In current study, 20 derivatives of 3-methyl flavones have
been synthesized with various substitution on benzopyrone
nucleus. The starting material is taken as few substituted
propiophenone and substituted benzaldehyde. All the
synthesized compounds were purified, characterized and
evaluated for cytotoxic activity on the HeLa cell line.
Materials and Methods
Reagents
All the chemicals and solvents used were of AR-grade and
LR-grade and obtained from Sigma-Aldrich, Sisco Research
Laboratories, Qualigens, Rankem, S.D. Fine, Hi-Media and
Merck and were used without further purification.
Synthesis of Substituted 3-methyl Chalcones.11
To a solution of 0.01 mole of ortho hydroxy Propiophenones
in 10ml of 40% KOH and 20ml of ethyl alcohol, 0.01mole
of substituted benzaldehyde was added and mixture was
stirred for 48-72 hours. The coloured solution was poured
into crushed ice and acidified with 1N HCl . The precipitate
so obtained was washed with cold water, filtered, dried
and recrystallized with absolute alcohol .
Reaction
2
R 1
1 3
R R
DMSO -I 2
R OH
REFLUX
CH3
O
J. Durg. Dis. Dev. 2017; 1(1)
Experimental & TLC analysis
Melting points were determined on a melting point
apparatus (Shital Scientific Industries, Mumbai) and are
uncorrected. The reactions were monitored by Thin-layer
chromatography (TLC) was performed on pre-coated
aluminium plates (Silica gel 60 F254, Merck). Plates were
visualized by UV light and iodine vapour and the Rf values
were determined on pre-coated TLC using the solvent system
n-hexane; ethyl acetate (9: 1) .ƛ max ‘and € max for the
synthesized test compounds were obtained on a UV-visible
spectrophotometer (Shimadzu UV, Vis spectrophotometer
UV-1650 PC) in methanol (HPLC grade).The FTIR studies
were done on a ShimadzuFTIR8310 spectrophotometer as
KBr pellets. 1HNMR spectra were taken on a NMR (AMX 400)
in DMSO-d6 (Merck) and the mass spectra were recorded
on a GC-MS(Shimadzu GCMSQP5050 corporation Japan.)
Synthesis of Substituted 3-Methyl Flavones12 (FA1-
FA20)
To a solution of 0.01 mole of chacone in a 50 ml of dimethyl
sulphoxide (DMSO) taken in a 100ml of round bottom flask
,fitted with reflux condenser was added of 15-20 granules
of iodine. The reaction mixture was reflux for 3-4 hours and
kept overnight. The precipitate was neutralized with sodium
thiosulphate to remove unreacted I2 washed with water,
filtered, dried and recrystallized with absolute alcohol.
Percentage yield and other physical data are present in
Table No;3.
2
R
3
R R
R O
CH3
O
14
J. Durg. Dis. Dev. 2017; 1(1) Alam A et al.

General Scheme of Synthesis

1
R
OH O
2
OHC R
CH3
+
3
R
R
1. KOH, C 2H5OH,r.t.
2. HCl

R2
1 3
R R

R OH

CH3
O

DMSO/I 2

R2
1
R R3

R O

CH3
O

List of Synthesized Substituted Flavones

Table 2
Compound R R1 R2 R3
FA-01 H H H N(CH3)2
FA-02 H H H CH3
FA-03 H H H H
FA-04 OH H H N (CH3)2
FA-05 H CH3 H H
FA-06 H Cl H H
FA-07 H H H OCH3
FA-08 H H H OH
FA-09 OCH3 H H Cl
FA-10 H H H NO2
FA-11 H Br H H
FA-12 H H H Cl
FA-13 H H H F
FA-14 H H H Br
FA-15 OCH3 H H H
FA-16 H F H H
FA-17 OH H H CH3
FA-18 H OCH3 H H
FA-19 H H OCH3 H
FA-20 H OH H H

15
Alam A et al. J. Durg. Dis. Dev. 2017; 1(1)

Physical data of synthesised 3-methylflavones (FA1-FA20)

Table 3
Compound Yield (%) M.P. (0C) ƛ max € max Rf* LogP
FA-01 72 120-125 338.0 1.026x104 0.53 1.57
FA-02 80 125-132 339.0 1.524x104 0.44 1.34
FA-03 55 110-112 298.4 6.621x103 0.33 1.01
FA-04 65 160-170 339.0 1.707x104 0.83 1.22
FA-05 72 117-120 253.2 1.663x104 0.45 1.33
FA-06 90 95-100 282.4 5.450x104 0.57 1.03
FA-07 85 90-95 312.0 8.764x104 0.38 1.36
FA-08 60 105-108 225.0 8.496x104 0.86 0.93
FA-09 45 160-110 273.4 3.155x104 0.53 1.66
FA-10 85 65-75 235.0 7.785x194 0.33 1.20
FA-11 72 82-85 282.4 1.344x104 0.53 0.96
FA-12 88 70-75 281.8 1.689x104 0.44 1.03
FA-13 90 90-95 285.0 9.587x103 0.33 1.10
FA-14 85 120-125 278.8 1.203x104 0.83 1.05
FA-15 72 85-90 275.0 2.048x104 0.45 1.16
FA-16 65 139-142 292.4 1.944x104 0.77 0.94
FA-17 60 105-110 323.6 2.378x104 0.55 1.62
FA-18 60 129-132 347.4 2.405x104 0.54 1.12
FA-19 65 121-125 341.9 1.340x104 0.56 1.61
FA-20 60 115-120 312.8 2.620x104 0.43 0.91
The compounds gave satisfactory CHN data.
*Solvent system - n-hexane : ethyl acetate (9: 1)

Cytotoxic Activity.13-15 Experimental

MTT assay is a laboratory test and a standard colometric
assay (an assay which measures changes in colour) for
measuring cellular growth. It can also be used to determine
cytotoxicity of potential medicinal agents and other toxic
materials. Yellow MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-
diphenyl tetrazolium bromide, a tetrazole) is reduced
to purple formazan in the mitochondria of living cells. A
solubilisation solution (usually either dimethyl sulphoxide,
an acidified ethanol solution, or a solution of the sodium
dodecyl sulphate in dilute hydrochloric acid, 0.04N acidified
isopropyl alcohol is added to dissolve the insoluble purple
product into a coloured solution. The absorbance of this
coloured solution can be quantified by measuring at
wavelength (540 nm) by ELISA reader. This reduction takes
place only when mitochondrial reductase enzymes are
active, and therefore conversion can be directly related
to the number of viable (living) cells.
Add 100 μl of cells to a 96 well plate at a cell density of
5-10x 10 4 cells per well. Incubate (37 0C, 5% CO2) overnight
to allow the cells to attach to the wells. Flick off old media
.Add 100 μl of (drug+ media) solution in each well according
to dilution. Same volume also keeps of blank, positive &
negative control. Incubate (37 0C, 5% CO2) for next 48-
72 hr. to allow the cells to attach to the wells. Flick off
old media and add 100 μl (1 mg/ ml) of MTT. Plates are
incubate (37 0C, 5% CO2) for next 4hr.Flick off MTT and
insoluble formazan product is dissolved in100 μl of DMSO
.Leave at room temperature for a few minutes to ensure
all crystals are dissolved. Read plate using a wavelength of
540 nm. Be sure to read plates within one hour of adding
the DMSO. Reagents MTT (3-(4, 5-dimethylthiazol-2-yl)-2,
5-diphenyl tetrazolium bromide (Sigma #M2128): dissolve
at 1 mg/mL in PBS, filter and sterilize. PBS = Phosphate
buffer saline pH 7.4

16
J. Durg. Dis. Dev. 2017; 1(1) Alam A et al.

Growth inhibition of HeLa cells

Table 4
Compound % Growth inhibition
6.25µg/ml 12.50 µg/ml 25 µg/ml 50 µg/ml
FA-01 4.52 9.08 41.45 91.62
FA-02 3.67 12.38 4 2.25 88.18
FA-03 0.9 7.46 38.17 85.64
FA-04 6.56 18.85 73.00 93.85
FA-05 1.41 4.77 14.29 58.19
FA-06 2.96 13.88 22.56 39.48
FA-07 2.78 16.90 40.58 87.49
FA-08 1.30 5.50 21.43 39.82
FA-09 0.88 2.66 16.08 29.76
FA-10 3.70 17.54 40.03 86.64
FA-11 3.80 19.29 40.35 86.68
FA-12 4.30 7.00 37.72 91.80
FA-13 8.77 31.75 47.70 91.90
FA-14 5.85 33.90 58.00 82.10
FA-15 2.90 28.50 60.00 92.20
FA-16 0.90 07.00 31.90 75.20
FA-17 0.52 04.25 27.80 72.90
FA-18 0.67 03.19 25.70 89.50
FA-19 2.10 8.80 39.90 84.50
FA-20 7.25 16.90 40.50 90.75

All the synthesized test compounds (FA-01 – FA-20) were (CTC50(mcg/ml) ) of the all test compounds are enlisted
screened for their cytotoxic activity. They were screened in table no; 5.
by MTT assay method. The 50% cytotoxic concentration

17
Alam A et al. J. Durg. Dis. Dev. 2017; 1(1)

Table 5
Compounds CTC50(mcg/ml)
FA-01 46.89
FA-02 45.45
FA-03 43.41
FA-04 22.00
FA-05 44.32
FA-06 46.82
FA-07 34.56
FA-08 32.89
FA-09 33.56
FA-10 26.24
FA-11 30.41
FA-12 30.50
FA-13 26.35
FA-14 44.38
FA-15 49.92
FA-16 53.48
FA-17 55.40
FA-18 40.66
FA-19 43.94
FA-20 25.49

Results and Discussion compounds showed moderate cytotoxic activity against

Preparation of various substituted 3-mety chalcone
based on Claisen- Schmidt condensation20. The starting
materials for the synthesis of various substituted 3-
methyl chalcones were 2- hydroxyl propiophenone and
substituted benzaldehyde. Substituted 3-methyl flavones
were synthesized from respective chalcones in the presence
of DMSO/I2.The purified compound s after recrystallization
were determined for their purity, by melting point, thin
layer chromatography, and structure were established by
IR,1H-NMR, and Mass spectral studies. The yields of final
synthesized compounds were in the range of 60-90 %. ƛ
max and € max were found were found to be in the range
of 225-347nm and 6.621x103-8.49 x104 respectively.
HeLa cell line. All twenty test compounds showed CTC50
value between 22.00- 55.40 µg/ml. Enlisted in table no;5
The standard Cisplastin had a value of 6.5 - 12 µg/ml.
The test compounds FA-04, FA-20, FA-10, and FA-13
showed CTC50 value between 22.00 – 26.38 µg/ml. The
test compounds FA-11, FA-12, FA-08, FA-09, FA-07 and
FA-18 showed CTC50 value between 30- 40 µg/ml. The
test compounds FA-01, FA-02, FA-04, FA-05, FA-06, FA-14,
FA-15, and FA-19 CTC50 value between 40- 50 µg/ml. The
test compounds FA-17 and FA-16 CTC50 value between
50- 56 µg/ml.
Major Molecular Mechanism of Action

In the present work, effect of 3- methyl substitution on the
solubility of flavones was studied. Out of the twenty methyl
flavones subjected for ‘P’ value determination, almost all
of them showed log P value16-19 in the range of 0.912-1.66,
as shown in the table no.3. Thus, it appears the presence
of methyl group in the flavones significantly influences on
the ‘P’ value of all the twenty test compounds.
Cytotoxic studies was determined by MTT assay at a
wavelength 540 nm .All test compounds (FA1-FA20) were
screened for cytotoxic evaluation .Most of the test
Studies in vitro and in vivo have shown that some flavonoids
modulate the metabolism and disposition of carcinogens
and can contribute to cancer prevention.21–25.One important
mechanism by which flavonoids may exert their effects is
through their interaction with phase I metabolizing enzymes
(e.g., cytochrome P450), which metabolically activate a
large number of pro carcinogens to reactive intermediates
that can interact with cellular nucleophiles and ultimately
trigger carcinogenesis. Flavonoids are demonstrated to
inhibit the activities of certain P450 isozymes such as
CYP1A1 and CYP1A2, 26-27 Thus, they are likely to have a

18
J. Durg. Dis. Dev. 2017; 1(1)
protective role against the induction of cellular damage
by the activation of carcinogens. Another mechanism of
action is the induction of phase II metabolizing enzymes
such as glutathione-S-transferase, Quinone reductase,
and UDP-glucuronyl transferase,28-29 by which carcinogens
are detoxified and thus more readily eliminated from the
body. This would also help to explain the chemo preventive
effects of flavonoids against carcinogenesis. Moreover,
some flavonoids have been reported as potent aromatase
inhibitors.30-33 Substantial evidence supports the concept
that oestrogens be involved in mammary carcinomas.
Estradiol, the most potent endogenous oestrogen, is
biosynthesized from androgens by the cytochrome P450
enzyme complex called aromatase. Inhibition of aromatase
is an important approach for reducing growth stimulatory
effects of oestrogens in hormone-dependent breast cancer30
Therefore, flavonoids could be considered potential agents
against breast cancer through the inhibition of aromatase
activity.
Conclusion
Cytotoxic activities of all test compounds were evaluated.
All test compounds showed activity at all the concentrations
(6.25, 12.50, 25.00 50 µg/ml), probably because of
benzopyrone nucleus/flavonoids ring. According to the
literature review compounds isolated from plant sources
having benzopyrone / flavonoids ring show promising
cytotoxic34-36 activity. The distance between two phenyl ring
A and B of our test compounds is very much comparable
to that of flavonols, flavones, isoflavones and flavanones
(Flavonoids family) obtained from the natural products like
kaempferol, chrysin, daidzein and hesperitin respectively as
all are potent anticancer agents.34-36 The structural activity
relationship of our test compounds showed cytotoxic activity
based on above observation and their probable molecular
mechanism. Thus there is much evidence that flavonoids
have important effect on inhibitory carcinogenesis. Now
we conclude that flavonoids are generally non-toxic,
non-steroidal and manifest a diverse range of beneficial
biological activities.
Future Scope
3-methyl flavones may become the probable potential class
of compounds for future study. The recent reports available
on analogues of 3-methyl flavones for their glutathione
transferase37 and farnesyltransferase38 inhibitors, will
initiate our study to synthesize many more of such
substituted flavones and test them for such activity, there
is a future scope for the synthetic flavones to be targeted
for newer targets such as CYP- 450 aromatase to exploit
their anticancer activity.
Acknowledgement
Authors thank Saif Central Instrumentation Laboratory ,
19
Alam A et al.
Punjab University ,Chandigarh for getting spectral data,
like NMR and Mass spectra and School of Pharmaceutical
Sciences, Shoolini University for research facilities.
Spectral Data
FA-01 IR (KBr) cm-1 ( C-H) 2794 ,(Ar C=C ) 1599 ,(Ar C-H)
3019 ,(C-N )1290 cm-1
(C=O) 1660; , 1HNMR(400 MHz CDCI3 ); δ 2.80 (6H,s,H-
4”-N-( CH3)2 ), 6.53(2H,d H-3”,5”-H), 7.13 (2H, d, 2”,6”-H),
1.95(1H,S,3-H), 7.66(1H, d, 5’-H), 7.0 (1H, dd,6’- H), 7.36
(1H,dd, H-7’), 6.90 (1H, d, H-8’); GCMS :m/z 281(M+1).
FA-02: IR (KBr) cm-1:3178 (ArC-H), 2813 (C-H), 1680
(C=O), 1570 (C=C); , 1HNMR(400 MHz CDCI3 ); δ 2.40
(3H,s,H-4”- CH3) , 7.03(2H,d H-3”,5”-H), 7.23 (2H, d, 2”,6”-
H), 2.95(1H,S,3-H), 7.64(1H, d, 5’-H), 7.08 (1H, t,6’- H),
7.36 (1H,t, H-7’), 7.00 (1H, d, H-8’); ; GCMS :m/z 254 (M +2)
FA-03 IR (KBr) cm-1:3072 (ArC-H), 2800 (C-H), 1690 (C=O),
1580 (C=C); , 1HNMR(400 MHz CDCI3 ); δ 7.14 (3H,s,H-4”-H
), 7.21(2H,d H-3”,5”-H), 7.30 (2H, d, 2”,6”-H), 2.0(1H,S,3-H),
7.64(1H, d, 5’-H), 7.01 (1H, t,6’- H), 7.37 (1H,t, H-7’), 6.90
(1H, d, H-8’); GCMS :m/z 238 (M +1.).
F-4: IR (KBr): 3390 (O-H), 3100 (ArC-H), 2800 (CH),1682
(C=O), 1561 (C=C), 1312 (C-N); , 1HNMR(400 MHz CDCI3
); δ 2.70 (3H,s,H-4”-N-( CH3)2 ), 6.93(2H,d H-3”,5”-H), 7.20
(2H, d, 2”,6”-H), 2.09(1H,S,3-H), 7.54(1H, d, 5’-H), 6.88
(1H, t,6’- H), 5.0 (1H,s, H-7’), 6.390(1H, d, H-8’); ); GCMS
:m/z 295 (M+1).
FA-05 IR (KBr) cm-1 ( C-H) 2794 ,(Ar C=C ) 1589 ,(Ar C-H)
3029 ,(C=O) 1660; , 1HNMR(400 MHz CDCI3 ); δ 7.04
(3H,s,H-4”-H ), 7.02(2H,d H-3”,5”-H), 7.28 (2H, d, 2”,),
2.35(3H,s,H-6”), 2.05(1H,S,3-H), 7.64(1H, d, 5’-H), 7.03
(1H, t,6’- H), 7.34 (1H,t, H-7’), 6.90 (1H, d, H-8’); GCMS
:m/z 253 (M+1)
FA-06 IR (KBr) cm-1 ( C-H) 2867 ,(Ar C=C ) 1573 ,(Ar C-H)
3072 ,(C=O) 1690, (C-Cl ) 710. , 1HNMR(400 MHz CDCI3
); δ 7.04 (1H,t,H-4”-H ), 7.09(2H,t H-3”-H), 7.22 (1H, d, 5’’-
H), 7.24(1H,d,2”-H) 2.95(1H,S,3-H), 7.64(1H, d, 5’-H), 7.08
(1H, t,6’- H), 7.36 (1H,t, H-7’), 7.00 (1H, d, H-8’); GCMS
:m/z 273.5 (M+1).
FA-07 IR (KBr) cm-1 ( C-H) 2917 ,(Ar C=C ) 1570 ,(Ar C-H)
3080 ,(C=O) 1685, (C-O) 1209; , 1HNMR(400 MHz CDCI3
); δ 3.70 (3H,s,H-4”-O-( CH3) , 6.73(2H,d H-3”,5”-H), 7.22
(2H, d, 2”,6”-H), 1.95(1H,S,3-H), 7.64(1H, d, 5’-H), 7.08
(1H, t,6’- H), 7.36 (1H,t, H-7’), 7.00 (1H, d, H-8’); GCMS
:m/z 268 (M-2).
FA-08 IR (KBr) cm-1 ( C-H) 2907 ,(Ar C=C ) 1580 ,(Ar C-H)
3060 ,(C=O) 1675, (O-H)3310: , 1HNMR(400 MHz CDCI3
); δ 2.40 (1H,s,4”-OH ), 6.63(2H,d H-3”,5”-H), 7.13 (2H,
d, 2”,6”-H), 1.95(1H,S,3-H), 7.64(1H, d, 5’-H), 7.08 (1H,
Alam A et al.
t,6’- H), 7.36 (1H,t, H-7’), 6.92 (1H, d, H-8’); Molecular
ion peak at m/e = 253(M+)
FA-09 IR (KBr) cm-1 ( C-H) 2860 ,(Ar C=C ) 1560 ,(Ar C-H)
3092 ,(C=O) 1680, (C-Cl ) 700. (C-O) 1209 , 1HNMR(400
MHz CDCI3 ); δ 7.23(2H,d H-3”,5”-H), 7.23 (2H, d, 2”,6”-
H), 2.95(1H,S,3-H), 7.54(1H, d, 5’-H), 7.08 (1H, d,6’- H),
3.73 (3H,s,OC H3-7’), 6.40 (1H, d, H-8’); GCMS :m/z 306
(M+2).
FA-10 IR (KBr) cm-1 ( C-H) 2910 ,(Ar C=C ) 1565 ,(Ar
C-H) 3069 ,(C=O) 1680, (C-N) 1295, , 1HNMR(400 MHz
CDCI3 ); δ 8.03(2H,d H-3”,5”-H), 7.53 (2H, d, 2”,6”-H),
1.95(1H,S,3-H), 7.64(1H, d, 5’-H), 7.08 (1H, t,6’- H), 7.36
(1H,t, H-7’), 6.930 (1H, d, H-8’); GCMS :m/z 284 (M+1).
FA-11 IR (KBr) cm-1 ( C-H) 2854 ,(Ar C=C ) 1500,(Ar C-H)
3090 ,(C=O) 1718,(C-Br) 604, (Ar=C-H) 801, , 1HNMR(400
MHz CDCI3 ); δ 7.40 (1H,t,H-4” ), 7.33(2H,d H-3”,5”-H),
7.20 (2H, d, 2”-H), 1.95(1H,S,3-H), 7.64(1H, d, 5’-H), 7.08
(1H, t,6’- H), 7.36 (1H,t, H-7’), 7.00 (1H, d, H-8’); GCMS
:m/z 318 (M+2).
FA-12 IR (KBr) cm-1 ( C-H) 2807 ,(Ar C=C ) 1553 ,(Ar
C-H) 3172 ,(C=O) 1700, (C-Cl ) 700. 1HNMR(400 MHz
CDCI3 ); δ 7.23(2H,d H-3”,5”-H), 7.24 (2H, d, 2”,6”-H),
1.95(1H,S,3-H), 7.64(1H, d, 5’-H), 7.08 (1H, t,6’- H), 7.36
(1H,t, H-7’), 6.92 (1H, d, H-8’GCMS :m/z 274.5 (M+2).
FA-13 IR (KBr) cm-1 ( C-H) 2790 ,(Ar C=C ) 1508 ,(Ar
C-H) 3142 ,(C=O) 1710, (C-F ) 1198. , 1HNMR(400 MHz
CDCI3 ); δ 6.73(2H,d H-3”,5”-H), 7.27 (2H, d, 2”,6”-H),
1.95(1H,S,3-H), 7.64(1H, d, 5’-H), 7.08 (1H, t,6’- H), 7.3
(1H,t, H-7’), 6.91.00 (1H, d, H-8’); GCMS :m/z 257 (M+1).
FA-14 IR (KBr) cm-1 ( C-H) 2890 ,(Ar C=C ) 1550 ,(Ar
C-H) 3092 ,(C=O) 1700, (C-Br ) 698.( Ar=C-H) , 785; ,
1
HNMR(400 MHz CDCI3 ); δ 7.31(2H,d H-3”,5”-H), 7.19
(2H, d, 2”,6”-H), 1.95(1H,S,3-H), 7.64(1H, d, 5’-H), 7.08
(1H, t,6’- H), 7.36 (1H,t, H-7’), 7.00 (1H, d, H-8’); GCMS
:m/z 318 (M+2).
FA-15 IR (KBr) cm-1 ( C-H) 2920 ,(Ar C=C ) 1572 ,(Ar C-H)
3082 ,(C=O) 1680, (C-O) 1200 , 1HNMR(400 MHz CDCI3
); δ 7.14 (1H,t,H-4’’), 7.31(2H,dd H-3”,5”-H), 7.33 (2H,
d, 2”,6”-H), 1.94(1H,S,3-H), 7.54(1H, d, 5’-H), 6.52 (1H,
d,6’- H), 3.74 (3H,t, H-7’), 6.43 (1H, s, H-8’); GCMS :m/z
268 (M-2).
FA-16 IR (KBr) cm-1 ( C-H) 2810 ,(Ar C=C ) 1505 ,(Ar C-H)
3140 ,(C=O) 1719, (C-F ) 1200. , 1HNMR(400 MHz CDCI3
); δ 7.12 (1H,t,H-4”), 6.98(2H,d H-3”)6.92(1H,d,5”-H),
7.28 (2H, d, 2”-H), 1.95(1H,S,3-H), 7.64(1H, d, 5’-H), 7.08
(1H, t,6’- H), 7.36 (1H,t, H-7’), 7.00 (1H, d, H-8’); GCMS
:m/z 257 (M+1).
FA-17: IR (KBr) cm-1:3175 (ArC-H), 2803 (C-H), 1690 (C=O),
J. Durg. Dis. Dev. 2017; 1(1)
1570 (C=C); 3360 (ArO-H) , 1HNMR(400 MHz CDCI3 ); δ
2.40 (3H,s,H-4”- CH3) , 7.02(2H,d H-3”,5”-H), 7.16 (2H, d,
2”,6”-H), 1.95(1H,S,3-H), 7.47(1H, d, 5’-H), 6.48 (1H, d,6’-
H), 5. (1H,s,O H-7’), 6.39 (1H, s, H-8’); GCMS :m/z 254 (M +2)
FA-18 IR (KBr) cm-1 ( C-H) 2915 ,(Ar C=C ) 1576 ,(Ar C-H)
3109 ,(C=O) 1680, (C-O) 1206; 1HNMR(400 MHz CDCI3
); δ 7.03 (3H,t,H-4” ), 7.03(2H,d H-3”,5”-H), 7.23 (2H, d,
2”-H), 3.73(3H,s,6’’-H) 1.95(1H,S,3-H), 7.64(1H, d, 5’-H),
7.08 (1H, t,6’- H), 7.36 (1H,t, H-7’), 7.00 (1H, d, H-8’);
GCMS :m/z 268 (M-2).
FA-19 IR (KBr) cm-1 ( C-H) 2917 ,(Ar C=C ) 1570 ,(Ar C-H)
3086 ,(C=O) 1683, (C-O) 1208; 1HNMR(400 MHz CDCI3 );
δ 6.63 (3H,d,H-4” ), 7.10(2H,t H-3”)3.37(3H,s,,5”-H), 6.83
(1H, d, 2”-H), 6.80(1H,s,6’’-H) 1.95(1H,S,3-H), 7.64(1H, d,
5’-H), 7.08 (1H, t,6’- H), 7.36 (1H,t, H-7’), 7.00 (1H, d, H-8’);
;GCMS :m/z 268 (M-2).
FA-20 IR (KBr) cm-1 ( C-H) 2900 ,(Ar C=C ) 1584 ,(Ar C-H)
3064 ,(C=O) 1670, (O-H) 3300; 1HNMR(400 MHz CDCI3 );
δ 6.93 (1H,t,H-4” ), 6.77(2H,t H-3”)6.68(1H,d,5”-H), 7.13
(1H, d, 2”-H), 5.0(1H,s,6’’-H) 1.95(1H,S,3-H), 7.64(1H, d,
5’-H), 7.08 (1H, t,6’- H), 7.36 (1H,t, H-7’), 6.92 (1H, d, H-8’);
Molecular ion peak at m/e = 253(M+).
Conflict of Interest: None
References
1. Foye WO. Principle of Medicinal chemistry. 3rd Ed.
Verghese Publishing house, Bombay; 1989 .
2. Karle BK , Hangargo RV ,Mane AS, Gill CH , Shingare
MS. Ind. J. Hetrocyclic chem. 2001; 11: 81-82.
3. Fritz B ,Tobias S,Albrechts K, Charlotte B ,Kent C , Anni
A , Franz J Joseph K . American Soc. Biochem and Mol.
Bio. 1996 Jan ;271(4):2262-2270.
4. Finar IL. Organic Chemistry volume 2. 5th ED. Pearson
Education Asia Ltd.
5. Ahluwalia VK, Parashar RK. Organic reaction mechanism
and applications. 1st Ed .Narosa Publishing House.
6. Lynda LS , Jerome KW , Sang K, Lee CG , Dial L ,
Richard CM , Robert MM ,John MP . Cancer Research.
1991 Feb ;59.
7. Silvia G, Cavalli A. Cytochrome P450 aromatase
inhibitors. J.Med. Chem2006;49:4777- 4780.
8. Izevbigie EB (2003). Discovery of Water-Soluble
Anticancer Agents (Edotides) from a Vegetable Found in
Benin City, Nigeria. Exp. Biol .and Med. 228:293-298.c
9. Havsteen BH ( 2002). The biochemistry and medical
significance of the flavonoids. Pharmacol. Therap.96.
P. 67-202.
10. Richardson MA (2001). Biopharmacologic and herbal
therapies for cancer: research update from NCCAM.
J. Nut. 131:3037S–3040S.
11. Wolff ME . Burger ‘s Medicinal Chemistry and Drug
Discovery 5th Ed . John Wiley and Sons New York.
20
J. Durg. Dis. Dev. 2017; 1(1)
12. Finar IL. Organic Chemistry volume 2. 5th ED. Pearson
Education Asia Ltd.
13. Block, J. H.; Beale, J. M. Jr. Wilson and Gisvold’s Textbook
of thOrganic, Medicinal and Pharmaceutical Chemistry.
11 edition, Lippincott. Williams and Wilkins. 2004,
249,310.
14. Jeffrey M Edmondson, Linda S. Armstrong and
Andrew O Martinez. A Rapid and Simple MTT-Based
Spectrophotometric Assay For Determining Drug
Sensitivity In Monolayer Culture, Tissue Culture
Methods, 1988 11, 15-17,.
15. Rubinstein LV, Shoemaker RH, Paull KD, Sinon RM, Tosini
S, Skehan P, Scudiero A Monks, Boyd MR., Comparison
of in-vitro Anticancer Drug screening data generated
with Tetrazolium Assay Versus a Protein assay Against
a Diverse Panel of Human Tumor Cell Lines. Journal of
National Cancer Institute, 1990. 82 (13), 1113-1118,
16. http://ecb.jrc.it/DOCUMENTS/Testing-Methods/
ANNEXV/AO8web1992.pdf.
17. Selassie, C. D. History of Quantitative Structure-Activity
Relationship. Burger’s
th
Medicinal Chemistry and Drug
Discovery. Vol I. 6 edition. Wiley Intersciences 2003,
15-23.
18. Taylor, P. J. Hydrophobic Properties ofst Drug.
Comprehensive Medicinal Chemistry Vol IV. 1 Indian
edition. Pergamon Press Elsevier, 2005, 270-273 .
19. Beckett, A. H.;thStenlake, J. B. Practical Pharmaceutical
Chemistry. 4 edition part-II. CBS Publishers and
Distributors. 2005, 275-278.
20. Markandi JK , Shashi , Surender k. Ind .J. Chem. 2004
April 43B :895-896.
21. Wattenberg LW. Inhibition of carcinogenesis by
minor dietary constituents. Cancer Res 1992 ;52: Ther 2001;90: 157–177.
2085s–2091s.
22. Calomme M, Pieters L, Vlietinck A, Vanden Berghe D.
Inhibition of bacterial mutagenesis by Citrus flavonoids.
Planta Med 1996; 62: 222–226.
23. Dashwood RH, Xu M, Hernaez JF, Hasaniya N, Youn K,
Razzuk A. Cancer chemo preventive Mechanisms of
tea against heterocyclic amine mutagens from cooked
meat. Proc Soc Exp Biol Med 1999;220: 239–243.
24. Williamson G, Faulkner K, PlumbGW. Glucosinolates
and phenolic as antioxidants from plant foods. Eur J
Cancer Prev 1998;7:17–21.
25. Carroll KK, Guthrie N, So FV, Chambers AF. Anticancer
properties of flavonoids, with emphasis on citrus
flavonoids. In: Rice-Evans CA, Packer L, editors.
Flavonoids in health and disease. New York:
MarcelDekker Inc.; 1998. p 437–446.
26. Lahiri-Chatterjee M, Katiyar SK, Mohan RR, Agarwal R.
21
Alam A et al.
A flavonoid antioxidant, Silymarin, afford exceptionally
high protection against tumor promotion in the
SENCAR mouse skin tumorigenesis model. Cancer
Res 1999;59:622–632.
27. Tsyrlov IB, Mikhailenko VM, Gelboin HV. Isozyme- and
species-specific susceptibility of cDNA expressed CYP1A
P-450s to different flavonoids. Biochim Biophys Acta
1994; 1205: 325–335.
28. Bu-Abbas A, Clifford MN,Walker R, Ioannides C.
Contribution of caffeine and flavanols in the induction
of hepatic Phase II activities by green tea. Food Chem
Toxicol 1998; 36: 617–621.
29. Sun XY, Plouzek CA, Henry JP,Wang TT, Phang JM.
Increased UDP-glucuronyl transferase activity and
decreased prostate specific antigen production
by biochanin A in prostate cancer cells. Cancer
es1998;58:2379–2384.
30. Brueggemeier RW. Aromatase, inhibitors, and breast
cancer. Am J Ther 2001;8: 333–344.
31. Pouget C, Fagnere C, Basly JP, Besson AE, Champavier
Y, Habrioux G, Chulia AJ. Synthesis and aromatase
inhibitory activity of flavanones. Pharm Res 2002;19:
286–291.
32. Jeong HJ, Shin YG, Kim IH, Pezzuto JM. Inhibition of
aromatase activity by flavonoids. Arch Pharm Res1999;
22: 309–312.
33. Wang C, Makela T, Hase T, Adlercreutz H, Kurzer MS.
Lignans and flavonoids inhibit aromatase enzyme in
human preadipocytes. J Steroid Biochem Mol Biol
1994;50: 205–212.
34. Birt DF, Hendrich S, Wang W. Dietary agents in cancer
prevention: Flavonoids and Isoflavonoids. Pharmacol
35. Wang HK. The therapeutic potential of flavonoids.
Expert Opin Invest Drugs 2000;9:2103–2119.
36. Le Marchand L. Cancer preventive effects of
flavonoids—A review. Biomed Pharmacotherapeutics
2002;56:296–301.
37. Viljanen Johan, Tegler Lotta Broo, IFM, Department of
Organic Chemistry, Linkoeping University Linkoeping,
Swed. Bioconjugate Chemistry. American Chemical
Society. 2004;15(4): 718-727.
38. Park J, Giew A. Computer-Aided Molecular Design
Laboratory, Mayo Clinic College of Medicine, Rochester,
MN, USA. Journal of Combinatorial Chemistry ,2004;
6(3):407-413.
Date of Submission: 2017-11-29
Date of Acceptance: 2017-12-30