Bioorganic & Medicinal Chemistry Letters
Discovery of lesser known flavones as inhibitors of NF-
in MDA-MB-231 breast cancer cells—A SAR study
jB signaling
K. Amrutha a, Pandurangan Nanjan a, Sanu K. Shaji a, Damu Sunilkumar a, K. Subhalakshmi a,
Lakshmi Rajakrishna b, Asoke Banerji a,
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a Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri Campus, Clappana P.O., Kollam 690 525, Kerala, India
b Anthem Biosciences, No. 49, Canara Bank Road, Bommasandra Industrial Area, Phase 1, Hosur Road, Bangalore 560 099, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Seventeen flavonoids with different substitutions were evaluated for inhibition of nuclear factor-jB
Received 2 May 2014
Revised 18 June 2014
Accepted 31 July 2014
Available online 14 August 2014
(NF-
engineered MDA-MB-231 cell line reporting NF-
NF- B regulated genes involved in tumorigenesis, matrix metalloproteinase-9 (MMP-9), and cyclooxy-
genase-2 (COX-2) were also analyzed in these cells. Among the compounds tested, all except gossypetin
and quercetagetin inhibited the activation of NF- B, and the expression of MMP-9 and COX-2 to different
jB) signaling in the invasive breast cancer cell line MDA-MB-231. They were screened using an
jB activation. The modulation of expression of two
j
j
Keywords:
Methylated flavonoids
Chrysoeriol
Breast cancer
Metastasis
degree. Methylated flavone, chrysoeriol (luteolin-30-methylether), was found to be the most potent inhib-
itor of MMP-9 and COX-2 expressions. The effect of chrysoeriol on cell proliferation, cell cycle, apoptosis
and metastasis was analyzed by established methods. Chrysoeriol caused cell cycle arrest at G2/M and
inhibited migration and invasion of MDA-MB-231 cells. The structure–activity relations amongst the
flavonoids as NF-
of various flavonoids on NF-
in general, were more active than the corresponding flavonols.
j
B signaling inhibitors was studied. The study indicates differences between the actions
NF-
COX-2
jB
j
B activation and on the biological activities of breast cancer cells. Flavones
Ó 2014 Elsevier Ltd. All rights reserved.
The activation of NF-
j
B in the transformation of normal cells
action of methyl transferases. The plasma from rats fed with quer-
cetin (3) were devoid of it, but contained its 30-methyl ether viz.
isorhamnetin (7).5 Similarly, luteolin (10) is metabolized into its
methyl derivatives viz. diosmetin (40-methyl luteolin, 13) and
chrysoeriol (30-methyl luteolin, 12) in rats.6 We have screened
the bioactivities of methylated and lesser known flavonoids for
into cancer cells strongly suggests its role in tumorigenesis. It stim-
ulates the expression of numerous genes involved in the prolifera-
tion, apoptosis, metastasis, angiogenesis which lead to progress of
cancers. There are evidences that a large number of phytochemi-
cals prevent cancer by suppression of NF-j
B activation.1 Flavo-
noids, which are generally endowed with rich functionalities, are
potent bioactive molecules and occur in many vegetables and
fruits as important dietary factors for humans. Recently, flavonoids
have been recognized for many novel biological properties.2
Out of large number of naturally occurring flavonoids, quercetin
(3) is the most extensively studied molecule.3 Amongst other prop-
erties, it is known to inhibit the activation of transcription factor
their possible role in the inhibition of nuclear factor-jB (NF-jB)
signaling in the invasive breast cancer cell line MDA-MB-231 and
related activities. Limited availability of such compounds in nature
prompted us to develop diversity-oriented syntheses to generate a
library of methylated as well as hydroxylated flavones and flavo-
nols.7,8 In the present study, besides quercetin (3), 16 other flavo-
noids with varied substitutions were synthesized and evaluated for
NF-
j
B, and therefore the expression of NF-
j
B regulated genes such
the inhibition of NF-jB activation, and the expressions of MMP-9
as matrix metalloproteinase-9 (MMP-9) and cyclooxygenase-2
(COX-2) which are involved in the metastasis of many cancers. It
inhibits the migration and invasion of the breast cancer cell line
MDA-MB-231.4 It has been reported that at least in some cases
the active principles are not the flavonoids themselves, but the
metabolites generated as a result metabolic processes including
and COX-2. Chrysoeriol (30-methyl luteolin, 12) was found to be
the most potent transcriptional inhibitor of MMP-9 and COX-2.
This was followed by acacetin (11), 7,40-dihydroxy-30-methoxy fla-
vone (15), diosmetin (13) and quercetin (3). The effect of chrysoe-
riol (12) on various biological parameters that are important in
considering its therapeutic potential, such as cell viability, migra-
tion, invasion, cell cycle, and apoptosis were studied in the highly
invasive breast cancer cell line MD-MBA-231. The protective effect
of chrysoeriol (12) against doxorubicin-induced cardiotoxicity has
⇑
Corresponding author.
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.