COMMUNICATION
Novel synthetic luteolin analogue-caused sensitization of tumor necrosis
factor-a-induced apoptosis in human tumor cells†
Lili Cheng,a Huiling Tan,b Xiaoyu Wu,a Ruijun Hu,a Carlin Aw,a Min Zhao,b Han-Ming Shen*b and
Yixin Lu*a,c
Received 12th August 2008, Accepted 24th September 2008
First published as an Advance Article on the web 9th October 2008
DOI: 10.1039/b813904k
Studies on the sensitization, by novel alkynyl luteolin ana-
logues, of TNF-a-induced apoptosis in HeLa and HepG2 cells
revealed that LA-12 showed better sensitizing effects on TNF-
a-induced cell death than luteolin, suggesting great potential
for alkynyl luteolin analogues in cancer therapy.
Luteolin is an important member of the flavonoid family, and
has been shown to exhibit anti-mutagenic,1 anti-inflammatory,2,3
and antioxidant4 activities. Recently, luteolin has attracted much
Fig. 1 Structures of luteolin and its analogues.
attention as a potential anti-cancer and anti-proliferative agent.
The hydroxy groups at C-3¢ and C-4¢ are deemed to be less
important,14 and we intended to delete these groups and install
a series of alkynyl groups at the C-4¢ position. Alkynes are useful
building blocks for unsaturated molecular scaffolds because of
their rigid structures and conjugating p systems. Alkynes are
surprisingly common in natural products that have been isolated
from plants and marine organisms, and they are also common
motifs in drugs e.g. enediyne antibiotics and contraceptive pills.
Furthermore, the unsaturated, high-energy carbon–carbon triple
bond makes alkyne an attractive functional group for further
derivation by many synthetic transformations.15 We anticipated
that the above described modifications to the luteolin could result
in novel analogues with interesting activity profiles.
The synthesis of luteolin analogues is outlined in
Scheme 1. 2¢,4¢,6¢-Trihydroxyacetophenone was protected as its
methoxymethyl ether (1). 4-Iodobenzaldehyde, which was readily
prepared from 4-iodobenzoic acid, then underwent aldol con-
densation with ketone 1 to afford chalcone 2. The cyclization
of 2 proceeded efficiently in the presence of 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) to yield the key intermediate
4¢-iodoflavone (3), which was then subjected to Sonogashira
couplings with various terminal alkynes, followed by deprotection,
to generate a series of desired luteolin analogues (LA-1 to LA-16).
The Sonogashira coupling under conventional thermal heating
conditions was very sluggish, and carrying out the reactions under
microwave irradiation16 greatly shortened the reaction time, and
provided much cleaner product.
The potential of luteolin in cancer therapy was demonstrated by
its inhibition of DNA topoisomerase I and II.5,6 Ko et al. also
showed that luteolin was effective at the inhibition of proliferation
and induction of apoptosis in human myeloid leukemia cells.7 Very
recently, the potential uses of luteolin as an anti-tumor agent in
prostate, colon, lung and mammary cancers were studied.8–11
Tumor necrosis factor (TNF) is a proinflammatory cytokine
with a wide spectrum of functions in many biological processes,
including cell growth, death and development, oncogenesis, im-
munity, and inflammatory and stress responses.12 Recently, we
reported that luteolin could significantly sensitize TNF-a-induced
apoptotic cell death in a number of human cancer cell lines,13
which demonstrated a novel anti-cancer effect of luteolin and
supported its potential application in cancer therapy. Herein,
we wish to report the discovery of a novel luteolin analogue
that possesses enhanced sensitizing effects on TNF-a-induced
apoptosis in human tumor cells.
Structure–activity relationship (SAR) studies on luteolin have
been very limited. More extensive studies on luteolin structural
analogues would be highly desirable due to its biological im-
portance. In our design of novel luteolin analogues (Fig. 1), we
decided to keep the core structural scaffold of luteolin (rings
A, B and C) intact to maintain the key biological activities of
luteolin. The two hydroxy groups at the C-5 and C-7 positions were
also kept as they are generally important in flavonoid activities.14
The luteolin analogues that we intended to synthesize are illus-
trated in Fig. 2. Alkynes are readily available, making structural
variations straightforward. In addition, we also prepared a number
of aromatic alkynes (alkyne moieties in LA-2, LA-4, LA-6, LA-9
and LA-11) following the literature procedure.17 Various aliphatic
alkynes which contained long alkyl chain, cycloalkyl, hydroxyalkyl
or ether structures were incorporated into the synthetic luteolins.
To examine the effects of aromatic alkynyl moieties in the luteolin
analogue structures, neutral, electron-deficient, electron-rich and
heteroaromatic (4-pyridine, imidazole) alkynes were used in the
Sonogashira coupling reactions.
aDepartment of Chemistry, National University of Singapore, 3 Science
Drive 3, Singapore, 117543, Republic of Singapore. E-mail: chmlyx@nus.
edu.sg; Fax: +65-6779-1691; Tel: +65-6516-1569
bDepartment of Community, Occupational and Family Medicine, Yong Loo
Lin School of Medicine, National University of Singapore, 16 Medical Drive,
Singapore, 117597, Republic of Singapore. E-mail: cofshm@nus.edu.sg;
Fax: (+65) 6779-1489
cMedicinal Chemistry Program, Life Sciences Institute, National University
of Singapore, Republic of Singapore
† Electronic supplementary information (ESI) available: Experimental
procedures and characterization of the novel luteolin analogues; details
of the cytotoxicity studies and sensitization experiments; 1H NMR spectra
of the products. See DOI: 10.1039/b813904k
4102 | Org. Biomol. Chem., 2008, 6, 4102–4104
This journal is
The Royal Society of Chemistry 2008
©
Cheng, Lili
