Synthesis and biological activity of flavanone derivatives

Article abstract of DOI:10.1016/j.bmcl.2010.07.090

A series of new flavanone derivatives of farrerol was synthesized by a convenient method. The in vitro anti-tumor activity of these compounds was evaluated against human Bel-7402, HL-60, BGC-823 and KB cell lines, the protein tyrosine kinase (PTK) inhibitor activity was also tested. Their cytoprotective activity was tested using hydrogen peroxide (H₂O₂)-induced injury in human umbilical vein endothelial cells. Their in vitro anti-atherosclerosis activity was tested on vascular smooth muscle cells by the MTT method using tetrandrine as a positive contrast drug. The structures of all compounds synthesized were confirmed by ¹H, ¹³C NMR and ESI-MS. Most of the compounds exhibited good pharmacological activity and the preliminary structure-activity relationships were described.

Full text of DOI:10.1016/j.bmcl.2010.07.090

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5466–5468
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological activity of flavanone derivatives
Lei Shi a, Xiu E Feng a, Jing Rong Cui b, Lian Hua Fang c, Guan Hua Du c, Qing Shan Li a,b,
*
a School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, China
b State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100083, China
c Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new flavanone derivatives of farrerol was synthesized by a convenient method. The in vitro
anti-tumor activity of these compounds was evaluated against human Bel-7402, HL-60, BGC-823 and
KB cell lines, the protein tyrosine kinase (PTK) inhibitor activity was also tested. Their cytoprotective
activity was tested using hydrogen peroxide (H2O2)-induced injury in human umbilical vein endothelial
cells. Their in vitro anti-atherosclerosis activity was tested on vascular smooth muscle cells by the MTT
method using tetrandrine as a positive contrast drug. The structures of all compounds synthesized were
confirmed by 1H, 13C NMR and ESI-MS. Most of the compounds exhibited good pharmacological activity
and the preliminary structure–activity relationships were described.
Received 2 April 2010
Revised 29 June 2010
Accepted 21 July 2010
Available online 25 July 2010
Keywords:
Synthesis
Flavanone derivatives
Anti-tumor activity
PTK inhibitor
Ó 2010 Elsevier Ltd. All rights reserved.
VSMC anti-vegetation activity
Cytoprotective activity
Flavanone is an important natural compound with significant
potential to cure, treat and prevent tumor, senescence and cardio-
vascular diseases. Flavanones have been a potential source in the
search for lead compounds and biologically active components
and have been the focus of much researches and development in
the last 30 years.1,2 Flavanone and 2-OH flavanone markedly inhib-
ited the invasion, motility and cell-matrix adhesion of A549 cells.3
Lavandulyl flavanones showed potent b-secretase inhibitory activ-
ity which was strongly implicated in the cause of Alzheimer’s dis-
ease.4 Naringin has been shown to play a role in preventing the
development of cardiovascular disease.5 However, biological utili-
zation rates are low because of their low content in natural prod-
ucts, which limits flavanone applications.6 Thus, investigation of
synthetic routes and chemical modification is a new direction in
flavanone research. Furthermore, structure–activity relationship
(SAR) studies of flavonoids are hampered by their structural diver-
sity and the different mechanisms of their effects. Thus, SAR of
flavanones is also an important area of research.
farrerol derivatives, as well as the primary SAR. To investigate
the positional effects of different groups on the B ring (Fig. 1) on
bioactivity, compounds were prepared using a straightforward
chemical approach, as shown in Scheme 1.
In a typical synthetic procedure, m-xylene was subjected to a
nitration reaction using a mixture of hydrochloric acid and nitric
acid to produce 1. Compound 1 was mixed with Sn powder and
hydrochloric acid and stirred at 60 °C until the solid was completely
dissolved. The mixture was then heated at 100 °C for 3 h. The pH of
the solution was adjusted to 3–4 by adding 40% NaOH and the solu-
tion was then refluxed for 24 h to afford 3. To a solution of compound
3 in acetonitrile, zinc chloride and HCl gas were added and the solu-
tion was reacted at 0 °C until a solid was produced. The solid was
redissolved in water and the solution was refluxed for 30 min to
yield 4. Finally, 4 was reacted with benzaldehyde, which has a differ-
ent substituent group, and boracic acid in ethylene glycol at 130 °C
to yield the target compounds.10–13
Generally the flavanone compounds could be prepared by
the method used in this article and by the Claisen–Schmidt
Farrerol is a flavanone-type compound and thus may have po-
tential anti-hypertension and anti-atherosclerosis uses.7,8 In recent
research, our team found that farrerol has good in vitro anti-tumor
activity against SGC-7901 cells in a time and dose-dependant man-
3'
ner. The IC50 value is 40 0.4 l
M for 24 h.9 These interesting phar-
2'
4'
macological activities prompted us to design a novel series of
flavanone derivatives in attempt to improve their activity. Here,
we report on the synthesis and in vitro activity of a series of
B
5'
O
C
7
2
6'
A
5
3
O
* Corresponding author. Tel.: +86 351 4690322; fax: +86 351 4690114.
E-mail address: qingshanl@yahoo.com (Q.S. Li).
Figure 1.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.07.090

L. Shi et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5466–5468
5467
O2N
NO2
b
HO
OH
c
H2N
NH2
a
NO2
1
OH
3
NH2
2
R1
HO
OH
O
HO
OH
HO
O
d
e
OH
4
O
OH
3
OH
5
Scheme 1. Reagent and conditions: (a) HCl (37%), HNO3 (69%), HNO3 (98%), 110 °C, 87%; (b) Sn powder, HCl (37%), 90–100 °C; (c) NaOH, reflux, 24 h, 62%; (d) CH3CN, ZnCl2,
HCl (gas), 0 °C, reflux, 58%; (e) EG, boracic acid, 130, 3 h, 20–30%.
Table 1
condensation. We tried the above two methods to synthesize the
In vitro anti-tumor activities of compounds 5a–5p (0.1 l )
mol LÀ1
target compounds. Compared with the Claisen–Schmidt conden-
sation, the method used here has less steps with only one col-
umn chromatography step to obtain the target compounds, and
the corresponding yield is similar to that obtained by the Clais-
en–Schmidt condensation method. So, we chosed this method to
prepare flavanone derivatives.
To examine the changes of bioactivity resulting from different
substituents and positions of the B ring, different benzaldehyde
was used to yield the target compounds. To investigate the effect
of changing the B ring to a heterocycle on bioactivity, different het-
erocyclic aldehydes were used to synthesize the target compounds
according to the method described in Scheme 1. The structures of
target compounds were described in Scheme 2.
Compound
IR (%)
HL-60
BGC-823
Bel-7402
KB
28.32
Cisplatin
5a
5b
5c
5d
5e
5f
5g
5h
5i
52.33
À3.37
À6.47
À4.04
À4.85
7.65
75.83
À23.52
À6.69
À7.60
À19.81
À22.45
36.98
À7.41
52.00
À28.89
4.85
35.76
À6.53
À1.80
À5.48
À7.68
À7.10
18.70
2.05
27.18
15.15
2.54
3.27
11.59
6.45
À7.21
44.54
28.66
45.30
15.89
28.63
À9.11
29.04
À11.99
À18.83
À26.34
16.07
10.47
3.64
2.94
À0.46
À6.16
8.52
À1.29
12.96
10.82
11.39
NDa
5l
5m
5n
5o
À9.68
50.71
1.67
As presented in Table 1,14 Compounds 5f, 5h exhibited signifi-
cant cytotoxic activity against all of the human tumor cell lines ex-
cept for the leukemia cell line HL-60, confirming the importance of
ortho electron-withdrawing groups on the B ring for flavonoid
cytotoxicity. Comparison of the activity of 5e, 5g and 5i suggests
that substitution of a para electron-withdrawing group or an elec-
tron-donating group decreases this activity. In addition, a hydroxy
group plays an important role in the anti-tumor activity of these
compounds. KB tumor cells seemed more sensitive to compounds
with a single hydroxy group on the B ring in the ortho- or meta-po-
sition, as shown in compounds 5b–c. A single para-substituted
analog had lower anti-tumor potency compared with these of the
other compounds. These results suggested that ortho and meta sub-
stituents may be crucial for anti-tumor activity.
5p
13.51
2.63
a
ND = Not detected.
The protein tyrosine kinase (PTK) plays critical roles in many of
the signal transduction processes that control cell growth, differen-
tiation, mitosis and apoptosis. So the inhibitory activity of PTK was
believed to have the potential activity of anti-tumor.15 In Table 2,16
most of the compounds show certain activity, but Compounds 5e
and 5g were inactive. Meanwhile, the heterocycle substituted ana-
log, compounds 5m, 5n and 5o have no activity on this assay. But
compared to the results in Table 1, 5n exhibited significant
Compd
5c
R1
R1
Compd
5d
R1
R1
Compd
5a
Compd
5b
HO
OH
OH
OH
Cl
OH
O2N
Cl
NO2
5h
5l
5f
5j
5g
5k
5o
5e
5i
O
O
O
O
O
OH
H
N
O
S
5p
5n
5m
Scheme 2. Target compounds.

5468
L. Shi et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5466–5468
Table 2
Inhibitory activity of PTK
HUVEC injury provokes VSMC vegetation. However, abnormal
and excessive proliferation of VSMC plays a critical role in the gen-
esis and development of hypertension and atherosclerosis.19,20 It is
interesting that we found that 5h and 5m exhibited high cytopro-
tective activity against HUVEC injury and good VSMC anti-vegeta-
tion activity. Thus, these compounds may be potent and specific
therapeutic agents for cardiovascular disease.
In summary, a number of new flavanone derivatives were syn-
thesized and evaluated for their in vitro anti-tumor activity and
five compounds displayed good activity. Cytoprotective activity
of the compounds on H2O2-induced HUVEC injury and in vitro
VSMC anti-vegetation activity was also assayed, and the results
showed that some compounds exhibited promising activities. Fur-
ther in vivo tests of the compounds are under way.
Compound
PTK inhibitor
Compound
PTK inhibitor
activity IC50 (lM)
activity IC50
(
l
M)
5a
5b
5c
5d
5e
5f
>200
55
51
>50
—
>50
—
5i
5j
5k
5l
5m
5n
5o
Genistein
>100
>100
a
—
>200
—
—
—
13.6
5g
5h
>50
a
— = inactive.
Table 3
In vitro VSMC anti-vegetation activity and cytoprotective activity against H2O2-
induced HUVEC injury
Acknowledgements
Financial supports form the National ‘863’ program of China
(No. 2006AA09Z446), from the State Key laboratory of Natural
and Biomimetic Drugs, Peking University and Shanxi Foundation
for overseas returned, by the Program for the Top Young and Mid-
dle-aged Innovative Talents of Higher Learning Institutions of
Shanxi Province and from the innovative program of Shanxi Med-
ical University (No. 38) is gratefully acknowledged.
Compound
VSMC anti-vegetation
Cytoprotective
activity EC50 (lM)
activity IC50
(l
M)
a
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
—
>20
>20
>20
>20
>50
>20
>20
>5
—
—
—
—
>20
—
9.9
>100
—
Supplementary data
—
>20
—
Supplementary data (experimental procedures and character-
ization data for all final compounds) associated with this article
can be found, in the online version, at doi:10.1016/j.bmcl.2010.
07.090.
—
>100
6.7
—
—
>100
1.48
>20
>20
>50
>10
—
Tetrandrine
NDb
References and notes
a
— = inactive.
ND = Not detected.
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