Effects of α-substitutions on structure and biological activity of anticancer chalcones

Article abstract of DOI:10.1016/j.bmcl.2006.08.065

Chalcones are known to exhibit antimitotic properties caused by inhibition of tubulin polymerisation. We describe here the effects of different α-substitutions, in particular α-fluorination, on the structure and biological activity of a series of chalcones.

Full text of DOI:10.1016/j.bmcl.2006.08.065

Bioorganic & Medicinal Chemistry Letters 16 (2006) 5844–5848
Effects of a-substitutions on structure and biological
activity of anticancer chalcones
b
b
Nicholas J. Lawrence,a,b, Richard P. Patterson, Li-Ling Ooi,
*
Darren Cookc and Sylvie Duckic
aDrug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, Department of Interdisciplinary Oncology,
University of South Florida, Tampa, FL 33612-9497, USA
bSchool of Chemistry, Cardiff University, PO Box 912, Cardiff CF10 3TB, UK
cCentre for Molecular Drug Design, Cockcroft Building, University of Salford, Salford M5 4WT, UK
Received 28 June 2006; revised 11 August 2006; accepted 12 August 2006
Available online 1 September 2006
Abstract—Chalcones are known to exhibit antimitotic properties caused by inhibition of tubulin polymerisation. We describe here
the effects of different a-substitutions, in particular a-fluorination, on the structure and biological activity of a series of chalcones.
Ó 2006 Elsevier Ltd. All rights reserved.
Chalcones, 1,3-diarylprop-1-enones, are a class of com-
pounds consisting of two aryl rings linked by an a,b-un-
saturated ketone moiety. The ease of synthesis of
chalcones, from substituted benzaldehydes and acetoph-
enones, makes them an attractive drug scaffold. Some
chalcones are natural products found in various plant
species around the world and in the last decade or so
they have been shown to display a wide range of medic-
inal properties including antiinflammatory,1 anti-malar-
ial,2 antibacterial3 and anticancer4–7 effects.
products paclitaxel and vincristine. Another important
tubulin-binding ligand is colchicine. Many small mole-
cules are known to bind at the colchicine site of tubulin.
These include combretastatin A4,8 its amide derivative
AVE8062,9 ZD6126.10 The compounds cause selective
damage to tumour vasculature, an effect that is related
to their tubulin-binding properties.11,12 In this way
tumours are starved of oxygen and nutrients and their
constituent cells die. Compounds such as these that
target tumour vasculature clearly have significant clini-
cal promise for the treatment of cancer. The tubulin
molecule has three known binding sites, which are
identified by the natural products known to bind to
them: TaxolÒ and its derivatives bind to one site and
prevent the depolymerisation of microtubules, vinca
alkaloids such as vincristine bind to another site and col-
chicine binds to the third. Chalcones, which are structur-
ally similar to colchicine, are believed to bind to the
latter.
The anticancer activity of certain chalcones is believed
to be a result of binding to tubulin and preventing it
from polymerising into microtubules. Tubulin exists as
a heterodimer of two homologous a- and b-subunits.
This dimer can couple together to make profilaments
consisting of alternating a and b units, 12 or more pro-
filaments can then further link together to form pipe-like
structures called microtubules. These structures play an
important role in a number of biochemical processes vi-
tal to cell survival and growth, one of these is the forma-
tion of the mitotic spindle, without which mitosis would
not be able to take place.
Work within our own group has led to the discovery of a
number of potent chalcones, particularly 1 and 2 with
cytotoxicities of 4.3 and 0.21 nM, respectively.4 We
believe that the a-methyl analogue is more active since
it adopts an s-trans conformation (as shown by X-ray
crystallography studies) as opposed to 1 which is s-cis,
as shown in Figure 1. This structural change is thought
to be a result of steric repulsion which would exist
between the methyl group and the A ring in the s-cis
conformation.
Tubulin and microtubules are the targets of a number of
clinically useful anticancer drugs such as the natural
Keywords: Anticancer; Chalcone; Tubulin; Fluorine; Fluorination.
*
Corresponding author. Fax: +1 813 979 6700; e-mail: Lawrennj@
moffitt.usf.edu
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.08.065

N. J. Lawrence et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5844–5848
5845
Me
NH
Me
NH
MeO
MeO
MeO
MeO
MeO
MeO
O
MeO
MeO
O
O
OMe
OMe
MeO
OH
N
OH
MeO
ZD6126
H
O
OMe
OMe
AVE8062
NH2
OPO(ONa)2
Colchicine
Combretastatin A4
OMe
O
O
MeO
MeO
MeO
MeO
OH
A
A
B
OH
OMe
OMe
B
OMe
1
OMe
2
Figure 1. Representative inhibitors of tubulin polymerisation and chalcones 1 and 2, represented as s-cis and s-trans conformers, respectively.
We were intrigued as to whether groups other than a
methyl moiety would impart high biological activity to
the chalcones. We herein report the synthesis and activ-
ity of a series of chalcones with cyano, ester or fluoro
groups in the a-position along with some preliminary
biological data. In particular the effects of fluorine at
this position were of interest,13 as fluorine is well known
to improve activity and metabolic properties14,15 in the
many fluorinated drugs which are already in develop-
ment.16 The fluorinated chalcones would also be useful
as probes to investigate their ability to induce tumour
vasculature damage via 18F positron emission tomogra-
phy (PET) and their interaction with tubulin by 19F
NMR spectroscopy.
the K562 human chronic myelogenous leukaemia cell
line using the MTT assay from a previously reported
procedure.17 The IC50 value is reported as the concen-
tration which results in a 50% inhibition in cell growth
after 5-day incubation. In the case of the most active
compounds, the tubulin inhibition IC50 values are also
shown in Table 1.
In the case of chalcones 6c and 8c crystals were grown
of suitable quality for their structures to be resolved by
X-ray analysis.18,19 Chalcone 6c showed an unusual
structure in which the a,b double bond was configured
E and the A and B rings were twisted out of plane
(Fig. 2). However, chalcones bearing an a-carboalkoxy
group are known to adopt this type of structure.24 This
lack of significant biological activity agrees with our
previous findings that those chalcones adopting an
s-trans conformation in the solid state usually possess
high cytotoxicity.4
Initially a series of chalcones of the type 4 with a nitrile
group at the a position was synthesized by Knoevenagel
condensation of a range of benzaldehydes with the b-
ketonitrile 3. A similar strategy was also used in the
preparation of a-ethyl ester chalcones of the type 6
and a-fluorochalcones 8 (Scheme 1). In both cases we
have opted to retain the 3,4,5-trimethoxy substitution
of the A-ring, since this is usually optimal and is a fea-
ture of many tubulin-binding agents.
The structure of 8c showed the molecule in the s-trans
conformation, typical of a-methyl chalcones. Again this
is surprising because this conformation is normally a re-
sult of steric interaction between the a group and the A
ring and therefore associated with large a groups. Fluo-
˚
The cell growth inhibitory properties of the substituted
chalcones (summarized in Table 1) were determined in
rine, with a van der Waals radius of 1.47 A, must there-
fore be sufficiently large (cf. hydrogen 1.20 A)16 to make
˚
O
O
O
O
O
O
CN
O
O
CN
Ar
O
O
O
O
NaH
EtOH
ArCHO
OH
OEt
piperidine
(cat.)
Cat. H2SO4
MeCN
O
O
3, 83%
O
O
81%
O
4
O
Ar
O
O
O
O
O
O
O
O
O
OEt
EtO
OEt
ArCHO
O
OEt
O
piperidine
(cat.)
Na
O
O
O
O
5, 67%
6
O
O
O
O
O
O
O
Br
O
O
F
O
O
F
Br2
AcOH
ArCHO
KF
18-crown-6
piperidine
(cat.)
Ar
43%
7, 94%
O
O
8
O
Scheme 1. Synthesis of the a-chalcone classes 4, 6 and 8.

5846
Table 1. Cell growth inhibitiona against the K562 cell line
Compound B-ring substitution Cytotoxicity Tubulin
N. J. Lawrence et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5844–5848
the conformation in this case. However, this structure
is consistent with the potent cytotoxicities and tubulin
inhibition properties shown by this type of compounds.
As far as we are aware this is only the second report of
the X-ray crystal structure of an a-fluorochalcone. The
crystal structure of the a,b-difluorochalcone bearing a
p-tolyl A-ring and phenyl B-ring also adopts an s-trans
conformation.25
IC50 (lM)
IC50
1
3-Hydroxy-4-methoxy
3-Hydroxy-4-methoxy
3,4-Methylenedioxy
4-Methoxy
0.0043
0.00021
>10
>10
>10
4.2
10 lm
1.8 lm
n.d.
2
4a
4b
4c
4d
4e
4f
4g
4h
4i
n.d.
n.d.
3-OTBDMS-4-methoxy
3-Hydroxy-4-methoxy
3,4-Dimethoxy
n.d.
n.d.
>10
>10
>10
>10
>10
>10
>10
4.29
0.87
>10
>10
0.8
In the case of the a-nitrile chalcones it was not possible to
obtain suitable crystals for X-ray analysis. However, in
an effort to determine their structure NOE experiments
were carried out; compound 4b showed a 29% enhance-
ment at Hb when irradiated at the H2/H6 position on
the A ring, which suggests it is more stable in the s-trans
conformation which is consistent with other reports.24
2,3,4-Trimethoxy
4-Trifluoromethyl
2-Fluoro-4-methoxy
3-Fluoro-4-methoxy
3-Bromo-4-methoxy
4-Methoxy
3-OTBDMS-4-methoxyb
3-Hydroxy-4-methoxy
3,4-Dimethoxy
n.d.
n.d.
n.d.
n.d.
4j
n.d.
n.d.
6a
6b
6c
6d
6e
8a
8b
8c
8d
8e
8f
8g
8h
n.d.
n.d.
n.d.
n.d.
Both the a-nitrile and a-ethyl ester chalcones show very
poor biological activity compared not only to the fluori-
nated compounds but also to 1 and 2.
2,3,4-Trimethoxy
3,4-Methylenedioxy
4-Methoxy
n.d.
0.39
0.0137
1.21
10
4.6 lM
0.6 lM
n.d.
3-Hydroxy-4-methoxy
3,4-Dimethoxy
The inactivity of the a-ethyl ester chalcones can be ex-
plained by their distorted structure, as discussed above,
but that of the a-nitrile is less clear. The nitrile group is
more electron withdrawing than either methyl or hydro-
gen and also much more polar, and is able to act as a
hydrogen bond acceptor. The electron-withdrawing nat-
ure of the ester and nitrile groups makes the enone sys-
tem particularly electrophilic and certainly more so than
1 and 2. It is possible that 4 and 6 are just too electro-
philic and react non-specifically, perhaps via hydrolysis,
and are therefore unable to target tubulin.
2,3,4-Trimethoxy
2-Fluoro-4-methoxy
3-Fluoro-4-methoxy
3-Bromo-4-methoxy
n.d.
n.d.
1.19
0.77
6.0
n.d.
n.d.
a As measured by the MTT assay after 5-day incubation of the drug
with the cells cultured at 37 °C.
b TBDMS, tert-butyldimethylsilyl; n.d., not determined.
The fluorinated chalcones, however, showed very high
cytotoxicity and tubulin inhibition and were nearly as
potent as 1 and 2.
In all cases the chalcones with the 3-hydroxy-4-methoxy
B ring show the highest cytotoxicities, as expected.
Where there is a fluorine atom in place of the hydroxyl
group, however (as in the case of 4i and 8g), the activity
was significantly lower. Replacement of a hydrogen or
hydroxyl group by a fluorine atom is a strategy widely
used in drug development to alter biological function.
The substitution of the hydroxyl group with a fluorine
atom would also block any potential metabolic clear-
ance via glucuronidation. Fluorine substitution often
significantly alters the chemical properties, cellular and
systemic distribution and biological activity of drugs.14
However, as measured by the MTT assay, the hydroxyl
replacement is not beneficial in these cases. The most
inactive compounds in all cases are those with bulky
B rings such as 3-OTBDMS-4-methoxy, 2,3,4-trimeth-
oxy and 3-bromo-4-methoxy. Clearly steric hindrance
prevents these molecules from binding effectively to
tubulin.
Figure 2. X-ray crystal structures of chalcones 6c and 8c.
In summary, chalcones with a fluorine atom in the a po-
sition have been shown by X-ray analysis to adopt the
s-trans conformation and show potent cytotoxic and
tubulin inhibitory properties. The a-ethyl ester chal-
cones have an unusual, twisted structure and are poor
tubulin inhibitors. The 3-hydroxy-4-methoxy B ring is
the a-fluoro chalcone adopt an s-trans conformation. It
is also interesting that the CO and CF dipoles are
aligned in the s-trans conformation. This would be
expected to disfavour the s-trans conformation but
clearly this is not a feature that by itself determines

N. J. Lawrence et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5844–5848
5847
19. General procedure for the synthesis of chalcones. The
appropriate ketone 3, 5 or 7 (0.5 mmol) and the appro-
priate aryl aldehyde (0.5 mmol) were warmed in ethanol
(50 ml) until they dissolved. The solution was then cooled
to room temperature and piperidine (3–5 drops) was
added. After 48 h at room temperature, the product
chalcone was isolated by filtration. If after 48 h the
chalcone product had not precipitated, the ethanol was
removed under vacuum and the residue partitioned
between DCM and water. The DCM fraction was dried
and evaporated and the chalcone isolated by column
chromatography (7:3 hexane/ethyl acetate, v/v).
key to high biological activity and no other substitution
pattern (including 3-fluoro-4-methoxy) is able to match
its effect.
Acknowledgments
The support of our work by the EPSRC (Research
Grant GR/S25456/01: 500 MHz NMR spectrometer;
the EPSRC Chemical Database Service at Daresbury,26
the EPSRC National Mass Spectrometry Centre at
Swansea University for High-Resolution Mass Spec-
trometry), BBSRC (Research Grants B18009 and
B18017), Cardiff University (Senior Research Fellow-
ship to N.J.L., and studentship to R.P.P.) and the
Moffitt Cancer Center is gratefully acknowledged.
Ethyl 3-oxo-3-(30,40,50-trimethoxyphenyl)propionate (5).20
Diethyl carbonate (50 ml) and dibutyl ether (50 ml) were
heated to reflux and sodium (2 g, 87 mmol) was added
cautiously with stirring over 30 min. The resulting purple
solution was stirred for 30 min and then 3,4,5-trimeth-
oxyacetophenone (4 g, 19 mmol) was added over 30 min.
The reaction mixture was refluxed for a further 4 h, cooled
to room temperature and poured into crushed ice and
acetic acid (200 ml) and extracted with ether. The extracts
were dried and evaporated and recrystallisation from
methanol yielded 5 as white needles (3.5 g, 67%). Mp 90–
91 °C (lit. mp21 93–94 °C); 1H NMR d (400 MHz; CDCl3),
1.28 (3H, t, J = 7.1 Hz, CH3), 3.93 (6H, s, OMe), 3.94 (3H,
s, OMe), 3.98 (2H, s, COCH2CO), 4.23 (2H, q, J = 7.1 Hz,
CH2), 7.27 (2H, s, H20 and H60).
References and notes
1. Hsieh, H. K.; Lee, T. H.; Wang, J. P.; Wang, J. J.; Lin, C.
N. Pharm. Res. 1998, 15, 39.
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(Z)-2-Ethoxycarbonyl-3-(300-hydroxy-400-methoxy-phen-
yl)-1- (30,40,50-trimethoxyphenyl)propen-1-one (6c). Pale
yellow, cubic crystals (70%); mp 123–125 °C (found: C,
63.46; H, 5.84. C22H24O8 requires C, 63.46; H, 5.77%);
m
max (CHCl3) 3412s,br, 2938s, 1664s, 1581s, 1510s, 1459m,
1
1324m, 1251s, 1128s, 754s cmꢀ1; H NMR d (400 MHz;
CDCl3), 1.14 (3H, t, J = 7.1 Hz, CH3), 3.76 (6H, s, OMe),
3.77 (3H, s, OMe), 3.84 (3H, s, OMe), 4.16 (2H, q,
J = 7.1 Hz, CH2), 5.67 (1H, s, OH), 6.65 (1H, d,
J = 8.1 Hz, H500), 6.84 (1H, dd, J = 2.2, 8.1 Hz, H600),
overlapping 6.85 (1H, d, J = 2.2 Hz, H200), 7.14 (2H, s, H20
and H60), 7.78 (1H, s, H3). 13C NMR d (100 MHz;
CDCl3), 14.2 (s, CH3), 55.9 (s, OMe), 56.2 (s, OMe), 60.9
(s, OMe), 61.5 (s, CH2), 106.4 (s, C20 and C60), 110.5 (s,
C200), 116.0 (s, C500), 123.7 (s, C600), 126.3 (s, C2),128.9 (s,
C100), 131.4 (s, C10), 142.5 (s, C3), 143.1 (s, C300), 145.5 (s,
C40), 148.5 (s, C400), 153.2 (s, C30 and C50), 165.3 (s,
COOEt), 194.7 (s, C1) (found [M+H]+, 417.1547,
C22H25O8 requires [M+H]+, 417.1544).
5. Edwards, M. L.; Stemerick, D. M.; Sunkara, P. S. J. Med.
Chem. 1990, 33, 1948.
6. Kumar, S. K.; Hager, E.; Pettit, C.; Gurulingappa, H.;
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McGown, A. T.; Hadfield, J. A. J. Fluorine Chem. 2003,
123, 101.
20-Bromo-3,4,5-trimethoxyacetophenone.22 Bromine (2.5 ml,
48.8 mmol) was added dropwise to a stirred solution of 3,4,5-
trimethoxyacetophenone (10 g, 47.6 mmol) in acetic acid
(50 ml) at room temperature. The mixture was then left for a
further 2 h. Water (200 ml) was added and the product was
extracted into DCM, washed with satd NaCl, dried over
MgSO4 and evaporated to leave a black oil. Purification by
silica chromatography using a 3:7 mixture of EtOAc/hexane
(Rf = 0.23) yielded white crystals (5.71 g, 43%). Mp 67–
68 °C (lit.23 mp 68–70 °C); 1H NMR d (400 MHz; CDCl3),
3.86 (6H, s, OMe), 3.87 (3H, s, OMe), 4.35 (2H, s, H20), 7.19
(2H, s, H2 and H6) (found [M+H]+, 289, C11H13O479Br
requires [M+H]+, 289).
14. Isanbor, C.; O’Hagan, D. J. Fluorine Chem. 2006, 127,
303.
15. Boehm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn,
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20-Fluoro-3,4,5-trimethoxyacetophenone (7). Potassium
fluoride (4.0 g, 71 mmol) was dried by heating in a two-
neck, round-bottomed flask with a Bunsen flame under high
vacuum and then cooled to room temperature under N2.
The freshly prepared 20-bromo-3,4,5-trimethoxyacetophe-
none (1.1 g, 4.0 mmol) and 18-crown-6 (0.2 g, 0.76 mmol) in
dry MeCN (20 ml) were then added and the mixture
refluxed for 24 h. The solvent was then removed under
vacuum and the residue partitioned between DCM and
water. The DCM fraction was dried and evaporated to leave
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18. The crystals for X-ray analysis were prepared by the
diffusion method between methanol and a solution of the
substrate in chloroform. CCDC 617654 and 617653
contain the supplementary crystallographic data for 6c
and 8c respectively. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre
via http://www.ccdc.cam.ac.uk/data_request/cif.

5848
N. J. Lawrence et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5844–5848
a brown oil. Purification by silica chromatography using a
2.0, 8.4 Hz, H600), 7.33 (1H, d, J = 2.0 Hz, H200); 19F NMR d
(283 MHz; CDCl3), ꢀ121.6 (1F, d, J = 37 Hz); 13C NMR d
(100 MHz; CDCl3), 56.0 (s, OMe), 56.3 (s, OMe), 61.0 (s,
OMe), 106.9 (d, J = 5 Hz, C3), 110.6 (s, C20 and C60), 116.3
(d, J = 10 Hz, C200), 120.1 (d, J = 5 Hz, C500), 124.1 (d,
J = 8 Hz, C600), 124.9 (d, J = 4 Hz, C100), 131.3 (s, C10),
142.3 (s, C40), 145.7 (s, C300), 148.2 (d, J = 3 Hz, C400), 152.9
(s, C30 and C50), 153.8 (d, J = 269 Hz, C2), 186.5 (d,
J = 28 Hz, C1) (found [M+H]+, 363.1243, C19H20O6F
requires [M+H]+, 363.1244).
4:6 mixture of EtOAc/hexane (Rf = 0.22) yielded 7 as yellow
crystals (0.75 g, 94%). Mp 120–122 °C (found: C, 58.46; H,
5.83. C11H13O4F requires C, 57.89; H, 5.74%); mmax (CHCl3)
2944m, 2359m, 1702s, 1587s, 1463s, 1416s, 1326m, 1128s,
990m, 820w cmꢀ1; 1H NMR d (400 MHz; CDCl3), 3.84 (6H,
s, OMe), 3.85 (3H, s, OMe), 5.49 (2H, d,J = 47.0 Hz, H20),
7.07 (2H, s, H2 and H6); 19F NMR d (283 MHz; CDCl3),
ꢀ173.4 (1F, t, J = 47 Hz); 13C NMR d (100 MHz; CDCl3),
56.4 (s, OMe), 61.0 (s, OMe), 83.6 (d, J = 226 Hz, C20),
105.3 (s, C2 and C3), 128.8 (s, C1), 143.4 (s, C4), 153.3 (s, C3
and C5), 192.3 (d,J = 15 Hz, C10) (found [M+H]+,
229.0874, C11H14O4F requires [M+H]+, 229.0876).
(Z)-2-Fluoro-3-(300-hydroxy-400-methoxyphenyl)-1-(30,40,
50-trimethoxyphenyl)prop-2-en-1-one (8c). Yellow crystals
(75%); mp 132–135 °C (found: C, 62.39; H, 5.16.
C19H19O6F requires C, 62.98; H, 5.25%); mmax (CHCl3)
3423w,br, 2940m, 1579s, 1506s, 1415m, 1334m, 1253m,
1127s, 1001w, 755w cmꢀ1; 1H NMR d (400 MHz; CDCl3),
3.86 (6H, s, OMe), 3.88 (3H, s, OMe), 3.89 (3H, s, OMe),
5.60 (1H, s, ArOH), 6.77 (1H, d, J = 37 Hz, H3), 6.83 (1H, d,
J = 8.4 Hz, H500), 7.11 (2H, s, H20 and H60), 7.15 (1H, dd, J
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