β′-Hydroxy-α,β-unsaturated ketones: A new pharmacophore for the design of anticancer drugs

Article abstract of DOI:10.1016/j.bmcl.2006.01.023

A series of β′-hydroxy-α,β-unsaturated ketones were prepared by means of an iron(III) catalyzed domino process. The in vitro antiproliferative activities were examined in the human solid tumor cell lines A2780, SW1573, and WiDr. The results showed that β′

Full text of DOI:10.1016/j.bmcl.2006.01.023

Bioorganic & Medicinal Chemistry Letters 16 (2006) 2266–2269
0
b -Hydroxy-a,b-unsaturated ketones: A new pharmacophore
for the design of anticancer drugs
a,b,c,
a
a,b
a,b
*
Jos e´ M. Padr o´ n,
Pedro O. Miranda, Juan I. Padr o´ n and V ´ı ctor S. Mart ´ı n
a
Instituto Universitario de Bio-Org a´ nica ‘‘Antonio Gonz a´ lez’’ (IUBO-AG), Universidad de La Laguna,
C/Astrof ı´ sico Francisco S a´ nchez 2, 38206 La Laguna, Spain
b
Instituto Canario de Investigaci o´ n del C a´ ncer (ICIC), Red Tem a´ tica de Investigaci o´ n Cooperativa de Centros de C a´ ncer (RTICCC),
Ctra. del Rosario s/n, 38010 S/C de Tenerife, Spain
c
Instituto Canario de Investigaci o´ n Biom e´ dica (ICIB), Hospital Universitario NS de Candelaria,
Ctra. del Rosario s/n, 38010 S/C de Tenerife, Spain
Received 9 December 2005; revised 5 January 2006; accepted 6 January 2006
Available online 24 January 2006
0
Abstract—A series of b -hydroxy-a,b-unsaturated ketones were prepared by means of an iron(III) catalyzed domino process. The
in vitro antiproliferative activities were examined in the human solid tumor cell lines A2780, SW1573, and WiDr. The results showed
0
that b -hydroxy-a,b-unsaturated ketones were more potent than a,b-unsaturated ketones. The best activity profiles were obtained
for the derivatives bearing cyclic or branched substituents on the side chains.
Ó 2006 Elsevier Ltd. All rights reserved.
0
The b -hydroxy-a,b-unsaturated ketone fragment is a
common structural feature present in diverse natural
Due to our interest in the discovery of novel pharmaco-
phores for the development of anticancer compounds,
we explored the possibility of b -hydroxy-a,b-unsaturat-
ed ketones as antitumor agents.
0
products such as the Alnus firma ketol yashabushiketol
1
(
americana), or the Streptomyces produced antifungal
1), persenones A (2) and B (3) from avocado (Persea
2
3
macrocyclic antibiotic 3874 H3 (Fig. 1). Persenones A
In this article, we present a systematic study on the syn-
thesis and growth inhibitory activity of diverse a,b-un-
saturated ketone derivatives obtained through iron(III)
chloride catalysis. As a model system to study the bio-
logical activity, the representative human solid tumor
cells A2780 (ovarian cancer), SW1573 (non-small cell
(
2) and B (3) are unique antioxidants that preferentially
suppress radical generation. In particular, persenone A
2) is an effective inhibitor of both nitric oxide and
superoxide generation in cell culture systems. Perse-
none A (2) at a concentration of 20 lM almost com-
pletely suppressed both inducible nitric oxide synthase
(
4
(
sion. In a parallel study, two important structural find-
ings for the activity were disclosed. The double bond
iNOS) and cyclooxygenase (COX-2) protein expres-
5
O
OH
β
6
α
β'
conjugated to the carbonyl group showed an important
factor for the activity. To the contrary, the absolute con-
figuration of the secondary hydroxyl group was not a
critical factor. Thus, persenones A (2) and B (3) appear
as possible food agents to prevent diseases such as
1
O
OH
O
O
C H
5
11
7
cancer.
2
O
OH
O
C12H25
O
Keywords: Unsaturated ketones; Solid tumors; Drug design; Structure–
activity relationships; Anticancer drugs.
3
0
a b -hydroxy-a,
*
Corresponding author. Tel.: +34 922 318 580; fax: +34 922 318
71; e-mail: jmpadron@ull.es
Figure 1. Structures of natural products with
b-unsaturated ketone fragment.
5
0
960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.01.023

J. M. Padr o´ n et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2266–2269
2267
lung cancer, NSCLC), and WiDr (colon cancer) were
A
O
O
FeX3
selected.
discussed.
structure–activity relationship is also
R3
R4
+
R1
R3
R1
H
CH Cl
2
2
R4
4
9
10
We have reported recently a novel 2-oxonia-[3,3]-sigma-
tropic rearrangement as competitive alternative pathway
to the alkyne Prins cyclization resulting in the addition
Scheme 2. Iron(III) promoted coupling of alkynes and aldehydes.
of secondary homopropargylic alcohols 4 to aldehydes
8
aromatic aldehydes did not react. The coupling between
terminal alkynes and aliphatic aldehydes led to a mix-
ture of (E,Z)-1,5-dihalo-1,4-dienes and disubstituted
(E)-a,b-unsaturated ketones 10.
5
catalyzed by iron(III). The procedure is depicted in
Scheme 1. This method represented an alternative to
the previously reported procedures employing vanadi-
9
10
um and indium, which required the preparation of
the appropriate allenol 6.
On the other hand, the reaction of non-terminal aromat-
ic acetylenes 9 with aldehydes gave the trisubstituted
(E)-a,b-unsaturated ketones 10 as the exclusive product.
Thus, derivatives 10b, 10d, and 10e were obtained in
80%, 68%, and 65% yield, respectively. The procedure
was not valid for aliphatic and unsaturated skipped
alkynes since mixtures were produced. To the contrary,
the procedure was compatible with homopropargylic
alcohol although modest yields were obtained (10c,
33% yield).
The method tolerated a wide range of aliphatic and aro-
matic aldehydes. The process produced in moderate to
good yield (40–70%) a mixture of derivatives 7 and 8.
0
The b -hydroxy-a,b-unsaturated ketone 7 was the major
product. With the exception of the Lewis acid catalyst,
any attempt to control the final balance of the obtained
products (7:8) by changing experimental conditions was
fruitless. Thus, when iron(III) bromide was used instead
of the usual iron(III) chloride the process became com-
0
pletely chemoselective, being the b -hydroxy-a,b-unsatu-
rated ketone 7 obtained as a single product.
The series of 16 products reported in this study is shown
1
3
in Table 1. Compounds 7a–i and 8a–b were obtained
according to the method shown in Scheme 1. The
remaining derivatives 10a–e were synthesized via the
strategy depicted in Scheme 2.
1
If this reaction were run with two diverse aldehydes (R
and R different) with varying reactivity, a cross-over
4
8
domino process took place. Similarly, the nature of
the Lewis acid catalyst is key for the outcome of the
reaction. When iron(III) bromide was used as the cata-
The lipophilicities of this series of compounds were cal-
culated to correlate their values with the antitumor
activity. In this study, lipophilicity is given as ClogP
and the values (Table 1) were calculated using the com-
0
lyst only the b -hydroxy-a,b-unsaturated ketone 7 was
obtained, although in modest yields (7g, 25% yield).
However, we should keep in mind that in this domino
process, three consecutive chemical events take place
in one-pot reaction with an average yield of 70–80%.
Overall, these domino processes run in a regioselective
and efficient manner. Domino processes have received
great attention from the chemical community because
they address fundamental principles of synthetic efficien-
Ò 14
puter program ClogP . This program is designed to
determine the partition coefficient of the non-ionized
form of a given compound. In a recent comparative
study, ClogP appeared the most accurate predictor
Ò
1
5
of ClogP values.
In addition to lipophilicity, the in vitro anticancer
activity was evaluated using the National Cancer
1
1
cy and reaction processing.
1
6
Institute (NCI) protocol. In this method, for each
drug a dose–response curve is generated and three
levels of effect can be calculated, when possible. The
effect is defined as percentage of growth (PG), where
50% growth inhibition (GI50), total growth inhibition
(TGI) and 50 % cell killing (LC50) represent the drug
concentration at which PG is +50, 0, and ꢀ50,
respectively.
An additional functional-diversity point on the synthesis
of a,b-unsaturated ketones was obtained by the iron(III)
promoted stereoselective coupling of alkynes and alde-
1
2
hydes (Scheme 2). The method allowed us to obtain
ketones of the general structure 10 with diverse substit-
4
uents at the a vinylic position (R ). The reaction worked
well with both aliphatic and aromatic alkynes, whilst
We screened growth inhibition and cytotoxicity against
the human solid tumor cell lines A2780, SW1573, and
WiDr after 48 h of drug exposure using the sulforhoda-
mine B (SRB) assay. The resulting biological activities
for each compound expressed as GI50 are reported in
Table 1.
O
OH
R4
O
R1
17
R3
R1
O
H
R3
.
4
R4
FeX3
H
7
+
Major
+
R3
CH Cl
R1
2
2
OH
O
The ClogP values obtained for the majority of com-
pounds were in the range 2.63–5.52. Only derivative 7c
showed a larger ClogP value of 9.46. On the other
hand, the growth inhibition results allowed us to classify
the compounds in three groups according to their anti-
cancer activity profile.
OH
R3
6
R1
R2
8
Minor
5
Scheme 1. Iron(III) promoted coupling of homopropargylic alcohols
and aldehydes.

2268
J. M. Padr o´ n et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2266–2269
a
Table 1. Lipophilicity and in vitro antiproliferative activity against human solid tumor cells
b.
Compound
ClogP
Substitutent
Cell line
SW1573
1
3
R
4
R
R
A2780
WiDr
7
7
7
7
7
7
7
7
7
8
8
1
1
1
1
1
a
5.52
4.47
9.46
3.14
2.88
3.01
2.95
3.45
4.12
3.16
2.63
4.21
4.52
3.08
5.24
5.18
n-Hex
c-Hex
H
n-Hex
c-Hex
26 (±2.0)
1.8 (±1.0)
16 (±2.0)
17 (±1.8)
9.9 (±4.8)
3.3 (±1.8)
2.6 (±0.7)
3.9 (±2.5)
5.5 (±3.6)
91 (±13)
21 (±7.4)
20 (±3.1)
>100
25 (±4.2)
3.1 (±0.7)
30 (±6.4)
27 (±4.9)
26 (±4.1)
4.3 (±1.3)
13 (±3.4)
12 (±5.8)
11 (±2.1)
79 (±37)
30 (±4.0)
31 (±1.1)
>100
31 (±6.2)
2.9 (±1.5)
32 (±8.0)
21 (±1.0)
59 (±14)
14 (±0.8)
16 (±6.3)
15 (±5.0)
12 (±5.3)
56 (±38)
23 (±4.1)
22 (±11)
>100
b
H
c
(CH
i-Bu
t-Bu
Ph
2
)
10Br
H
(CH
i-Bu
t-Bu
Ph
2
)10Br
d
H
e
H
f
H
g
Ph
H
i-Bu
i-Bu
i-Bu
h
p-MePh
p-BrPh
n-Hex
c-Hex
i-Bu
H
i
Me
H
a
b
H
0a
0b
0c
0d
0e
Ph
Ph
Ph
Ph
Ph
H
Me
i-Bu
i-Bu
i-Bu
CH
Ph
2
OH
18 (±2.5)
21 (±6.2)
28 (±4.5)
24 (±3.3)
33 (±4.0)
36 (±5.7)
19 (±8.7)
21 (±8.8)
41 (±25)
c-Hex
Me
a
Values representing GI50 are given in lM and are means of two to four experiments, standard deviation given in parentheses.
Ref. 14.
b
A first group is comprised of compounds 7b and 7f–i.
These products gave GI50 values in the range 1.8–5.5,
7d). The antiproliferative activities were in the order
c-Hex > Ph > t-Bu > n-alkyl ꢁ i-Bu. For the cross-over
products 7g–i no significant difference in activity was ob-
served with respect to the parent derivative 7f against
ovarian and colon cells. However, the NSCLC cell line
was more sensitive to 7f than to 7g–i.
2
.8–13, and 2.9–16 lM against A2780, SW1573, and
WiDr cells, respectively. The most potent compound
evaluated was 7b that showed GI50 values in the low
micromolar range against all cell lines (Table 1). The
activity profile of this derivative was similar in the three
cancer cell lines. This is an interesting result, since con-
ventional and investigational anticancer drugs showed
that colon cancer cells were more drug resistant than
Although the experiments are preliminary, we found that
these synthetic derivatives induce considerably growth
inhibition in a panel of three diverse human solid tumor
cells and did not show cytotoxicity at the maximum con-
1
8
ovarian cancer cells. The set of derivatives 7a, 7c–e,
b, 10a, and 10c–e exhibited a slightly decreased activity.
The GI50 values for these products were in the range 16–
9 lM. Finally, compounds 8a and 10b were included in
0
8
centration test. Therefore, these b -hydroxy-a,b-unsatu-
rated ketones may be considered cytostatic drugs.
Cytostatic drugs are interesting in antiangiogenic thera-
py because they do not kill cells in the same way that
cytotoxic drugs do; rather, they prevent them from grow-
ing and dividing. Targeting angiogenesis is radically dif-
ferent from conventional chemotherapy and represents a
changing view on the curability of cancer that may com-
pletely revolutionize cancer treatment.
5
the inactive group. The derivatives demonstrated a sig-
nificant decrease in activity as shown by the GI50 values
(
GI50 >50 lM).
The observation that the vast majority of the derivatives
evaluated in this study present antitumor activity in all
cell lines is consistent with our hypothesis considering
the a,b-unsaturated ketone fragment as a privileged
scaffold with the substituents modulating the biological
activity. In view of these results, it appears that the in vi-
tro biological activity of these a,b-unsaturated ketones
does not correlate with the calculated ClogP values.
However, the substitution pattern and steric hindrance
in both side chains are important.
In conclusion, we have prepared a series of a,b-unsaturat-
ed ketones and evaluated their ability to inhibit tumor cell
0
growth. The results show that b -hydroxy-a,b-unsaturat-
ed ketones are promising scaffolds for the design of new
anticancer drugs. Based on these results, it is anticipated
that these compounds will be active against both sensitive
and resistant solid tumors.
Analysis of the obtained dose–response parameters pro-
vides the following structure–activity relationships. In
general, those compounds having a b -hydroxy-a,b-un-
Acknowledgments
0
saturated ketone fragment (7a–i, 10c) showed superior
activity than those with only the a,b-unsaturated ketone
fragment (8a–b, 10a–b, and 10d–e). The most potent
derivative 7b bears two cyclohexyl groups. Compounds
This research was supported by the Ministerio de Edu-
caci o´ n y Ciencia of Spain (CTQ2005-09074-C02-01/
BQU) and the Canary Islands Government. We are
indebted to Prof. Godefridus J. Peters for providing us
with the cell lines. J. M. P. is recipient of a postdoctoral
fellowship from the ICIC. P. M. C. thanks the Spanish
MCYT for an FPI fellowship. J. I. P. thanks the Spanish
MCYT-FSE for a Ram o´ n y Cajal contract.
1
4
with cyclic (R and R = c-Hex 7b, Ph 7f) or branched
1
R and R = t-Bu 7e) substituents on the side chains
4
(
were more active than the corresponding linear deriva-
1
tives (R and R = n-Hex 7a, (CH ) Br 7c, and i-Bu
4
2
10

J. M. Padr o´ n et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2266–2269
2269
References and notes
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analytical and spectroscopic data in full accord with their
assigned structures.
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4
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