Design and multi-step synthesis of chalcone-polyamine conjugates as potent antiproliferative agents

Article abstract of DOI:10.1016/j.bmcl.2017.08.024

The aim of this study is to synthesize chalcone-polyamine conjugates in order to enhance bioavailability and selectivity of chalcone core towards cancer cells, using polyamine-based vectors. 3-hydroxy-3′,4,4′,5′-tetramethoxychalcone (1) and 3′,4,4′,5′-tet

Full text of DOI:10.1016/j.bmcl.2017.08.024

Accepted Manuscript
Design and multi-step synthesis of chalcone-polyamine conjugates as potent
antiproliferative agents
Benjamin Rioux, Christelle Pouget, Chloë Fidanzi-Dugas, Aurélie Gamond,
Aurélie Laurent, Josiane Semaan, Aline Pinon, Yves Champavier, David Y.
Léger, Bertrand Liagre, Jean-Luc Duroux, Catherine Fagnère, Vincent Sol
PII:
S0960-894X(17)30825-9
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.08.024
BMCL 25218
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 June 2017
10 August 2017
12 August 2017
Please cite this article as: Rioux, B., Pouget, C., Fidanzi-Dugas, C., Gamond, A., Laurent, A., Semaan, J., Pinon,
A., Champavier, Y., Léger, D.Y., Liagre, B., Duroux, J-L., Fagnère, C., Sol, V., Design and multi-step synthesis of
chalcone-polyamine conjugates as potent antiproliferative agents, Bioorganic & Medicinal Chemistry Letters
(2017), doi: http://dx.doi.org/10.1016/j.bmcl.2017.08.024
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Design and multi-step synthesis of chalcone-polyamine
conjugates as potent antiproliferative agents.
Leave this area blank for abstract info.
Benjamin Rioux, Christelle Pouget, Chloë Fidanzi-Dugas,
Aurélie Gamond, Aurélie Laurent, Josiane Semaan, Aline Pinon,
Yves Champavier, David Y. Léger, Bertrand Liagre, Jean-Luc Duroux, Catherine Fagnère, Vincent Sol *

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.els evier.com
Design and multi-step synthesis of chalcone-polyamine conjugates as potent
antiproliferative agents.
Benjamin Rioux,a Christelle Pouget,a Chloë Fidanzi-Dugas, a Aurélie Gamond, a Aurélie Laurent, a Josiane
a
a
a
a
a
Semaan, Aline Pinon, Yves Champavier,b David Y. Léger, Bertrand Liagre, Jean-Luc Duroux,
Catherine Fagnère,a Vincent Sol a*
a Université de Limoges, Laboratoire de Chimie des Substances Naturelles, EA 1069, F-87000 Limoges, France.
b Université de Limoges, BISCEm, F-87000 Limoges, France.
ARTICLE INFO
ABSTRACT
Article history:
Received
The aim of this study is to synthesize chalcone-polyamine conjugates in order to enhance
bioavailability and selectivity of chalcone core towards cancer cells, using polyamine-based vectors.
3-hydroxy-3’,4,4’,5’-tetramethoxychalcone (1) and 3’,4,4’,5’-tetramethoxychalcone (2) were selected
as parent chalcones since they were found to be efficient anti-proliferative agents on various cancer
cells. A series of ten chalcone-polyamine conjugates was obtained by reacting carboxychalcones with
different polyamine tails. Chalcones 1 and 2 showed a strong cytotoxic activity against two prostatic
cancer (PC-3 and DU-145) and two colorectal cancer (HT-29 and HCT-116) cell lines. Then,
chalcone-spermine conjugates 7d and 8d were shown to be the most active of the series and could be
considered as promising compounds for colon and prostatic cancer adjuvant therapy.
Revised
Accepted
Available online
Keywords:
Chalcones
Polyamines
Organic synthesis
Anti-proliferative activity
Prostate and colorectal cancer cell lines
2009 Elsevier Ltd. All rights reserved.
Chalcones constitute an important group of natural
study, Figure 1) was found to inhibit the proliferation of ovarian
cancer cells. Considering these findings, we became interested in
performing structural modifications of the chalcone core to
improve both bioavailability and selectivity towards cancer cells.
Our study focused on the derivatization of chalcones 1 and 2.
An interesting approach for enhanced drug delivery is the use of
polyamine-based vectors. Polyamines such as putrescine,
spermidine or spermine, play an essential role as regulators of
cell proliferation and differentiation.16-17 It has been shown that
many tumor cell lines are highly dependent on these growth
factors.18 Cancer cells are unable to biosynthesize enough
polyamines to sustain their rapid growth rate. They consequently
rely on exogenous polyamines, imported by the polyamine
transport system (PTS) which is actually hyperactive in cancer
cells. This system has been shown to display a relatively loose
specificity;19 accordingly, some polyamine-drug conjugates have
been reported to be delivered into tumor cells expressing the
PTS.20-25
products belonging to the flavonoid family.1 They are open-chain
molecules in which two aromatic rings are joined by a three-
carbon enone fragment. Chalcones and derivatives received
significant attention due to their wide range of pharmacological
activities, including anti-inflammatory,2 anti-bacterial,3 and anti-
cancer properties.4-6 More particularly, some of these compounds
have been found to induce apoptosis in a variety of cell lines.7-10
Considering structure-activity relationship, a trimethoxyphenyl
ring is thought to be of great interest for anticancer activity of
chalcones.11-13 As reported by Ducki et al., 3-hydroxy-3’,4,4’,5’-
tetramethoxychalcone (chalcone 1 in our study, Figure 1), have
shown an important antiproliferative activity against K562 cell
line.12 This chalcone, bearing the same aromatic substitution
pattern as combretastatin A4 (CA-4) (Figure 1), a highly
cytotoxic natural product, also demonstrated an antiproliferative
effect against various cancer cells and was further used as a lead
compound of a series of anti-mitotic and pro-apoptotic agents.14
Besides, Qi et al. reported a series of CA-4 related chalcones;15
among them, 3’,4,4’,5’-tetramethoxychalcone (chalcone 2 in our
Figure 1 Chemical structures of combretastatin A4 (CA-4), 3-hydroxy-3’,4,4’,5’-tetramethoxychalcone (1) and 3’,4,4’,5’-tetramethoxychalcone (2).

Figure 2 Chemical structures of chalcone-polyamine conjugates
The present work deals with the synthesis of chalcone-polyamine
give 3 in a quantitative yield (Scheme 1A). Finally, the ester
function was turned into a carboxylic acid in quantitative yield
too, through the action of lithium hydroxide.
conjugates 7a-e, 8a-e (Figure 2). Then, antiproliferative activities
of these derivatives were evaluated against two colorectal (HT-29
and HCT-116) and two prostatic (PC-3 and DU-145) cancer cell
lines, and compared with those of parent chalcones 1 and 2.
Chalcones 1 and 2 were prepared using the Claisen-Schmidt
The synthesis of carboxy-chalcone 6 used a different synthetic
pathway in order to avoid the multistep synthesis of the 4-
hydroxy-3’,4’,5’-trimethoxychalcone as an intermediate. Indeed,
the preparation of 4-hydroxychalcones involved a preliminary
protection step of 4-hydroxy-benzaldehyde prior to the Claisen-
Schmidt condensation. A new pathway consisted in the O-
substitution of 4-hydroxy-benzaldehyde, by reaction with ethyl-
4-bromobutyrate, followed by the Claisen-Schmidt condensation
with 3’,4’,5’-trimethoxyacetophenone (Scheme 1B). Due to the
alkaline conditions, condensation and saponification occurred
during the same step, leading directly to compound 6. This
strategy only involved two steps with a 57% global yield.
Protected linear polyamines were purchased whereas ramified
polyamines were prepared following the strategy developed in
our laboratory and previously described.23 Many ways for the
selective protection of polyamines have been reported.26 In our
study, we chose the BOC-protective group that can be selectively
removed with TFA or HCl.
condensation
from
building-blocks,
namely
3,4,5-
trimethoxyacetophenone and appropriate benzaldehydes.10, 15 1H
NMR spectra showed that the (E)-stereoisomers were specifically
generated since the coupling constant between the two ethylenic
protons was about 15-16 Hz. Chalcone 2 was obtained from 4-
methoxybenzaldehyde in 51% yield while chalcone 1 was
prepared in
methoxybenzaldehyde.
a
good yield (69%) from 3-hydroxy-4-
Ten polyamine-chalcone conjugates (7a-e, 8a-e) were
synthesized, following a multistep strategy where chalcone core
and polyamine tails were fused through an amide bond. The
synthetic pathway involved the preparation of carboxy-chalcones
4 and 6 for the synthesis of the series 7 and 8 respectively. The
preparation of carboxy-chalcone 4 first started with alkylation of
the phenolic function of chalcone 1 by ethyl-4-bromobutyrate, to
Scheme 1 A: Reagents and conditions for synthesis of compound 4: (i) K2CO3 (20 eq), ethyl-4-bromobutyrate (10 eq), DMF, rt, 2h, 98%; (ii)
LiOH (5 eq), THF/H2O (8/2), rt, 3h, 94%. B: Reagents and conditions for synthesis of 6: (i) K2CO3 (20 eq), ethyl-4-bromobutyrate (10 eq),
DMF, rt, 1h, 98%; (ii) 3,4,5-trimethoxyacetophenone (0.84 eq), NaOH (4.17 eq), MeOH, reflux, 1h, 58%.

Scheme 2 (i) Corresponding polyamine tail (1.1 eq), DCC (1.1 eq), HOBt (1.1 eq), CH2Cl2/MeOH (10/1), rt, 4h; (ii) HCl (12 eq), EtOH, reflux, 1h30.
Lipophilicity could be indicated, for example, by the logarithm of
The synthetic pathway of polyamine-chalcone conjugates
through the formation of an amide bond was described in Scheme
2 ; it involved the coupling of the carboxylic acid function of
chalcones 4 and 6, with the primary amine function of the
polyamine tails, in presence of N,N'-dicyclohexylcarbodiimide
(DCC) and hydroxybenzotriazole (HOBt) as coupling agents.
Removal of the tert-butoxy-carbonyl (BOC) was performed
using aqueous hydrochloric acid in ethanol at reflux. All the
yields are reported in Table 1.
a partition coefficient, log P, which reflects the equilibrium
partitioning of a molecule between a nonpolar and a polar phase,
such as the 1-octanol/water system.27 In this work, we determined
log P of parent chalcones 1, 2 and chalcone-polyamine
conjugates 7a, 8b, 7d and 8d as log ([Chalcone]1-octanol
/[Chalcone]water) (see supplementary data). Results indicated that
the addition of polyamines tails strongly increased the
hydrophilic character of chalcones which is a very interesting
property for biological applications. (Table 2).
Table 2: partition coefficients of chalcone 1, 2 and chalcone polyamine
conjugates 7a, 8b, 7d and 8d.
Table 1: synthesis conditions of polyamine-chalcone conjugates 7 & 8.
Compounds
Coupling yield
BOC removing
yield (%) (ii)
Global yield
Derivatives
(%) (i)
77
88
66
96
(%)
57
1
2.99 3.10 -1.28
2
7a
7d
-1.57
8b
-1.43
8d
-1.98
7a
7b
7c
7d
7e
74
95
82
54
49
log P
84
55
Parent chalcones 1 and 2, considered as reference standards, as
well as the synthesized polyamine-chalcone conjugates were
evaluated for their antiproliferative effect against two colorectal
(HT-29 and HCT-116) and two prostatic (PC-3 and DU-145)
cancer cell lines using a MTT-based assay (supplementary data).
Chalcones 1 and 2 are known to possess promising anticancer
activity. Thus, chalcone 1 was identified for antiproliferative
activity on leukemia (K562) and lung (A549) cancer cell lines,11-
52
43
87
8a
8b
8c
8d
8e
68
64
64
62
68
44
51
38
45
33
30
33
25
28
23
14
while chalcone 2 proved antiproliferative activity against
The coupling reaction between the carboxy-chalcones and
polyamine tails, using DCC and HOBt as coupling agents, was
really efficient since all yields were higher than 60%. On the
other hand, removal of the BOC groups was more difficult. Usual
conditions with trifluoroacetic acid (TFA) in dichloromethane
(CH2Cl2) led to the degradation of the reaction mixture. Improved
results were obtained in presence of hydrochloric acid (HCl) in
ethanol (EtOH) although with variable and sometimes moderate
yields, due to the formation of by-products. Synthetic procedures
ovarian cancer cell lines.15 Our work is focused for a long time
on colorectal and prostatic cancers.28-31 Thus, a previous study
was performed to explore the cell death pathway induced by
chalcone 1 in colorectal cancer cell lines.32
In the present work, chalcones 1 and 2 were found to be active on
all the cancer cell lines studied. The results are outlined in Table
2. Chalcone 1 showed a higher activity than chalcone 2 except
against HT-29 cell line, which is COX-2 sufficient. Meanwhile, it
has been demonstrated that COX-2 plays a critical role in
resistance to apoptosis.28,29,32 Antiproliferative effects of
chalcone-polyamine conjugates were moderate in comparison
with those of parent chalcones 1 and 2. Comparison of the IC50
and characterizations (FTIR, H and 13C NMR, MS) are detailed
in supplementary data.
In medicinal chemistry, balance between hydrophilicity and
lipophilicity has proven to be an important molecular descriptor
that often is well-correlated with the bioactivity of drugs.
1

values between the two series 7 and 8 shows that compounds
bearing the same substituent pattern do not display significant
differences in their respective cytotoxicities, with the exception
of experiments on HCT-116 cell line. Indeed, in this case, IC50 of
series 8 conjugates are generally lower than IC50 of series 7 ones.
Considering the four cell lines, HT-29 appeared as the most
resistant. Indeed, all the IC50 were higher than 70 µM. On the
contrary, HCT-116 which is COX-2 deficient, seemed to be the
most sensitive cell line. Among the ten conjugates, half of them
possessed IC50 lower than 40 µM. Thus, 8a conjugate was the
most active compound against HCT-116 cells, with an IC50 of 20
µM. These results highlighted the potential of the N8 spermidine
tail and the total lack of interest of the N1 spermidine tail, and
were in agreement with those obtained against PC-3 and DU-145
cell lines. The 7b and 8b conjugates were devoid of activity
against these prostatic cancer cells whereas 7a and 8a exhibited a
weak, but measurable, activity. Therefore, the architecture of the
spermidine tail clearly affected the bioactivity. As described for
artemisinin spermidine conjugates,25 coupling at the N8-centre of
the spermidine tail provided compounds more active than the N1-
conjugates (Figure 2).
therapeutics since, on the one hand, their polyamine tail is
intended to increase their hydrophilic character and improve drug
delivery and selectivity toward cancer cells and, on the other
hand, their in vitro antiproliferative effect is significant.35 Thus,
N8-spermidine conjugate 8a could be a promising compound for
colon cancer adjuvant therapy since it demonstrated a great
antiproliferative activity against HCT-116 cells. Besides,
spermine conjugates also gave good results: 8d displayed an
interesting effect on three cancer cell lines (HCT-116, PC-3 and
DU-145) and 7d even showed a slightly better activity than 8d on
prostatic cancer cell lines. These latter molecules may be
considered as potent compounds for prostatic cancer therapy.
Further studies are necessary to more closely examine the
underlying molecular mechanisms of these compounds but also
to design new polyamine-chalcone conjugates with a view to
studying the influence of the linker and the length of the spacer
on cytotoxic properties.
Acknowledgments
We thank the ‘Conseil Régional du Limousin’ for financial
support. The authors are indebted to Dr. Michel Guilloton for
manuscript editing and to Dr. Cyril Colas, from the "Fédération
de Recherche" ICOA/CBM (FR2708) platform, for the HRMS
analysis.
Concerning PC-3 and DU-145 cell lines, interesting results were
obtained with derivatives built with the linear spermine pattern as
shown in 7d and 8d. Indeed, in both series 7 and 8, this
polyamine moiety provided compounds with IC50 values around
30 µM whereas all other conjugates gave IC50 higher than 50 µM.
Supplementary data
In a global manner, spermine conjugates 7d and 8d appeared as
the most interesting compounds. These two compounds were not
only the most active against PC-3 and DU-145 cell lines but they
also presented an antiproliferative effect against HCT-116 cells.
These results are in agreement with published studies showing
that the spermine tail is able to increase the water solubility of the
spermine-drug conjugate, to serve as cell delivery vector by using
the PTS for tumor cell delivery as well as DNA anchor.20, 33,34 In
our case, and even if these conjugates are less active in vitro than
their parent chalcone 1 and 2, the water solubility is really
increased and, the lower cytotoxicity of 7d and 8d, can be
explained by the higher affinity of spermine for DNA which are
not the key intracellular target of our chalcone derivatives.
Supplementary data (experimental procedure for the synthesis,
spectral data, and experimental information concerning partition
coefficient measurement) associated with this article can be
found in the online version, at
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