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Journal ArticleDOI

6-Substituted 2-oxo-2H-1-benzopyran-3-carboxylic acid derivatives in a new approach of the treatment of cancer cell invasion and metastasis

01 Dec 2008-European Journal of Medicinal Chemistry (Elsevier)-Vol. 43, Iss: 12, pp 2735-2750

TL;DR: Novel 6-substituted 2-oxo-2H-1-benzopyran-3-carboxylic acid derivatives were synthesized and their potency in reducing the invasive behaviour of HT 1080 fibrosarcoma cells was evaluated.

AbstractNovel 6-substituted 2-oxo-2H-1-benzopyran-3-carboxylic acid derivatives were synthesized and their potency in reducing the invasive behaviour of HT 1080 fibrosarcoma cells was evaluated. Structure-activity relationships were deduced from biological results and will be used in further design of new active compounds. In particular, the acetoxymethyl substituent found at the 6-position of previously described active compounds can be replaced by an acetamidomethyl substituent without loss of potency; while the presence of an aryl ester function at the 3-position was preferred to a thioester or an amide function to induce marked biological activity. This work confirms the interest of aryl esters of 6-substituted coumarin-3-carboxylic acids as potential new anti-cancer agents.

Topics: Aryl (54%), Thioester (53%), Carboxylic acid (53%), Substituent (52%), Amide (51%)

Summary (2 min read)

1. Introduction

  • One of the most difficult problems arising during cancer therapy is the occurrence of cancer cell invasion responsible for the spread of tumour cells throughout the body.
  • Indeed, many efforts are now focussed on the search of compounds interfering with the cancer cell invasion process and expressing antiangiogenic properties [1].
  • The authors recently reported that two synthetic 6-substituted coumarin-3-carboxylic acid derivatives, 3- chlorophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate (1) and 3-bromophenyl 6-acetoxymethyl2-oxo-2H-1-benzopyran-3-carboxylate (2) (Fig. 1), expressed a marked potency in inhibiting cancer cell invasion in vitro and tumour growth in vivo [10].
  • Particular attention was paid to the replacement of the oxygen atom included in the exocyclic ester function in the 3-position by a sulphur atom or by a nitrogen atom with or without a methyl group.
  • The importance of the nature and the size of the substituent in the 6-position was also examined.

2. Chemistry

  • Scheme 1 illustrates the synthetic pathway giving access to the coumarinic derivatives characterised by the introduction of a thioester function or an amide function in the 3-position.
  • Starting from 11, acylation, with the appropriate anhydride, of the exocyclic OH function located on the hydroxymethyl group in the 6-position led to the acid esters 17 (Scheme 2).
  • Examples of coumarin derivatives with a nitro group in the 6-position were obtained according to Scheme 3.
  • Compounds 25 previously described [23] reacted with hexamethylenetetramine to give the hexaminium salts 26.

3. Results and discussion

  • The new synthetic coumarins were examined in a 'Boyden chamber' invasion assay using HT 1080 fibrosarcoma cells in order to determine their potency in reducing the invasive behaviour of tumour cells [10].
  • Results were compared to those observed with a reference compound, GI 129471 (29, Fig. 3), a well-known broad-spectrum hydroxamate-type MMP inhibitor, used at 1 µM concentration, previously reported to be active in this model [10], and also compared to those obtained with the active coumarin derivatives 1 and 2 at three different concentrations: 0.1, 1 and 10 µM.
  • As previously reported, the bromo-substituted coumarin 2 giving 78% inhibition of cell invasion at 1 µM concentration was found to be more potent than the reference compound GI 129471, whereas the corresponding chloro-substituted analogue 1 was also active (51% inhibition of cell invasion at 1 µM) but less potent than the two formers [10].
  • Such an effect could be explained by the fact that amides such as 15a may adopt a stable conformation in which a strong hydrogen bond interaction is established between the NH group and the lactonic carbonyl oxygen.
  • Thus, except in the case of an iodine atom, another halogen atom on the phenyl ring didn't improve the activity.

4. Conclusion

  • The present work aimed at describing new examples of coumarin-3-carboxylic acid derivatives structurally related to lead coumarins 1 and 2 expressing anti-invasive activity in vitro and anti-tumoral effect in vivo.
  • Among the different chemical modifications examined, the replacement of the ester function in the 6-position of 1 and 2 by an amide function was allowed without loss of potency in the 'Boyden chamber' chemoinvasion assay with HT 1080 fibrosarcoma cells.
  • By contrast, an aryl ester function in the 3-position was strongly recommended since its replacement by a thioester or an amide function was responsible for a significant decrease of the antiinvasive activity.
  • The increase of the size of the alkyl chain located on the acyloxymethyl moiety in the 6-position reduced the anti-invasive activity, although a short branched chain such as an isopropyl or a tert-butyl chain was allowed without markedly reducing the activity in the chemoinvasion assay.

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Published in: European Journal of Medicinal Chemistry (2008), vol. 43, iss. 12, pp. 2735-2750.
Status : Postprint (Author’s version)
6-Substituted 2-oxo-2H-1-benzopyran-3-carboxylic acid derivatives in a
new approach of the treatment of cancer cell invasion and metastasis
Isabelle Kempen
a
, Marc Hemmer
a
, Stéphane Counerotte
a
, Lionel Pochet
b
, Pascal de Tullio
a
, Jean-Michel
Foidart
c
, Silvia Blacher
c
, Agnès Noël
c
, Francis Frankenne
c
, Bernard Pirotte
a
a
Drug Research Center, Laboratoire de Chimie Pharmaceutique, Université de Liège, 1 Avenue de l'Hôpital, tour 4 (+5), Sart-Tilman, B-
4000 Liège, Belgium
b
Département de Pharmacie, Université de Namur, FUNDP, 61 rue de Bruxelles, B-5000 Namur, Belgium
c
Laboratoire de Biologie des Tumeurs et du Développement, Université de Liège, 1 Avenue de l'Hôpital, tour 3 (+4), Sart-Tilman, B-4000
Liège, Belgium
Abstract
Novel 6-substituted 2-oxo-2H-1-benzopyran-3-carboxylic acid derivatives were synthesized and their potency in
reducing the invasive behaviour of HT 1080 fibrosarcoma cells was evaluated. Structure—activity relationships
were deduced from biological results and will be used in further design of new active compounds. In particular,
the acetoxymethyl substituent found at the 6-position of previously described active compounds can be replaced
by an acetamidomethyl substituent without loss of potency; while the presence of an aryl ester function at the 3-
position was preferred to a thioester or an amide function to induce marked biological activity.
This work confirms the interest of aryl esters of 6-substituted coumarin-3-carboxylic acids as potential new anti-
cancer agents.
Keywords: coumarin derivatives; cancer; cell invasion; anti-cancer drug
1. Introduction
One of the most difficult problems arising during cancer therapy is the occurrence of cancer cell invasion
responsible for the spread of tumour cells throughout the body. Such an event leading to metastases is an
important cause of the bad prognosis of numerous cancers. Although anti-cancer chemotherapy mainly consists
in the use of cytotoxic agents interfering with cell division, another research field has recently emerged with the
design and identification of agents able to inhibit or limit the metastatic process. Indeed, many efforts are now
focussed on the search of compounds interfering with the cancer cell invasion process and expressing anti-
angiogenic properties [1]. Examples of drugs, among which monoclonal antibodies and small molecules, are
currently under clinical investigation and some of them have recently been approved for use in man in the
treatment of several cancers associated or not with conventional chemotherapies or radiation therapies [2-9].
These drugs comprise vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) inhibitors
(monoclonal antibodies) as well as VEGF and EGF receptor tyrosine kinase inhibitors (small-molecule
inhibitors), but also matrix metalloproteinase (MMP), urokinase (uPA), cycloogygenase-2 (COX-2) or
methionine aminopeptidase inhibitors [1].
We recently reported that two synthetic 6-substituted coumarin-3-carboxylic acid derivatives, 3-
chlorophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate (1) and 3-bromophenyl 6-acetoxymethyl-
2-oxo-2H-1-benzopyran-3-carboxylate (2) (Fig. 1), expressed a marked potency in inhibiting cancer cell invasion
in vitro and tumour growth in vivo [10]. Simple natural and synthetic coumarins such as esculetin (3), osthole (4)
and the synthetic 6-nitro-substituted coumarin (5) (Fig. 1) are also known for a long time to exert anti-cancer
properties, but, for most of them, by an unknown mechanism [11-14]. Recently reported coumarin derivatives
such as G8935 (6) (Fig. 1), structurally related to 1 and 2 and identified as mitogen activated protein (MAP)
kinase/extracellular signal-regulated kinase (ERK) kinase inhibitors (MEK1 inhibitors), raise the possibility that
the coumarin-3-carboxylates 1 and 2 may exert their anti-cancer activity through inhibition of MEK1 [15].
Another recent work showed that coumarin-3-carboxamides (7, Fig. 1) tightly related to the chemical structure of
1 and 2 selectively inhibited the tumour cells that have a high level of epidermal growth factor receptor (EGRF
or erbB1) and erbB2 (HER2) receptor expression [16].
Interestingly, the chemical structure of the active coumarins 1 and 2 may be compared to that of linomide
(roquinimex) (8, Fig. 2), a quinolinone isostere of coumarins known to be an immunomodulator, but also
expressing anti-angiogenic activity in vitro and in vivo [17-19]. Moreover, the preferred conformation adopted
by linomide, as found in the crystal [20] (8'; Fig. 2), can be superimposed to the preferential conformation
adopted, in the solid state and probably in solution, by aryl esters of coumarin-3-carboxylic acid derivatives (9';
Fig. 2) in accordance to recent published crystallographic and molecular modelling studies [21,22]. In contrast to

Published in: European Journal of Medicinal Chemistry (2008), vol. 43, iss. 12, pp. 2735-2750.
Status : Postprint (Author’s version)
aryl esters of 6-substituted coumarin-3-carboxylic acids, the corresponding aryl amides 10 (Fig. 2) are not able to
adopt such conformation because a strong intra-molecular hydrogen bound is established between the hydrogen
atom of the exocyclic NH group and the lactonic carbonyl group [21].
Using coumarins 1 and 2 as lead compounds, the present work aimed at describing new examples of coumarin-3-
carboxylic acid derivatives in order to better define structure-activity relationships that could explain their anti-
invasive activity. Particular attention was paid to the replacement of the oxygen atom included in the exocyclic
ester function in the 3-position by a sulphur atom (thioesters) or by a nitrogen atom (amides) with or without a
methyl group. The importance of the nature and the size of the substituent in the 6-position was also examined.
Among them, the replacement of the metabolically labile ester function (acetoxymethyl moiety) in the 6-position
by a more stable amide function (acetamidomethyl moiety) was investigated. In these series, the presence of a
halogen atom in the meta position of the phenyl ring in the 3 -position (preferably a chlorine or a bromine atom)
was maintained like in the structure of the lead compounds 1 and 2.
Fig. 1. Chemical structure of coumarins known to exert anti-cancer activity.

Published in: European Journal of Medicinal Chemistry (2008), vol. 43, iss. 12, pp. 2735-2750.
Status : Postprint (Author’s version)
Fig. 2. Structure of the anti-angiogenic drug linomide (8) in two different conformations. The 'cis' conformation
of linomide (8') can be superimposed to the low energy 'cis' conformation of the coumarinic aryl esters (9') but
not to the stable conformation of the coumarinic aryl amides (10) characterised by the existence of a strong
intra-molecular hydrogen bond.
2. Chemistry
Scheme 1 illustrates the synthetic pathway giving access to the coumarinic derivatives characterised by the
introduction of a thioester function or an amide function in the 3-position.
Compound 12 obtained from 11 by acetylation was converted into the corresponding acid chloride 13 as
previously described [21,23]. The acyl chloride intermediate 13 then reacted with appropriate thiophenols and
anilines to provide the thioesters 14, the secondary amides 15 and the tertiary amides 16 (Scheme 1).
Starting from 11, acylation, with the appropriate anhydride, of the exocyclic OH function located on the
hydroxymethyl group in the 6-position led to the acid esters 17 (Scheme 2). The latter intermediates were
converted into the acyl chlorides 18 and then into the 3-bromophenyl esters 19 after reaction of 18 with 3-
bromophenol in the presence of a base (Scheme 2).
Examples of coumarin derivatives with a nitro group in the 6-position were obtained according to Scheme 3. The
commercially available 5-nitrosalicylaldehyde 20 was converted into ethyl 6-nitrocoumarin-3-carboxylate 21
after reaction with ethyl malonate in the 'Knoevenaegel' reaction conditions. The ethyl ester 21 was hydrolyzed
to provide the corresponding carboxylic acid 22. The latter was converted into the acyl chloride 23 which then
reacted with the appropriate metahalophenol to provide the aryl esters 24.
Finally, 6-aminomethyl- (27) and 6-acetamidomethyl-substituted (28) halophenyl esters of coumarin-3-
carboxylic acid were obtained according to Scheme 4. Compounds 25 previously described [23] reacted with
hexamethylenetetramine to give the hexaminium salts 26. The 'Delepine' reaction conditions of hydrolysis were
then used to convert the hexaminium salts into the corresponding primary amines 27. In the last step, acetylation
of the amine function of 27 provided the corresponding acetamides 28.

Published in: European Journal of Medicinal Chemistry (2008), vol. 43, iss. 12, pp. 2735-2750.
Status : Postprint (Author’s version)
Scheme 1. Reagents: (i) Ac
2
O; (ii) SOCl
2
; (iii) ArSH, pyridine, dioxane; (iv) ArNH
2
, pyridine, dioxane; and (v)
ArNHCH
3
, pyridine, dioxane.
Scheme 2. Reagents: (i) (RCO)
2
O; (ii) SOCl
2
; and (iii) 3-bromophenol, pyridine, dioxane.

Published in: European Journal of Medicinal Chemistry (2008), vol. 43, iss. 12, pp. 2735-2750.
Status : Postprint (Author’s version)
Scheme 3. Reagents: (i) diethyl malonate, piperidine, HOAc, EtOH; (ii) NaOH, H
2
O; (iii) SOCl
2
; and (iv) 3-
halophenol, pyridine, dioxane.
Scheme 4. Reagents: (i) hexamethylenetetramine, CHCl
3
; (ii) HCl, EtOH; and (iii) Ac
2
O, TEA, DMF.
3. Results and discussion
The new synthetic coumarins were examined in a 'Boyden chamber' invasion assay using HT 1080 fibrosarcoma
cells in order to determine their potency in reducing the invasive behaviour of tumour cells [10]. The assay
consists in measuring the ability of cells treated or not with the coumarinic derivatives tested at different
concentrations to pass through type IV collagen-coated Transwell cell culture inserts (chemoinvasion assay).
Cell invasion in the absence of coumarin derivative was considered as 100%. Results were compared to those

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Q1. What are the contributions in "6-substituted 2-oxo-2h-1-benzopyran-3-carboxylic acid derivatives in a new approach of the treatment of cancer cell invasion and metastasis" ?

This work confirms the interest of aryl esters of 6-substituted coumarin-3-carboxylic acids as potential new anticancer agents.