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

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.

About: This article is published in European Journal of Medicinal Chemistry.The article was published on 2008-12-01 and is currently open access. It has received 48 citations till now. The article focuses on the topics: Aryl & Thioester.

Summary

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.

Figures

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.

Fig. 3. Chemical structure of two synthetic MMP inhibitors.

Fig. 1. Chemical structure of coumarins known to exert anti-cancer activity.

Frequently asked questions

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.