3-Bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate inhibits cancer cell invasion in vitro and tumour growth in vivo

Abstract

In search for new anticancer agents, we have evaluated the antiinvasive and antimigrative properties of recently developed synthetic coumarin derivatives among which two compounds revealed important activity: 3-chlorophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate and 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate. Both drugs were able to inhibit cell invasion markedly in a Boyden chamber assay, the bromo derivative being more potent than the reference matrix metalloprotease (MMP) inhibitor GI 129471. In vivo, tumour growth was reduced when nude mice grafted with HT1080 or MDA-MB231 cells were treated i.p. 3 days week À1 with the bromo coumarin derivative. These effects were not associated with the inhibition of urokinase, plasmin, MMP-2 or MMP-9. The mechanism of action of the drugs remains to be elucidated. However, these two coumarin derivatives may serve as new lead compounds of an original class of antitumour agents.

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

“…The other MMP inhibitor, Ro 28-2653, was found to be equally active to GI 129471 at 1 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].…”

“…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).…”

“…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. The activity at 1 µM of another synthetic MMP inhibitor, Ro 28-2653 (30, 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.…”

“…(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.…”