Synthetic Coumarin Derivatives Research Articles

NO2 functionalized coumarin derivatives suppress cancer progression and facilitate apoptotic cell death in KRAS mutant colon cancer

Colon cancer is one of the most lethal cancers worldwide even with the significant progress made in screening techniques and therapeutic agents. Genetic mutations in tumors complicated the treatments, and the survival rate remains low for patients at late or metastatic stages. KRAS gene mutation which leads to failure of the EGFR targeted therapies stands for an example of the challenges in clinical sites. Therefore, development of novel agents for colon cancer treatment is in need. Natural and synthetic coumarin derivatives have been suggested with various biological activities with pharmacologic potential including anti-cancer capacity. Here in this study, five coumarin derivatives, include trifluoromethyl-, dimethoxy-, and/or nitro-substitutions at different positions, were synthesized. Their cancer inhibition potential was investigated in various cancer cell lines. Our data demonstrated that one nitro-coumarin derivate, 5,7-Dimethoxy-4-methyl-6-nitro-chromen-2-one, exhibits cytotoxicity specifically towards colon cancer cells under competitive EC50. Our results showed that this compound can effectively suppress colon cancer cells harboring either wild type or mutant KRAS genes, and that it could inhibit short-term proliferation, long term proliferation, and migration capacities of cancer cells. Finally, we demonstrated that this coumarin derivate facilitates cancer cell death through activation of apoptosis pathway. Our results suggest that this coumarin derivate is a promising lead drug worth further investigation and development for future cancer treatment.

Anticancer Activity Study of Chromone and Coumarin Hybrids using Electrical Impedance Spectroscopy.

Oncology treatments aim at selective toxicity for tumor (compared to normal) cells, and chromone- coumarin hybrids have shown such activity. In this study, we test a novel series of synthetic chromone and coumarin derivatives (1-9) for cytotoxic activity against a panel of tumor cell lines (MCF-7, A549, HepG2, HTC-116, B16 and Caco-2) opposed to non-tumor cells (HEK-293t). Electrical impedance spectroscopy was used to monitor cell viability in real time. Compound 8 showed the most potent activity, and it significantly diminished cancer cell proliferation and viability in different cell lines. It induced apoptosis in a dose-dependent manner, as shown by Western blot and flow cytometry. Electrical impedance spectroscopy appears to be a convenient tool for in vitro cytotoxicity analysis, which could be useful for identifying drug effects and side effects during early phases of drug discovery and development.

Synthesis of Some Novel Sydnone Derivatives Containing Coumarine Moiety and Evaluation of Their Antimicrobial and Antitubercular Activities

The family of natural plant metabolites known as coumarin derivatives holds significant importance due to their diverse range of biological actions. Synthetic coumarin derivatives have demonstrated considerable potential in the realms of anticancer, antitumor, and anti-proliferative actions. The objective of this investigation was to produce a new series of sydnone derivatives containing coumarine, namely 3-(4-chlorophenyl)-4-(chlorosulfonyl) sydnone, through the synthesis of 7-amino-4-methyl-3-substituted phenyl-2H-chromen-2-one 2a-j. The recently produced chemicals were analyzed using infrared (IR), nuclear magnetic resonance (NMR), and elemental analysis. The antibacterial, antifungal, and antitubercular properties of the produced compounds were assessed. The majority of these drugs exhibited favourable to moderate efficacy against the microorganisms that were tested.

A biological, fluorescence and computational examination of synthetic coumarin derivatives with antithrombotic potential.

Scientists still look for new drugs, which have anticoagulant properties. This is so important because existing anticoagulant drugs give many side effects, for example major bleeding. In this study we examined nine coumarin derivatives - candidates to be future antithrombotic drugs, which were synthetized and crystallized in our previous paper. Here we show the fluorescence and fluorescence quenching of coumarin derivatives with di- or trimethoxybenzylamine moieties in C-3 position. All nine compounds were checked by lactate dehydrogenase assay to examine their cytotoxic activity on hepatic cells. We also investigated the other biological properties (bioactivity, drug-likeness and blind docking) using computational tools. Lipophilicity coefficient logP of all obtained compounds was determined using by RP-TLC and compared to theoretical predictions. The obtained coumarins exhibited low lipophilic character. The substances bound with HSA and did not demonstrate cytotoxicity against isolated liver cells. The most interesting compound (3b) possessed two methoxy- group in 2- and 4-position in benzene ring, ability to interact with two HSA binding sites and probably smaller steric hindrance in comparison to other synthesized derivatives. Our present study shows that after examination of fluorescence, cytotoxic activity, lipophilicity, theoretical bioactivity, drug-likeness and blind docking of our synthesized compounds they have potential as antithrombotic medicines and may be candidates to be drugs after further studies.

ANTIOXIDANT, ANTICANCER AND IMMUNOCYTOCHEMISTRY ACTIVITIES OF THREE SYNTHETIC COUMARIN DERIVATIVES

Many biological studies have indicated that coumarin and itsderivatives can act as chemoperventive agents. In this study, three syntheticcoumarin derivatives were investigated for their free radical scavenging,anticancer and cell signaling activities. Compound A showed antioxidanteffects with 100% decoloration of DPPH at concentration of more than 150µg/ml with IC50 of 102.12 ± 0.15 µg/ml. Compound B and C inducedantioxidant effects with 100% decoloration at 100 and 50 µg/ml,respectively. Also, the IC50 of compounds B and C was 28.35 ± 0.04 and6.12 ± 0.05 µg/ml, respectively. Moreover, these compounds suppressedPC-3 prostate and MDA-MB-453 breast cancer cells proliferation with IC50of 20 µM, 70 µM and 50 µM, respectively for PC-3 cells. However, it needshigher dosage to inhibit MDA-MB-453 breast cancer cell growth with IC50at 25 µM, 137 µM and 100 µM, respectively. All of these compoundsactivated the apoptotic death signals downstream by activating caspasepathway. And showed many apoptotic characterizations including, DNAfragmentation and apoptotic bodies formation.

4-Methylumbelliferones Analogues as Anticancer Agents: Synthesis and in Cell Pharmacological Studies.

Cancer is one of the most serious clinical problems worldwide, and considerable efforts have been devoted to discovering therapeutic agents with novel modes of action. Natural and synthetic coumarin derivatives have attracted intense research interest due to their diverse structural features and remarkable array of biological properties. In the present study, we synthesized a series of 4-MU derivatives containing urea-piperazine and thioureapiperazine moieties and evaluated their antitumor activities to find efficacy antitumor drugs. Cell proliferation, apoptosis, cell cycle, the generation of reactive oxygen species and calcium were measured using MTT assay and flow cytometry, respectively. The expression of apoptosis- and proliferation-related proteins was determined by western blotting. The effect of 4l on apoptosis-related mRNA expression in NCI-H460 cells was detected by RT-PCR. Most of the target compounds exhibited potential anticancer activities against tested cancer cells but had low cytotoxicity to normal cells. Compound 4l inhibited the growth and proliferation of NCI-H460 cells and resulted in apoptosis. Successive studies conducted with 4l in NCI-H460 cells demonstrated that this compound induced the intracellular reactive oxygen species generation and calcium overload, suppressed nuclear factor-κB (NF-κB) activity and regulated anti- and pro-apoptotic proteins. In addition, compound 4l effectively arrested NCI-H460 cells in G2 phase and altered the cell cycle regulatory proteins especially cyclin B1. Compound 4l exerts significant anticancer effects on NCI-H460 cells in vitro through targeting of mitochondria-dependent apoptotic pathway. These results indicate that the strategy for rational design of 4-MU derivatives may identify potential anticancer agents.

Phytotoxic Potential and Biological Activity of Three Synthetic Coumarin Derivatives as New Natural-Like Herbicides.

Coumarin is a natural compound well known for its phytotoxic potential. In the search for new herbicidal compounds to manage weeds, three synthetic derivatives bearing the coumarin scaffold (1–3), synthesized by a carbonylative organometallic approach, were in vitro assayed on germination and root growth of two noxious weeds, Amaranthus retroflexus and Echinochloa crus-galli. Moreover, the synthetic coumarins 1–3 were also in vitro assayed on seedlings growth of the model species Arabidopsis thaliana to identify the possible physiological targets. All molecules strongly affected seed germination and root growth of both weeds. Interestingly, the effects of synthetic coumarins on weed germination were higher than template natural coumarin, pointing out ED50 values ranging from 50–115 µM. Moreover, all synthetic coumarins showed a strong phytotoxic potential on both Arabidopsis shoot and root growth, causing a strong reduction in shoot fresh weight (ED50 values ≤ 60 µM), accompanied by leaf development and a decrease in pigment content. Furthermore, they caused a strong alteration in root growth (ED50 values ≤ 170 µM) and morphology with evident alterations in root tip anatomy. Taken together, our results highlight the promising potential herbicidal activity of these compounds.

Coumarin: a promising scaffold for anticancer agents.

Coumarin enjoys an important place in drug discovery process due to its presence in diversity of biologically active compounds. Many compounds of plant origin are derivatives of coumarin. Taking these natural products as lead, research groups across the globe have designed and synthesized numerous coumarin analogues for treatment of varied diseases. Cancer is one of the dreadful chronic diseases, and many drugs are available for its treatment. However, due to heterogeneity of cancer, the search is still on to develop drugs for specific types of cancers. The present review is an attempt to study various coumarin derivatives of natural as well as synthetic origins, which are identified or developed for the treatment of different types of cancers. Herein, we have classified various anticancer coumarin derivatives on the basis of their origin as well as substitution around it. These are discussed under the headings of natural, semi-synthetic and synthetic coumarin derivatives. The synthetic coumarin derivatives are further classified as mono-, di- and poly-substituted and fused coumarin derivatives. Of the six positions available for substituents on coumarin nucleus, only three positions (C-3, C-4 and C-7) are exploited for the selection of functional groups appropriate for anticancer activity. The other positions (C-5, C-6 and C-8) are either unexplored or very less exploited. The present review is expected to provide the medicinal chemists a guide to choose new functional groups for substitution at different positions of coumarin nucleus for development of novel compounds for the treatment of a specific type of cancer.

Fragmentation pathways of synthetic and naturally occurring coumarin derivatives by ion trap and quadrupole time-of-flight mass spectrometry.

Synthetic and natural coumarin derivatives possess a wide range of biological activities. Fragmentation pathway studies are important in identifying both naturally occurring coumarins and synthetic coumarins with novel structures and properties. The fragmentation pathways of eleven coumarin derivatives are investigated by electrospray ionization (ESI) ion-trap mass spectrometry (ESI-ITMSn ) and ESI quadrupole time-of-flight mass spectrometry (QTOFMS) in positive mode. Compounds 1-9 in this study were newly synthesized in our laboratory. Compounds 10 and 11 were isolated from the root of Zanthoxylum armatum. The major fragmentation pathways for 11 coumarin derivatives are greatly affected by the heterocyclic ring structures and the side-chain substituents. Typical losses of small neutral molecules, such as CH3 CH2 OH, CH2 =CH2 , CO, and H2 O, are observed for compounds 1-5. Compounds 6-9 share similar fragmentation pathways through losses of CO, aromatic rings, and the coumarin skeleton. The main product ions at m/z 205, 219, and 220 observed for compounds 10 and 11 are produced by the loss of C5 H12 O2 , C4 H10 O2 , and the C4 H9 O2 radical, respectively. The fragmentation pathways of 11 coumarin derivatives are elucidated based on ITMSn and QTOFMS spectral data. Differences in the structures of the heterocyclic rings and side-chain substituents strongly affect the fragmentation pathways of the coumarins. The present results will facilitate further research into the fragmentation pathways and structural characterization of these classes of compounds with diverse structures. Copyright © 2015 John Wiley & Sons, Ltd.

Structure–activity relationship studies of 4-methylcoumarin derivatives as anticancer agents

Context: Cancer is a leading cause of death worldwide and novel chemotherapeutic agents with better efficacy and safety profiles are much needed. Coumarins are natural polyphenolic compounds with important pharmacological activities, which are present in many dietary plants and herbal remedies.Objectives: The objective of this study is to investigate natural and synthetic coumarin derivatives with considerable anticancer capacity against three human cancer cell lines.Materials and methods: We synthesized 27 coumarin derivatives (mostly having 4-methyl moiety) and examined their cytotoxic effect on three human cancer cell lines, K562 (chronic myelogenous leukemia), LS180 (colon adenocarcinoma), and MCF-7 (breast adenocarcinoma) by MTT reduction assay. Screened compounds included 7-hydroxy-4-methylcoumarins (7-HMCs), 7-acetoxy-4-methylcoumarins (7-AMCs), and different dihydroxy-4-methylcoumarin (DHMC) and diacetoxy-4-methylcoumarin (DAMC) derivatives. Some compounds with methoxy, amine, and bromine substitutions were also examined.Results: 7,8-DHMCs bearing alkyl groups at C3 position were the most effective subgroup, and of which, the most potent is compound 11, with an n-decyl chain at C3, which had IC50 values of 42.4, 25.2, and 25.1 µM against K562, LS180, and MCF-7 cells, respectively. The second most active subgroup was 7,8-DAMCs containing ethoxycarbonylmethyl and ethoxycarbonylethyl moieties at C3 position. Compound 27 (6-bromo-4-bromomethyl-7-hydroxycoumarin), the only derivative containing bromine also showed reasonable cytotoxic activities (IC50 range: 32.7–45.8 µM).Discussion and conclusion: This structure–activity relationship (SAR) study of 4-methylcoumarins shows that further investigation of these derivatives may lead to the discovery of novel anticancer agents.

Evaluation of luminol chemiluminescence based on simultaneous introducing of coumarin derivatives as green fluorophores and chitosan-induced Au/Ag alloy nanoparticle as catalyst for the sensitive determination of glucose.

We report herein the development of a novel chemiluminescence system based on simultaneous introducing of synthetic coumarin derivatives and chitosan-induced Au/Ag alloy NPs on the luminol CL system and suggest how it may be useful for determination of glucose. Chitosan-induced Au/Ag nanoalloys in the coumarin derivatives intensified-luminol CL system, in addition to catalyze CL reaction can make a change in the process of coumarin derivatives effect as fluorophore on the luminol CL system. This phenomenon is caused by interaction between active functional groups of coumarin derivatives and chitosan. The interaction strength depends on the coumarin derivatives' structure and their substituents. Considering the inevitable trend luminol radical and superoxide anion radical to absorption on the surface of the embedded Au/Ag nanoalloy in the chitosan matrix, it can be concluded that chitosan acts as a platform for all reagents involved in the CL reaction including coumarin derivatives, Au/Ag nanoalloy and luminol, and electron-transfer taking place on it; Placing all chemiluminescent reagents together on the chitosan network can lead to a powerful CL due to increasing rigidity of CL system. The most efficient coumarin derivative on the Au/Ag nanoalloy-fluorophore-luminol-H2O2 CL system, in relation to interaction capability with chitosan' functional groups, was selected and the CL condition in presence of it was optimized. Whereas the glucose oxidase-mediated oxidation of glucose yields gluconic acid and H2O2, under optimum condition the most efficient CL system was applied to detection of glucose due to enzymatically production of hydrogen peroxide. The linear response range of 1.5 × 10(-6)-5.0 × 10(-3)M and the detection limit (defined as the concentration that could be detected at the signal-to-noise ratio of 3) of 7.5 × 10(-7)M was found for the glucose standards. Also, the developed method was successfully applied to determination of glucose in real serum and urine samples of diabetic patients and validated against colorimetric spectroscopy method.

ChemInform Abstract: Comparative SAR of Synthetic Coumarin Derivatives for Their Anti‐inflammatory Activity

AbstractReview: 21 refs.

A small library of 4-(alkylamino)-3-nitrocoumarin derivatives with potent antimicrobial activity against gastrointestinal pathogens

Due to a confirmed antimicrobial activity of both natural and synthetic coumarin derivatives, the present study was envisaged to provide a further insight into the antimicrobial potential of coumarins through a screening of a designed library of nine 4-(alkylamino)-3-nitrocoumarins against a panel of 24 laboratory strains and resistant (isolates) bacterial and fungal pathogens. All compounds showed some degree of strain-selective activity, that was, in some cases, very pronounced, reaching the value of 0.04 nmol/ml (i.e. 12 ng/ml) for the minimal inhibitory concentration against Candida albicans. The observed activity was higher against Gram-negative strains, among which the most susceptible strain, among both ATCC strains and clinical isolates, was Salmonella enteritidis. These results point out to a high potential of these coumarins as antimicrobials for the treatment of gastrointestinal and other infections caused by highly resistant microbial strains. Finally, a multivariate statistical analysis of the herein obtained and previous results on the antimicrobial activity of related selected coumarins was performed to allow an easier structure-activity discussion.

Synthetic Models Related to Methoxalen and Menthofuran–Cytochrome P450 (CYP) 2A6 Interactions. Benzofuran and Coumarin Derivatives as Potent and Selective Inhibitors of CYP2A6

Human microsomal cytochrome P450 (CYP) 2A6 contributes extensively to nicotine detoxication but also activates tobacco-specific procarcinogens to mutagenic products. We prepared a series of benzofuran and coumarin derivatives that have inhibitory effects on the activity of human CYP2A6. The reported compounds methoxalen and menthofuran had potent inhibitory effects on the activity of CYP2A6 with IC50 values of 0.47 µM and 1.27 µM, respectively. Synthetic benzofuran (4-methoxybenzofuran: IC₅₀=2.20 µM) and coumarin (5-methoxycoumarin: IC₅₀=0.13 µM and 6-methoxycoumarin: IC₅₀=0.64 µM) derivatives, which have more selective effects than those of methoxalen and menthofuran, exhibited comparable activities against CYP2A6. These compounds can be used as a lead compounds in the design of CYP2A6 inhibitor drugs to reduce smoking and tobacco-related cancers.

Study of Possible Mechanisms Involved in the Inhibitory Effects of Coumarin Derivatives on Neutrophil Activity

To specify the site of action of the synthetic coumarin derivatives 7-hydroxy-3-(4′-hydroxyphenyl) coumarin (HHC) and 7-hydroxy-3-(4′-hydroxyphenyl) dihydrocoumarin (HHDC), we evaluated their effects on extra- and intracellular reactive oxygen species (ROS) formation in phorbol-myristate-13-acetate (PMA) stimulated human neutrophils. We studied also the effects of HHC and HHDC on possible molecular mechanisms which participate in the activation of NADPH oxidase, that is, on PKC activity, on phosphorylation of some PKC isoforms (α, βII, and δ), and on phosphorylation of the NADPH oxidase subunit p40phox. Without affecting cytotoxicity, both coumarines tested were effective inhibitors/scavengers of ROS produced by neutrophils on extracellular level. HHC markedly diminished oxidant production and also, intracellularly, decreased PKC activity and partly phosphorylation of PKCα, βII. On the other hand, we did not observe any effect of coumarin derivatives on phosphorylation of PKCδ and on phosphorylation of the NADPH oxidase subunit p40phox, which were suggested to be involved in the PMA-dependent intracellular activation process. In agreement with our previous findings, we assume that the different molecular structures of HHC and HHDC with their different physicochemical and free radical scavenging characteristics are responsible for their diverse effects on the parameters tested.

Synthesis of 3-amino-4-hydroxy coumarin and dihydroxy-phenyl coumarins as novel anticoagulants

Natural and synthetic coumarin derivatives have been shown to possess several beneficial pharmacological effects. The anticoagulation and antithrombotic activities of the 4-hydroxy coumarin derivatives are well known. In this study, besides the 4-hydroxy substituent phenyl and p-methylphenyl derivatives were synthesized and confirmed on the basis of their spectral data. 3-Amino-4-hydroxy coumarin, 5,7-dihydroxy-4-phenyl coumarin and 7,8-dihydroxy-3-(4-methylphenyl)coumarin were tested in rats to determine whether they had any effect on vitamin K inhibition by investigating the prothrombin time (PT). PT values of coumarin derivatives were compared with those of warfarin (CAS 81-81-2), which is the most commonly used anticoagulant. 7,8-Dihydroxy-3-(4-methylphenyl)coumarin increased PT when compared to saline treated control group and other coumarins synthesized, 3-amino-4-hydroxy coumarin and 5,7-dihydroxy-4-phenyl coumarin.

Novel inhibition of some pathogenic fungal and bacterial species by new synthetic phytochemical coumarin derivatives

novel antifungal and antibacterial activities of new synthesized phytochemical coumarin compounds [H2L1, HL2 and H2L3] and their copper (II) complexes [L1Cu], [L2Cu(OAc)] and [(L3)Cu2(H2O)4(OAc)2] were evaluated against nine pathogenic fungal species (Alternaria alternata, Aspergillus flavus, Botrytis cinerea, Cladosporium herbarum, Fusarium moniliforme, Helminthosporium tetramera, Penicillium expansum, Rhizopus stolonifer andVerticillium albo-atrum) and eight pathogenic bacterial species, from which four Gram-positive bacteria (Bacillus subtilis, Micrococcus luteus, Staphylococcus citrus andStreptococcus pneumoniae) and four Gram-negative bacteria (Enterobacter aerogenes, Escherichia coli, Pseudomonas aeruginosa andSalmonella typhi). The phytochemical copper (II) complex [L2Cu(OAc)] was the most effective derivative, where it reaches to 90 and 100% inhibition in the most sensitive pathogens (B. subtilis and A. flavus), respectively accompanied with a significant reduction in pectinolytic and cellulytic enzyme activities in all tested pathogenic species. Addition of [L2Cu(OAc)] complex leading to leakage of sugars and electrolytes from the most sensitive microbial cells accompanied with collapsed hyphae ofA. Flavus and membrane blobbing ofB. Subtilis. The production of mycotoxins decreased with the extension exposure to [L2Cu(OAc)] complex reaching to a minimum values for the mycelium originating from the inoculum exposed to the minimum inhibitory concentration (2%). Both aflatoxin (AFB1) and citrinin were the most sensitive toxins.

Novel inhibition of some pathogenic fungal and bacterial species by new synthetic phytochemical coumarin derivatives

novel antifungal and antibacterial activities of new synthesized phytochemical coumarin compounds [H 2 L 1 , HL 2 and H 2 L 3 ] and their copper (II) complexes [L 1 Cu], [L 2 Cu(OAc)] and [(L 3 )Cu 2 (H 2 O) 4 (OAc) 2 ] were evaluated against nine pathogenic fungal species (Alternaria alternata, Aspergillus flavus, Botrytis cinerea, Cladosporium herbarum, Fusarium moniliforme, Helminthosporium tetramera, Penicillium expansum, Rhizopus stolonifer and Verticillium albo-atrum) and eight pathogenic bacterial species, from which four Gram-positive bacteria (Bacillus subtilis, Micrococcus luteus, Staphylococcus citrus and Streptococcus pneumoniae) and four Gram-negative bacteria (Enterobacter aerogenes, Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi). The phytochemical copper (II) complex [L 2 Cu(OAc)] was the most effective derivative, where it reaches to 90 and 100% inhibition in the most sensitive pathogens (B. subtilis and A. flavus), respectively accompanied with a significant reduction in pectinolytic and cellulytic enzyme activities in all tested pathogenic species. Addition of [L 2 Cu(OAc)] complex leading to leakage of sugars and electrolytes from the most sensitive microbial cells accompanied with collapsed hyphae of A. flavus and membrane blobbing of B. subtilis. The production of mycotoxins decreased with the extension exposure to [L 2 Cu(OAc)] complex reaching to a minimum values for the mycelium originating from the inoculum exposed to the minimum inhibitory concentration (2%). Both aflatoxin (AFB 1 ) and citrinin were the most sensitive toxins.

Natural and Synthetic Coumarin Derivatives with Anti-Inflammatory / Antioxidant Activities

Several natural products with a coumarinic moiety have been reported to have multiple biological activities. It is to be expected that, in a similar way to isomeric flavonoids, coumarins might affect the formation and scavenging of reactive oxygen species (ROS) and influence processes involving free radical-mediated injury. Coumarin can reduce tissue edema and inflammation. Moreover coumarin and its 7-hydroxy-derivative inhibit prostaglandin biosynthesis, which involves fatty acid hydroperoxy intermediates. Natural products like esculetin, fraxetin, daphnetin and other related coumarin derivatives are recognised as inhibitors not only of the lipoxygenase and cycloxygenase enzymic systems, but also of the neutrophil-dependent superoxide anion generation. Due to the unquestionable importance of coumarin derivatives considerable efforts have been made by several investigators, to prepare new compounds bearing single substituents, or more complicated systems, including heterocyclic rings mainly at 3-, 4- and/or 7-positions. In this review we shall deal with naturally occurring or synthetically derived coumarin derivatives, which possess anti-inflammatory as well as antioxidant activities.

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

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−1 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.