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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

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.
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.

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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Citations
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Journal ArticleDOI
TL;DR: The whole range of medicinal chemistry in the current developments of coumarin compounds as anticoagulant, antineurodegenerative, anticancer, antioxidative, antibacterial, antifungal, antiviral, antiparasitic, antiinflammatory and analgesic, antidiabetic, antidepressive and other bioactive agents as well as supramolecular medicinal drugs, diagnostic agents and pathologic probes, and biological stains are presented.
Abstract: Coumarin compounds represent an important type of naturally occurring and synthetic oxygen-containing heterocycles with typical benzopyrone framework. This type of special benzopyrone structure enables its derivatives readily interact with a diversity of enzymes and receptors in organisms through weak bond interactions, thereby exhibit wide potentiality as medicinal drugs. So far, some coumarin-based drugs such as anticoagulant and antineurodegenerative agents have been extensively used in clinic. Coumarin-containing supramolecular medicinal agents as a new increasing expansion of supramolecular chemistry in pharmaceutical science have also been actively investigated in recent years. Coumarin-derived artificial ion receptors, fluorescent probes and biological stains are growing quickly and have a variety of potential applications in monitoring timely enzyme activity, complex biological events as well as accurate pharmacological and pharmacokinetic properties. This review provides a systematic summary and insight of the whole range of medicinal chemistry in the current developments of coumarin compounds as anticoagulant, antineurodegenerative, anticancer, antioxidative, antibacterial, antifungal, antiviral, antiparasitic, antiinflammatory and analgesic, antidiabetic, antidepressive and other bioactive agents as well as supramolecular medicinal drugs, diagnostic agents and pathologic probes, and biological stains. Some rational design strategies, structure-activity relationships and action mechanisms are discussed. The perspectives of the future development of coumarinbased medicinal chemistry are also presented.

369 citations


Cites background from "6-Substituted 2-oxo-2H-1-benzopyran..."

  • ...Apart from the above mentioned cancers, coumarin compounds still exert influential potency against other cancers [124-126]....

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TL;DR: The current developments of coumarin-based anticancer agents are covered and the structure-activity relationship of the most potent compounds are discussed.
Abstract: Cancer is one of the leading health hazards and the prominent cause of death in the world. A number of anticancer agents are currently in clinical practice and used for treatment of various kinds of cancers. There is no doubt that the existing arsenal of anticancer agents is insufficient due to the high incidence of side effects and multidrug resistance. In the efforts to develop suitable anticancer drugs, medicinal chemists have focused on coumarin derivatives. Coumarin is a naturally occurring compound and a versatile synthetic scaffold possessing wide spectrum of biological effects including potential anticancer activity. This review article covers the current developments of coumarin-based anticancer agents and also discusses the structure-activity relationship of the most potent compounds.

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Journal ArticleDOI
Longhuo Wu1, Xiao Wang, William Xu, Farzin Farzaneh, Ruian Xu 
TL;DR: This review will focus on recent advances in molecular and cellular mechanisms of coumarin action involved with the relationship between structure and activity.
Abstract: Coumarins are of many different structures. They constitute an important class of pharmacological agents possessing a range of different physiological activities including anti-cancer, anti-oxidant, anti- inflammation, anti-HIV, anti-coagulant, anti-bacterial, analgesic and comparative immune-modulation. Recently, coumarins have attracted intense research interest. Of great interest is the possibility that this class of molecules could be a source of drugs for the therapy of several diseases. These include recent insights into inhibiting cell proliferation by interfering with mitotic spindle microtubule function, decrease Matrix Metalloproteinase (MMP) activity, block the cell cycle in the S or G2/M phases to interfere with processes of cell division, suppress O2(-) generation in leukocytes, inhibit different protein kinases, modulate the signalings, induce carcinogen-detoxifying enzymes glutathione S-transferases (GSTs) and/or NAD(P)H quinine oxidoreductase (NQO1), suppress the phosphorylation of Akt/PKB as a mechanism inhibiting inflammation, progress in structure modification to increase in anti-fungal action, to broaden against bacteria spectrum, to enhance inhibiting activities of nitric oxide synthase (NOS) and cyclooxygenase (COX), to strengthen anti-oxidant activity and to exhibite a much higher cytotoxicity against human umbilical vein endothelial cell (HUVEC). With fewer non-hemorrhagic side effects than the indanedione derivatives, they can be applied as an oral anticoagulant commonly for preventing venous thromboembolism following orthopedic surgery, recurrent myocardial infarction and the treatment of systemic embolism in atrial fibrillation, together with the significant advances in the basis of drug action. It is therefore useful to build up some correlations with the data available in order to better explore the molecular and cellular mechanism of coumarin action in the treatment of diseases. This review will focus on recent advances in molecular and cellular mechanisms of coumarin action involved with the relationship between structure and activity.

217 citations

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TL;DR: The occurence, synthesis and specific biological activities of various coumarin derivatives are described for the discovery and development of new synthetic strategies that could help in structure–activity relationship (SAR) studies.
Abstract: Coumarins are oxygen-containing molecules with specific benzopyrone nucleus. Different coumarins are identified as antineurodegeneratives, anticoagulants, antioxidants, antimicrobials, anticancers, antivirals, antidiabetics, antidepressants, supramoleculars, antiparasitics, anti-inflammatory, analgesics, biological stains, pathological probes and diagnostics. Coumarins have received more attention as compared to 1-azacoumarins. Many attempts have been made for the comparison of both the systems at different stages to discover novel synthetic methodologies, reactivity strategies and biological activities. Translation of current knowledge into novel potent lead compounds and repositioning of well-known compounds for the treatment of different acute and chronic diseases are the current challenges of coumarins. This review article focusses on the occurence, synthesis and specific biological activities of various coumarin derivatives. Some novel research approaches are also described for the discovery and development of new synthetic strategies that could help in structure–activity relationship (SAR) studies. Cellular and molecular mechanisms of coumarins involved in SAR studies are also described.

99 citations


Cites background from "6-Substituted 2-oxo-2H-1-benzopyran..."

  • ..., 2008; Henry and Yen, 2008), anticancer (Win et al., 2008; Isabelle et al., 2008), anticonvulsant (Fatma et al....

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  • ...…(Kalkhambkar et al., 2008; Grimm et al., 2006), antiplatelet aggregation (Juan et al., 2008; Henry and Yen, 2008), anticancer (Win et al., 2008; Isabelle et al., 2008), anticonvulsant (Fatma et al., 2008), comparative immunomodulatory (Cherng et al., 2008) and analgesic (Hu et al., 2008;…...

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Journal ArticleDOI
TL;DR: In this article, the carbon-carbon (C-C) bond forms the backbone of nearly every organic molecule and lies at the heart of the chemical sciences, and the most effective way to save energy is to develop strategies/protocols that are capable enough to carry out the transformations at ambient temperature and pressure.
Abstract: The carbon–carbon (C–C) bond forms the ‘backbone’ of nearly every organic molecule, and lies at the heart of the chemical sciences! This transformation has always been one of the most useful and fundamental reactions in the development of organic chemistry. Currently, the concept of ‘green chemistry’ is globally acclaimed and has already advanced quite significantly to emerge as a distinct branch of chemical sciences. Among the principles of ‘green chemistry’, one principle is dedicated to the “design of energy efficiency” – that is to develop synthetic strategies that require less/minimum amounts of energy to carry out a specific reaction with optimum productivity. And the most effective way to save energy is to develop strategies/protocols that are capable enough to carry out the transformations at ambient temperature and pressure! As part of the on-going developments in green synthetic strategies, designing for reactions under ambient conditions coupled with other green aspects is, thus, an area of current choice. This review is aimed at offering an up-to-date development on the design of carbon–carbon bond forming protocols to access a wide variety of organic molecules of topical significance under ambient conditions. The account highlights the brilliant applications of reaction conditions such as the use of solvents or no solvent, catalysts or no catalyst, and the use of green tools like ball-milling, ultrasonication and visible light in achieving the goal!

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References
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TL;DR: These studies suggest that both genistein and esculetin exerted the most potent inhibitory effect on cell growth in comparison to the other two compounds, which may lead to its use in cancer therapy.
Abstract: The Benzopyrones are a group of compounds whose members include coumarins and flavonoids. Dietary exposure to benzopyrones is quite significant, as these compounds are found in vegetables, fruit, seeds, nuts, coffee, tea and wine. It is estimated that the average western diet contains approximately 1 g/day of mixed benzopyrones. It is, therefore, not difficult to see why extensive research into their pharmacological and therapeutic properties is underway over many years. Coumarin is a natural substance that has shown anti-tumour activity in vivo, with the effect believed to be due to its metabolites (e.g. 7-hydroxycoumarin). This review is based on recent studies of coumarins and coumarin related compounds. Therefore, the focus will be on these relevant compounds and their therapeutic importance. A recent study has shown that 7-hydroxycoumarin inhibits the release of Cyclin D1, which is overexpressed in many types of cancer. This knowledge may lead to its use in cancer therapy. Esculetin inhibits growth and cell cycle progression by inducing arrest of the G(1) phase in HL-60 leukaemia cells, resulting from the inhibition of retinoblastoma protein phosphorylation. Recent studies investigating the potential of flavonoids as therapeutic agents have suggested they may have use in various therapeutic settings ranging from leukaemia treatment to the treatment of patients with HIV. Genistein is a well-known isoflavone and is a tyrosine kinase inhibitor. Studies have indicated that genistein elicits inhibitory effects on cell growth of various carcinoma cell-lines and may be a potential candidate for cancer therapy. In our research, we have investigated the effects of coumarins and coumarin-related compounds on a panel of cell-lines. The most recent work involves two cell-lines, MCF-7 a breast carcinoma and A549 a lung carcinoma. Microtitre assays were performed along with real-time analysis of cell viability using a biosensor called the Cytosensor microphysiometer. These studies suggest that both genistein and esculetin exerted the most potent inhibitory effect on cell growth in comparison to the other two compounds.

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TL;DR: There is still a long way to go until the authors know which cytotoxic agent will clinically be suitable for what tumor entity for treatment, because promising data have been reported for a series of these agents, and the results from different coumarins with various tumor lines are contradictory in part.
Abstract: Coumarins, an old class of compounds, are naturally occurring benzopyrene derivatives. A lot of coumarins have been identified from natural sources, especially green plants. The pharmacological and biochemical properties and therapeutic applications of simple coumarins depend upon the pattern of substitution. Coumarins have attracted intense interest in recent years because of their diverse pharmacological properties. Among these properties, their cytotoxic effects were most extensively examined. In this review, their broad range of effects on the tumors as shown by various in vitro and in vivo experiments and clinical studies are discussed. Hence, these cytotoxic coumarins represent an exploitable source of new anticancer agents, which might also help addressing side-toxicity and resistance phenomena. These natural compounds have served as valuable leads for further design and synthesis of more active analogues. In this review, plant derived coumarins and their synthetic analogues were systematically evaluated based on their plant origin, structure-activity relationship and anticancer efficacy. Owing the their diverse effects and inconclusive results from different in vitro studies, the mechanism of their action is not yet fully understood and correlation of effects with chemical structures is not conclusive at the moment. It is the objective of this review to summarize experimental data for different coumarins, used as cytotoxic agents, because promising data have been reported for a series of these agents. Yet, the results from different coumarins with various tumor lines are contradictory in part. We therefore conclude that there is still a long way to go until we know which cytotoxic agent will clinically be suitable for what tumor entity for treatment. Their ability to bind metal ions represents an additional means of modulating their pharmacological responses.

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TL;DR: The present review provides an updated summary of emerging clinical experience with Sunitinib malate, an oral multitargeted tyrosine kinase inhibitor with antitumour and antiangiogenic activity that recently received approval from the FDA.
Abstract: Receptor tyrosine kinases (RTKs) play important roles in the regulation of cellular growth, and mutated or overexpressed RTKs have been implicated in various human cancers. Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor with antitumour and antiangiogenic activity that recently received approval from the FDA for the treatment of advanced renal cell carcinoma and of gastrointestinal stromal tumours after disease progression on or intolerance to imatinib mesilate therapy. Sunitinib has also demonstrated promising clinical activity in the treatment of other advanced solid tumours. The present review provides an updated summary of emerging clinical experience with this promising new anticancer agent.

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TL;DR: It was demonstrated that due to its antiangiogenic activity, linomide treatment of rats bearing prostate cancers resulted in a more than 40% decrease in tumor blood flow and blood flow to a variety of non-tumor bearing organs was not decreased suggesting that linomides selectively inhibits angiogenesis and does not induce loss of established blood vessels.
Abstract: Linomide ( N -phenylmethyl-1,2-dihydro-4-hydroxyl-1-methyl-2-oxoquinoline-3-carboxamide) has a reproducible in vivo antitumor effect against a series of both androgen responsive and independent Dunning R-3327 rat prostatic cancers. This antitumor effect of linomide is host mediated. One possible mechanism involving the host is that linomide has antiangiogenic activity. An indication that linomide treatment has antiangiogenic activity is the observation that prostatic cancers from linomide treated rats have more focal necrosis than sized matched tumors from untreated rats. To directly test if linomide has antiangiogenic activity, a newly developed Matrigel based quantitative in vivo angiogenic assay was used. These experiments demonstrated that linomide has dose dependent, antiangiogenic activity in vivo in the rat. Additional studies demonstrated that due to its antiangiogenic activity, linomide treatment of rats bearing prostate cancers resulted in a more than 40% decrease in tumor blood flow. Blood flow to a variety of non-tumor bearing organs was not decreased suggesting that linomide selectively inhibits angiogenesis and does not induce loss of established blood vessels. Using as a model the response of human umbilical vein endothelial cells to linomide treatment in a variety of in vitro assays, linomide was demonstrated to have cytostatic but not cytotoxic effect on human umbilical vein endothelial cells at a medium concentration of ≥100 µg/ml. In addition, both endothelial cell chemotactic migration and invasion are steps in angiogenesis inhibited by linomide treatment.

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TL;DR: Early results suggest that acute toxicity is acceptable, planned surgery after such treatment is feasible, and that further evaluation of such combined modality treatment is warranted.
Abstract: Angiogenesis inhibitors combined with cytotoxic chemotherapy have recently entered routine oncological practice. Several rationales exist for combining these agents with ionizing radiation, a primary curative cancer treatment, either in bimodal or trimodal fashion, i.e. with or without additional chemotherapy. More than 20 different anti-angiogenic agents have been studied in preclinical animal tumor models. This systematic review compares the results of preclinical studies published before February 2006. The combination of vascular endothelial growth factor (VEGF) inhibitors with irradiation consistently resulted in improved tumor growth delay (at least additive effects), despite different radiation schedules, drugs and doses, and combination regimens. Only two studies evaluated tumor control dose (TCD)50 as a measure of tumor cure (radiation dose yielding permanent local control in 50% of the tumors). While anti-VEGF receptor (VEGFR) antibody treatment improved the outcome, a VEGFR tyrosine kinase inhibitor showed negative results. For agents interfering with other pathways, the results are also not consistent, although most studies were positive. Trimodal approaches seem to improve tumor growth delay even further. Importantly, both radiotherapy schedule and sequence of the modalities in combined treatment may impact on the outcome. Hence, further preclinical studies examining these parameters need to be conducted. While preclinical research is ongoing, phase I and II clinical trials with bevacizumab, combretastatin A-4, thalidomide and different receptor tyrosine kinase inhibitors, usually combined with radio- and chemotherapy, have been designed. Early results suggest that acute toxicity is acceptable, planned surgery after such treatment is feasible, and that further evaluation of such combined modality treatment is warranted.

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Frequently Asked Questions (1)
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.