Current developments of coumarin-based anti-cancer agents in medicinal chemistry

Coumarin derivatives were recently shown to constitute a totally new class of inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), being hydrolyzed within the CA active site to 2-hydroxycinnamic acids. We explore here a new series of variously substituted coumarins and a thiocoumarin for their interaction with 13 mammalian CA isoforms, detecting low nanomolar and isoform selective inhibitors. The mechanism of action of this class of inhibitors is delineated in detail by resolving the X-ray crystal structure of CA II in complex with trans-2-hydroxy-cinnamic acid, the in situ hydrolysis product of simple coumarin. Thiocoumarins also act as efficient CAIs, similarly to coumarins. The versatility of the (thio)coumarin chemistry, the cis-trans isomerization evidenced here, and easy derivatization of the (thio)coumarin rings, coupled with the nanomolar inhibition range of several isozymes, afford isoform-selective CAIs with various biomedical applications, which render these classes of compounds superior to the clinically used sulfonamides.

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Deciphering the mechanism of carbonic anhydrase inhibition with coumarins and thiocoumarins.

Synthesis, spectral characterization, in vitro antibacterial, antifungal and cytotoxic activities of Co(II), Ni(II) and Cu(II) complexes with 1,2,4-triazole Schiff bases.

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.

The Structure and Pharmacological Functions of Coumarins and Their Derivatives

Biological importance of structurally diversified chromenes

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.

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

A series of esters and amides of 6-(chloromethyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid were synthesized and evaluated in vitro for their inhibitory activity toward bovine α-chymotrypsin and human leukocyte elastase. Both series behaved as time-dependent inhibitors of α-chymotrypsin, but ester-type coumarins were clearly more efficient than the corresponding amides in inactivating the serine proteinase. The best inactivations were observed with “aromatic” esters, in particular with meta-substituted phenyl esters such as m-chlorophenyl 6-(chloromethyl)-2-oxo-2H-1-benzopyran-3-carboxylate, which appears to be one of the most powerful inactivators of α-chymotrypsin yet reported (kinact/KI = 760 000 M-1 s-1 at pH 7.5 and 25 °C). Usually, the coumarin derivatives failed to inhibit significantly human leukocyte elastase. As a result, the reported series of aromatic coumarinic esters behaves as a new chemical family of selective α-chymotrypsin inhibitors.

Esters and Amides of 6-(Chloromethyl)-2-oxo-2H-1-benzopyran-3-carboxylic Acid as Inhibitors of α-Chymotrypsin: Significance of the “Aromatic” Nature of the Novel Ester-Type Coumarin for Strong Inhibitory Activity

Enhancement of aflatoxin B1 cytotoxicity in differentiated rat hepatoma cultures by a prior glucocorticoid treatment of the monolayer

Esters and Amides of 6‐(Chloromethyl)‐2‐oxo‐2H‐1‐benzopyran‐3‐ carboxylic Acid as Inhibitors of α‐Chymotrypsin: Significance of the “Aromatic” Nature of the Novel Ester‐Type Coumarin for Strong Inhibitory Activity.

In cultures of the differentiated clones Faza 967, Fao and HF, derived from Reuber hepatoma, physiological doses of glucocorticoid induce chenodeoxycholate 6 beta-hydroxylation, a microsomal cytochrome-P-450-mediated activity (enhanced in liver by phenobarbital and not by benzo[a]anthracene). Whereas 12-O-tetradecanoylphorbol 13-acetate (TPA) alone has no effect the tumor promoter, when added to dexamethasone, enhances this induction. This enhancement, half-maximum with 10 ng/ml TPA, is a function of the dose between 1 ng/ml and 50 ng/ml; 50 ng/ml (80 nM) increase 4-7-fold the induction rate (as measured in cultures by the amount of bile acid hydroxylated per 10(6) cells in 24 h, and in homogenates from treated cells) and 2.5-fold the maximum activity attained by the third day of induction. When added to cultures of the dedifferentiated clone H5, treated with benzo[a]anthracene, TPA does not influence benzo[a]pyrene hydroxylase induction, as shown by the total and relative amounts of the various hydrosoluble benzo[a]pyrene metabolites. TPA does not affect tyrosine aminotransferase induction in dexamethasone-treated Fao cultures. The enhancement is not suppressed by indomethacin, an inhibitor of prostaglandin synthesis. After dexamethasone removal from induced Faza 967 cultures, addition of TPA to the medium does not affect the decay rate of the chenodeoxycholate-hydroxylating activity. Retinoic acid similarly enhances the induction by dexamethasone of chenodeoxycholate hydroxylation, both in treated Faza 967 cultures and in homogenates from treated cultures. The effects of TPA and retinoic acid are additive. These results suggest a possible cooperation at the transcriptional level between transactive factors, involving TPA-mediated alterations, retinoic acid and glucocorticoid receptors. The system described might provide a convenient experimental approach in the study of its mechanism.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1988.tb14233.x

N. Thierry

Papers

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

Esters and Amides of 6-(Chloromethyl)-2-oxo-2H-1-benzopyran-3-carboxylic Acid as Inhibitors of α-Chymotrypsin: Significance of the “Aromatic” Nature of the Novel Ester-Type Coumarin for Strong Inhibitory Activity

Enhancement of aflatoxin B1 cytotoxicity in differentiated rat hepatoma cultures by a prior glucocorticoid treatment of the monolayer

Esters and Amides of 6‐(Chloromethyl)‐2‐oxo‐2H‐1‐benzopyran‐3‐ carboxylic Acid as Inhibitors of α‐Chymotrypsin: Significance of the “Aromatic” Nature of the Novel Ester‐Type Coumarin for Strong Inhibitory Activity.

Enhancing effect of a phorbol ester and of retinoic acid on glucocorticoid induction of chenodeoxycholate hydroxylation in hepatoma cultures.