Dimitra Hadjipavlou-Litina

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.

Biological Evaluation of Several Coumarin Derivatives Designed as Possible Anti-inflammatory/Antioxidant Agents

Several linear and angular coumarins designed and synthesised as possible anti-inflammatory and antioxidant agents were evaluated for their biological activities, using the carrageenin-induced rat paw oedema model. In general, the compounds were found to be potent anti-inflammatory agents. Compound (4) was found to possess protective properties in adjuvant-induced arthritis in rats. The compounds were found to interact with 1,1-diphenyl-2-picryl-hydrazyl stable free radical (DPPH) whereas most of them were essentially inactive in other tests. The anti-inflammatory activity seemed to be connected with their reducing activity. R M values were determined as an expression of their lipophilicity which was also calculated as clog P. Only a poor relationship existed between lipophilicity and anti-inflammatory activity.

Synthesis and evaluation of the antioxidant and anti-inflammatory activity of novel coumarin-3-aminoamides and their alpha-lipoic acid adducts

In the present work a series of novel coumarin-3-carboxamides and their hybrids with the alpha-lipoic acid were designed, synthesized and tested as potent antioxidant and anti-inflammatory agents. The new compounds were evaluated for their antioxidant activity, their activity to inhibit in vitro lipoxygenase and their in vivo anti-inflammatory activity. In general, the derivatives were generally found to present antioxidant and anti-inflammatory activities. Discussion is made based on the results for the structure-activity relationships in order to define the structural features required for activity.

Synthesis and biological evaluation of several coumarin-4-carboxamidoxime and 3-(coumarin-4-yl)-1,2,4-oxadiazole derivatives

A series of novel coumarin-4-carboxamidoximes 6a-g and 3-(coumarin-4-yl)-1,2,4-oxadiazoles 9a-e were synthesized from coumarin-4-carboxaldehyde 1 via the intermediate coumarin-4-nitriloxide 4. These coumarin derivatives were isolated and characterized, and evaluated for their ability to inhibit trypsin, glucuronidase, and soybean lipoxygenase. The compounds were also tested for antioxidant activity, and as antiiflammatory agents in the rat carrageenin paw edema assay.

Synthesis of hydroxycoumarins and hydroxybenzo[f]- or [h]coumarins as lipid peroxidation inhibitors.

Substituted hydroxycoumarins and 7- or 8-hydroxybenzo[f]coumarins were prepared by the treatment of phenols and naphthalenediols, respectively, with malic acid and H(2)SO(4) under microwave irradiation. 7- or 8-Hydroxybenzo[f]coumarins and 6-hydroxybenzo[h]coumarin were synthesized by the reaction of naphthalenediols with ethylpropiolate in the presence of ZnCl(2) in refluxing dioxane. The compounds were tested in vitro for their ability: (i) to interact with 1,1-diphenyl-2-picryl-hydrazyl (DPPH) stable free radical, (ii) to inhibit lipid peroxidation, (iii) to scavenge the superoxide anion, (iv) to inhibit the activity of soybean lipoxygenase and (v) to inhibit in vivo the carrageenin-induced rat paw edema. Most of them are potent superoxide anion scavengers and inhibit in vitro lipid peroxidation. The majority of the compounds did not show high lipoxygenase inhibitory activity. No differences were observed between biological responses of hydroxycoumarins and hydroxybenzocoumarins. Compound 3i was found to present a promising antioxidant profile.

A novel synthesis of 3-aryl coumarins and evaluation of their antioxidant and lipoxygenase inhibitory activity.

A series of coumarin analogues bearing a substituted phenyl ring on position 3 were synthesized via a novel methodology, through an intermolecular condensation reaction of 2-hydroxyacetophenones and 2-hydroxybenzaldehyde, with imidazolyl phenylacetic acid active intermediates. The in vitro antioxidant activity of the synthesized compounds was evaluated using two different antioxidant assays (radical scavenging ability of DPPH stable free radical and inhibition of lipid peroxidation induced by the thermal free radical AAPH). Moreover, the ability of the compounds to inhibit soybean lipoxygenase was determined as an indication of potential anti-inflammatory activity.

Coumarin-based drugs: a patent review (2008 -- present).

Introduction: Coumarins are a group of plant-derived polyphenolic compounds. They belong to the benzopyrones family and possess a wide variety of cytoprotective and modulatory functions, which may be translated to therapeutic potentials for multiple diseases. Their physicochemical properties seem to define the extent of the biological activity. Areas covered: In this review recent patent publications (2008 – 2011), describing coumarins and their derivatives, are analyzed. Synthesis, combinatorial techniques, biological evaluation in vitro/in vivo/ex vivo, e.g. antimitotic, immunomodulating, antiviral, anticancer and cytotoxic agents, as well as some new biological assays, are included. In addition to selected biological data, a wide range of pharmaceutical applications and pharmaceutical compositions are also summarized. Expert opinion: Several natural and synthetic coumarins and derivatives with potent in vivo/in vitro biological responses appear to be promising anticancer activities. Their clinical evaluation will be critical to assess therapeutic utility. The compounds for which the mechanism of action is well defined can serve as lead compounds for the design of new more promising molecules.

Chalcones in cancer: understanding their role in terms of QSAR.

Chalcones are a group of plant-derived polyphenolic compounds belonging to the flavonoids family and possess a wide variety of cytoprotective and modulatory functions. The results showed that chalcones inhibit the proliferation of MCF-7 and MDA-MB-231 by inducing apoptosis and blocking cell cycle progression in the G2/M phase. Immunoblot assay showed that chalcones significantly decreased the expression of cyclin Bl, cyclin A and Cdc2 protein, as well as increased the expression of p21 and p27 in a p53-independent manner, contributing to cell cycle arrest. In this research we tried to review the anticancer effect of chalcones derivatives, and to evaluate new QSARs which will help in the understanding of the role of chalcones and of their analogues on cancer. Simultaneously a comparative study will be presented. Our QSAR results reveal that in almost all cases, the clog P parameter plays an important part in the QSAR relationships (linear or bilinear model). In some cases the steric factors such as the CMR or the substituents MR (linear) are important. Electronic effects are comparatively unimportant. The study shows that log P as calculated from the Clog P program is suitable for this form of QSAR study.

Systemic and Intrathecal Effects of a Novel Series of Phospholipase A2 Inhibitors on Hyperalgesia and Spinal Pge2 Release

Phospholipase A2 (PLA2) forms are expressed in spinal cord, and inhibiting spinal PLA2 induces a potent antihyperalgesia. Here, we examined the antihyperalgesic effects after systemic and i.t. delivery of four compounds constructed with a common motif consisting of a 2-oxoamide with a hydrocarbon tail and a four-carbon tether. These molecules were characterized for their ability to block group IVA calcium-dependent PLA2 (cPLA2) and group VIA calcium-independent PLA2 (iPLA2) in inhibition assays using human recombinant enzyme. The rank ordering of potency in blocking group IVA cPLA2 was AX048 (ethyl 4-[(2-oxohexadecanoyl)amino]butanoate), AX006 (4-[(2-oxohexadecanoyl)amino]butanoic acid), and AX057 (tert-butyl 4-[(2-oxohexadecanoyl)amino]butanoate) > AX010 (methyl 4-[(2-oxohexadecanoyl)amino]butanoate) and for inhibiting group VIA iPLA2 was AX048, AX057 > AX006, and AX010. No agent altered recombinant cyclooxygenase activity. In vivo, i.t. (30 μg) and systemic (0.2-3 mg/kg i.p.) AX048 blocked carrageenan hyperalgesia and after systemic delivery in a model of spinally mediated hyperalgesia induced by i.t. substance P (SP). The other agents were without activity. In rats prepared with lumbar i.t. loop dialysis catheters, SP evoked spinal prostaglandin E2 (PGE2) release. AX048 alone inhibited PGE2 release. Intrathecal SR141617, a cannabinoid CB1 inhibitor at doses that blocked the effects of i.t. anandamide had no effect upon i.t. AX048. These results suggest that AX048 is the first systemically bioavailable compound with a significant affinity for group IVA cPLA2, which produces a potent antihyperalgesia. The other agents, although demonstrating enzymatic activity in cell-free assays, appear unable to gain access to the intracellular PLA2 toward which their action is targeted.

Adamantane derivatives of thiazolyl-N-substituted amide, as possible non-steroidal anti-inflammatory agents

A series of adamantane derivatives of thiazolyl-N-substituted amides were synthesized in a three-step reaction and tested for anti-inflammatory activity as well as lipoxygenase and cycloxygenase inhibitory actions. Theoretical calculation of their lipophilicity, as ClogP was performed. The effect of the synthesized compounds on inflammation, using the carrageenin-induced mouse paw oedema model was studied and compared to indomethacin. In general, the studied compounds were found to be potent anti-inflammatory agents (29.6-81.5%). Anti-inflammatory activity was influenced by some structural characteristics of the synthesized compounds. The lipoxygenase inhibitory activity was tested by the conversion of sodium linoleate to 13-hydroperoxylinoleic acid. Low inhibitory activity was observed. Evaluation of COX-1 and COX-2 inhibitory activities of the compounds revealed a COX-1 inhibitory potential, comparable to that of naproxen for some of the compounds and a low to moderate COX-2 inhibitory potential. Comparison of the in vivo and in vitro results leads to the conclusion that most compounds of this series may be involved in other mechanisms of inflammation, too.