No abstract

A series of new spiro-substituted pyranocoumarin derivatives have been synthesized starting from the commercially available 7-hydroxycoumarin and the conformation of the pyran ring was investigated. The antioxidant activity of the compounds was evaluated in-vitro, by means of three different tests: the interaction with the stable free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH), the competition with DMSO for hydroxyl radicals scavenging ability and the quenching of superoxide anions generated by the enzymic xanthine-xanthine oxidase system. In the DPPH test the spiroadamantane derivative 13 was the most active and possessed a 40% inhibition at a concentration of 400 microM. All compounds successfully compete with DMSO for hydroxyl radicals generated by the Fe(3+)/ascorbic acid system. Compound 13 inhibited the oxidation of DMSO (3.125 mM) by 93% at 2 mM and by 71% at 0.25 mM. The corresponding second-order rate constants have been estimated and all compounds demonstrated higher rate constants compared with the reference compounds, 7-hydroxycoumarin and mannitol. Derivatives possessing extended conjugation showed the highest inhibitory activity for superoxide anions generated by the xanthine-xanthine oxidase system, although the results of this experiment possessed partial parallelism with the results observed in the other two tests. The overall obtained data indicate that the size of the different spiro- substituents influence the degree of free radical scavenging and demonstrate the importance of extended conjugation for the antioxidant activity. Due to its multiple mechanism of protective action, derivative 13 may serve as a lead for the development of analogues that could be useful for the treatment of pathophysiological processes dependent upon reactive oxygen species.

The cellular damage caused by the reactions of oxygen centered free radicals and reactive oxygen species (ROS) with DNA, structural or enzymatic proteins, polyunsaturated fatty acids and other macromolecules has been implicated in a variety of pathological events underlying age-related and post ischemic neurodegeneration 1) and other biological disorders such as heart disease, atherosclerosis, stroke, inflammation and cancer.2-4) Mammalian cells have evolved an array of biochemical defense systems, including enzymes (superoxide dismutase, catalase and peroxidase) and low molecular weight compounds (ascorbic acid, vitamin E and glutathione) for protecting their components against the ROS that arise from endogenous metabolic processes or from various exogenous sources. However, the overproduction of these species and/or the decreased production of cellular antioxidants are responsible for the oxidative stress state, in which oxidant production surpasses the endogenous antioxidant capacities. Some tissues and the brain in particular are easily susceptible to oxidative damage under conditions of oxidative stress, due to their high levels of oxygen consumption and the elevated unsaturated fatty acids and iron stores. 5)Consequently, elucidation of the mechanism of action and research on more active antioxidants of natural or synthetic origin continue to receive a great deal of attention for use in the development of potential chemoprotective therapeutics able to prevent or reduce oxidative stress-induced damage.A number of quinolinones, including the novel antiulcer agent rebamipide (2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid, Fig. 1) have been shown to scavenge hydroxyl radicals and inhibit superoxide production from polymorphonuclear leukocytes.6,7) On the other hand, ethoquin (1,2-dihydro-6-ethoxy-2,2,4-trimethylquinoline, Fig. 1) and several 1,2-dihydro and 1,2,3,4-tetrahydroquinoline derivatives have been described as powerful antioxidants for the potential treatment of pathologies implicating central oxidative stress. [8][9][10] With these in mind, we have synthesized a number of structurally related derivatives in an effort to investigate their potential to act as radical scavengers and to exhibit antioxidant activity thereof. The new compounds possess the quinolin-2-one ring system fused to a pyrane or dihydropyrane ring, which bears spiro-substituents of various sizes. We investigated the importance of the extended conjugation, which is due to the presence of the pyrane ring, towards the flexibility adopted by the corresponding dihydropyrane analogues. Results and DiscussionChemistry For the synthesis of the target derivatives we used the 2-spirocyclical substituted 4-chromanones 3a, 11) 3b11) and 3c (Chart 1), which were prepared through nitration of the commercial 2-hydroxyacetophenone (1) 12) and subsequent treatment with the appropriate carbocyclic ketone in the presence of pyrrolidine.13) The nitro group of the chromanones 3a-c was then reduced with tin(II) chloride in refluxing a...

Drugs with antioxidant mechanisms are being widely proposed as starting point for the development of new therapeutic interventions in several pathological disorders associated with oxidative damage, caused by reactive oxygen species (ROS), including hydrogen peroxide, superoxide anion and hydroxyl radical, under conditions of 'oxidative stress.' 1,2) This term refers to an imbalance between ROS production and detoxification, in favour of the former, and it is characterized by excessive production of ROS and/or reduction in the responsible for their metabolism antioxidant defences. 3,4)The quinoline ring system is often found in natural alkaloids and in many synthetic derivatives exhibiting antibacterial, immunomodulatory, anti-inflammatory and antioxidant properties.5-11) Among these compounds, the novel quinolinone derivative TA 270 (4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone, Fig. 1), was initially designed as ROS scavenger and further pharmacological results suggest its therapeutic use in bronchial asthma.12) Also, the antiulcer drug rebamipide, (2-(4-chlorobenzoylamino)-3-[2-(1H)-quinolinon-4-yl]propionic acid, Fig. 1) developed in Japan, inhibits lipid peroxidation and has a suppressive effect on oxygen derived free radical production in gastric mucosa. Rebamipide has been selected from a series of over 500 synthesized quinolinone derivatives tested for gastroprotective action and was found to possess anti-inflammatory properties, by stimulating endogenous prostaglandin and mucus glycoprotein synthesis and inhibiting inflammatory cytokines and chemokines. 13,14) It has been shown by the EPR (electron paramagnetic resonance) spin trapping method that rebamipide scavenges hydroxyl radicals and inhibits superoxide production.15) Structure-activity studies revealed that the 3,4-double bond and the 2-oxo functionality of the quinolinone moiety are important determinants of the hydroxyl radical scavenging properties of this class of compounds and a reaction pathway was thus proposed, in which one molecule of the drug traps two hydroxyl radicals to form an unstable diol that readily decomposes to yield 3-hydroxylated rebamipide, as the major reaction product. 16)Prompted by the interesting activity of several quinoline derivatives and in continuation of our efforts towards the study of structure-activity relationships of spiropyranoquinolinones as well as of spiropyranocoumarin derivatives, [17][18][19] we report the synthesis of some new lipophilic 4-hydroxypyrano quinolinones and the corresponding dihydropyrano cis-diols bearing spiro-substituents of various sizes on the pyran moiety. The antioxidant potential of these new compounds was also evaluated in vitro by means of their interaction with the stable 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) and the quenching of superoxide anions generated by the enzymic xanthine-xanthine oxidase system. Results and DiscussionChemistry For the synthesis of the target pyranoquinolinones 6a-d (Chart 1) we have used as starting material the 2-spirocyc...

Fused pyridine derivativesFused pyridine derivatives R 0450 Synthesis, Conformational Analysis and Free Radical Scavenging Activity of Some New Spiropyranoquinolinones. -The title compounds (XV) show radical--scavenging properties. However, the precursors (XIV) are more potent than (XV). -(PANTELEON, V.; MARAKOS, P.; POULI*, N.; MIKROS, E.; ANDREADOU, I.; Chem. Pharm. Bull. 51 (2003) 5, 522-529; Dep. Pharm., Div. Pharm. Chem., Univ. Athens, GR-15771 Athens, Greece; Eng.) -C. Oppel 42-143 2003 Fused pyridine derivatives