Synthesis, Conformational Analysis and Free Radical Scavenging Activity of Some New Spiropyranoquinolinones
Chemical and pharmaceutical bulletin
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
... hemical 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. 8-10) 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 Discussion Chemistry For the synthesis of the target derivatives we used the 2-spirocyclical substituted 4-chromanones 3a, 11) 3b 11) 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 acetone to result in the corresponding anilines 4a-c, which upon treatment with acetic anhydride gave the acetamides 5a-c. Nitration of these acetamides with fuming nitric acid in acetic acid 14) provided the 2-spirocyclical substituted 5-nitro-6-acetamido-4-chromanones 6a-c, which were subjected to borohydride reduction, followed by dehydration of the resulting 2-spiro-4-chromanols 7ac, in the presence of an acidic catalyst, to furnish the 2spirochromenes 8a-c. For the preparation of the corresponding spiroadamantylchromene 14, we used 3-nitro-4-acetamidophenol (12) 15) as starting material, obtained from commercial 4-acetamidophenol (9), as depicted in Chart 2. Reaction of 12 with 2chloro-2-ethynyladamantane 16) provided the acetylenic ether 13 which upon thermal cyclization in refluxing N,N-diethylaniline provided the isomeric chromenes 14 and 15. Both isomers were easily separated by flash chromatography on silica gel and fully characterized on the basis of NMR data. Acid hydrolysis of the acetamides 8a-c and 14 with a 5 N HCl solution resulted in the corresponding 6-aminoderivatives 16a-d (Chart 3), which via diazotization and reaction with potassium iodide were converted to the corresponding A series of novel spiroadamantyl-and spirocyclical substituted pyranoquinolin-2-ones were synthesized and the conformation of the pyran ring was investigated. The free radical scavenging activity of the synthesized compounds was determined by their interaction with the stable free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH). All compounds tested scavenged the DPPH radical and among them derivatives possessing extended conjugation showed the highest activity. a: conc. HNO 3 , AcOH, 30°C, 56%, b: carbocyclic ketone, pyrrolidine, toluene, reflux, 70-90%, c: SnCl 2 · 2H 2 O, acetone, reflux, 80-85%, d: Ac 2 O, r.t., 90-95%, e: fuming HNO 3 , AcOH, r.t., 80-87%, f: NaBH 4 , MeOH, r.t., 95%, g: p-TsOH, toluene, reflux, 90-95%. Chart 1 a: Ac 2 O, reflux, 96%, b: fuming HNO 3 , AcOH, reflux, 40%, c: 40% NaOH, r.t., 85%, d: 2-chloro-2-ethynyladamantane, K 2 CO 3 , KI, CuI, acetone, reflux, 82%, e: N,N-diethylaniline, reflux, 64% of 14, 4% of 15.