A large series of coumarin derivatives (71 compounds) were tested for their monoamine oxidase A and B (MAO-A and MAO-B) inhibitory activity. Most of the compounds acted preferentially on MAO-B with IC(50) values in the micromolar to low-nanomolar range; high inhibitory activities toward MAO-A were also measured for sulfonic acid esters. The most active compound was 7-[(3, 4-difluorobenzyl)oxy]-3,4-dimethylcoumarin, with an IC(50) value toward MAO-B of 1.14 nM. A QSAR study of 7-X-benzyloxy meta-substituted 3,4-dimethylcoumarin derivatives acting on MAO-B yielded good statistical results (q(2)() = 0.72, r(2)() = 0.86), revealing the importance of lipophilic interactions in modulating the inhibition and excluding any dependence on electronic properties. CoMFA was performed on two data sets of MAO-A and MAO-B inhibitors. The GOLPE procedure, with variable selection criteria, was applied to improve the predictivity of the models and to facilitate the graphical interpretation of results.

Inhibition of monoamine oxidases by functionalized coumarin derivatives: biological activities, QSARs, and 3D-QSARs.

Publisher Summary The chapter focuses tautomerism and electronic Structure of biological pyrimidines. The understanding of the tautomeric properties of the purine and pyrimidine bases of the nucleic acids and the determination of the electronic properties of the principal tautomers are of fundamental importance in molecular biology, in particular, in connection with the theory of mutations. The principal tautomeric properties of the fundamental biological pyrimidines-cytosine, uracil, and thymine-are due to the presence in these N-heteroaromatic compounds of electron-donor substituents, such as NH and OH, and of SH in some important analogs. The chapter discusses tautomerism of cytosine and presents the essential physicochemical properties of cytosine and some of its derivatives and to the theoretical interpretation of these properties. The chapter also discusses tautomerism and physicochemical properties of uracil and thymines and to give a theoretical interpretation of these properties. The study of the optical properties of naturally occurring pyrimidines and purines is a problem of great interest in molecular biology. The knowledge of these properties provide information important for understanding energy transfer, hypochromism, photochemistry, optical rotatory dispersion, circular dichroism, magnetic optical rotator dispersion, and magnetic circular dichroism of DNA, RNA, and related model systems. Tautomerism, electronic structures, and spectra of rare pyrimidine bases of the nucleic acids have also been discussed.

Taulomerism and Electronic Structure of Biological Pyrimidines

Quantum yields for the photosensitized production of singlet oxygen and superoxide ion by the several quinones 1,4-benzoquinone, BQ, 2-methyl-1,4-benzoquinone, MBQ, sodium 1,4-naphthoquinone-2-sulfonate, NQ2S, sodium 9,10-anthraquinone-2-sulfonate, AQ2S, 1,4-naphthoquinone, NQ, 2-hydroxy-1,4-naphthoquinone, LWQ, 5,8-dihydroxy-1,4-naphthoquinone, NZQ, 5-hydroxy-1,4-naphthoquinone, JQ, and disodium 9,10-anthraquinone-1,5-disulfonate, AQDS in aqueous buffer (pH 7), at wavelengths above 310 nm, have been determined. Quantum yields for the production of singlet oxygen were found to be smaller than that for the production of superoxide. The quantum yield for the production of the hydroxyl adduct of 5,5-dimethyl pyrroline-1-oxide, DMPO-OH, by NQ was also determined and was found to be oxygen-concentration-dependent while the photoproduction of this adduct by hydroxynaphthoquinones was not observed. Evidence was obtained which suggests that the observed DMPO-OH adduct is produced by the free hydroxyl radical, at least at low NQ concentration.

Photochemistry of water-soluble quinones. Production of the hydroxyl radical, singlet oxygen and the superoxide ion

Coumarin, a widely used fragrance ingredient, is a rat liver and mouse lung toxicant. Species differences in toxicity are metabolism-dependent, with injury resulting from the cytochrome P450-mediated formation of coumarin 3,4-epoxide (CE). In this study, the enzymes responsible for coumarin activation in liver and lung were determined. Recombinant human and rat CYP1A forms and recombinant human CYP2E1 readily catalyzed CE production. Coinhibition with CYP1A1/2 and CYP2E1 antibodies blocked CE formation by 38, 84, and 67 to 92% (n = 3 individual samples) in mouse, rat, and human hepatic microsomes, respectively. Although CYP1A and 2E forms seem to be the most active catalysts of CE formation in liver, studies conducted with the mechanism-based inhibitor 5-phenyl-pentyne demonstrated that CYP2F2 is responsible for up to 67% of CE formation in whole mouse lung microsomes. In contrast to the CE pathway, coumarin 3-hydroxylation is a minor product of coumarin in liver microsomes from mice, rats, and humans and is catalyzed predominately by CYP3A and CYP1A forms, confirming that CE and 3-hydroxycoumarin are formed via distinct metabolic pathways.

Identification of the cytochromes P450 that catalyze coumarin 3,4-epoxidation and 3-hydroxylation.

Publisher Summary The chapter focuses on the recent advances in the chemistry of benzo[b]furan and its derivatives. The chemistry of benzofuran derivatives has developed in a spectacular fashion: research in this field has reached such a scale that the period covered by this review has given rise to a larger number of papers than that between 1870 and 1950. It has proceeded along the following three main lines: (1) Extraction, determination of structures, partial or total synthesis of the simple or complex heterocyclic derivatives constituting the natural benzofuran derivatives of vegetable origin. (2) Synthesis of benzofuran derivatives with physiological, pharmacological, therapeutic, or toxic properties. (3) Studies on the reactivity of benzofuran and its derivatives from the chemical and physical point of view. Many substances with physiological, pharmacological, therapeutic, or toxic properties are to be found among natural products with a benzofuran ring. As to synthetic benzofuran derivatives prepared for the study of their physiological properties, their number is large. Benzofuran is prepared in semicommercial amounts. The chapter discusses the presence of benzofurans in coal tar and in petroleum. Natural benzofuran derivatives have also been discussed. The numerous syntheses of the benzofuran ring may be classified under four headings: (1) Formation of the heterocyclic ring from an aromatic substrate (2) formation of the heterocyclic ring from a nonaromatic substrate (3) fusion of the benzene ring to a furan substrate (4) formation of the heterocyclic ring from other heterocyclic compounds.

Recent Advances in the Chemistry of Benzo[b]furan and Its Derivatives. Part I: Occurrence and Synthesis

Preparations of formyl-1,4-benzoquinone, 1,4-benzoquinonylacetaldehyde, 3-(1,4-benzoquinonyl) propionaldehyde, 2-(1,4-benzoquinonyl)-2-methylpropionaldehyde, and 2-methyl-2-(1,4-naphthoquinon-2-yl) propionaldehyde are described. Irradiation of solutions of these quinones in benzene with visible light leads to the isolation of 2,5-dihydroxybenzoic acid from formyl-1,4-benzoquinone, and to the formation of 5-hydroxycoumaran-2-one and 3,4-dihydro-6-hydroxycoumarin from the next two quinones, respectively; the last two quinones in the series lose the elements of formaldehyde, and give 5-hydroxy-3-methylbenzofuran and 5-hydroxy-3-methylnaphtho-[1,2-b]furan, respectively. None of the irradiations proceeded cleanly.

Light-induced and related reactions of quinones. Part VI. Reactions of some p-quinones carrying formyl groups

Illumination of 1,4-benzoquinone in acetaldehyde with visible light yields acetylquinol which is shown by the use of 1,1-diphenylethylene as a scavenger to be formed via attack of acetyl radicals on the quinone. Supporting evidence is provided by reactions initiated in the dark by di-t-butyl diperoxalate.

Light-induced and related reactions of quinones. Part I. The mechanism of formation of acetylquinol from 1,4-benzoquinone and acetaldehyde

The synthesis is described of 1,4-benzoquinones carrying, severally, the following side-chains: CH(OH)·CH2Ph,CD(OH)·CH2Ph, CMe(OH)·CH2Ph, CH(OH)·CHPh2, CH(OH)·CH2·CH:CH2, and CMe(OH)·CH2·CH:CH2. When irradiated with visible light all the secondary alcohols yield 2,5-dihydroxybenzaldehyde, and all the tertiary alcohols give 2,5-dihydroxyacetophenone, probably via fragmentation of the derived alkoxyl radicals. The tertiary alcohols also yield isomers in which reorganisation of the side-chain has occurred. Mechanisms are suggested.

Light-induced and related reactions of quinones. Part VII. Cleavage and isomerisation of some (1-hydroxyalkyl)-1,4-benzoquinones

The synthesis of 1,4-benzoquinones carrying, severally, the side-chains [CH2]2·OH, CH2·CH(OH)Me, [CH2]2·Ph, CH2·CHPh2, [CH2]2·CO2Et, CH2·CH(CO2Et)2, cis- and trans-CHCHPh, CHCPh2, and CO·CHCHPh is described. When irradiated with visible light the hydroxyalkylquinones yield the corresponding carbonyl compounds. The phenyl-, diphenyl-, and ethoxycarbonyl-ethylquinones and the β-phenylstyrylquinone give 2,3-dihydrobenzofurans. Mechanisms are discussed. Diethyl (1,4-benzoquinonyl)methylmalonate is essentially unchanged. The remaining quinones afford unidentified amorphous products.

Light-induced and related reactions of quinones. Part VIII. Some (2-hydroxyalkyl)-, phenethyl-, (2-ethoxycarbonylethyl)-, and styryl-1,4-benzoquinones

The mono-, di-, and tri-methyl homologues of 1,4-benzoquinone, and acetyl- and 2,3-dichloro-1,4-benzoquinone all yield acetylquinols when irradiated with visible light in acetaldehyde. 1,4-Benzoquinone yields pivaloylquinol when irradiated in trimethylacetaldehyde. Diacylquinols are additional products in some cases. 1,4-Benzoquinone gives the corresponding aroylquinols with p-t-butyl-, p-methyl-, and p-methoxy-benzaldehyde, but yields a mixture of benzoylquinol and quinol monobenzoate with benzaldehyde; only the corresponding quinol monoesters are formed with p-nitrobenzaldehyde and cinnamaldehyde. Quinizarinquinone yields quinizarin monoesters exclusively. The significance of these results is discussed.

J. Malcolm Bruce

Papers

Light-induced and related reactions of quinones. Part VI. Reactions of some p-quinones carrying formyl groups

Light-induced and related reactions of quinones. Part I. The mechanism of formation of acetylquinol from 1,4-benzoquinone and acetaldehyde

Light-induced and related reactions of quinones. Part VII. Cleavage and isomerisation of some (1-hydroxyalkyl)-1,4-benzoquinones

Light-induced and related reactions of quinones. Part VIII. Some (2-hydroxyalkyl)-, phenethyl-, (2-ethoxycarbonylethyl)-, and styryl-1,4-benzoquinones

Light-induced and related reactions of quinones. Part IV. Reactions of some p-quinones with aliphatic and aromatic aldehydes