Chemistry of naphthazarin derivatives: XV. Bromination of naphthazarin and its derivatives

Bromination of a number of naphthazarin (5,8-dihydroxy-1,4-naphthoquinone) derivatives having different substituents in the aromatic ring with molecular bromine in carbon tetrachloride was studied. Preparative procedures for the synthesis of 2-bromo-5,8-dihydroxy-7-methoxy-1,4-naphthoquinone, 2-bromo-6,7-dichloro-5,8-dihydroxy-1,4-naphthoquinone, 2-bromo-3,5,8-trihydroxy-1,4-naphthoquinone, and 2-bromo-6,7-dichloro-3,5,8-trihydroxy-1,4-naphthoquinone were developed.     

Exploring the trifluoromenadione core as a template to design antimalarial redox-active agents interacting with glutathione reductase

Menadione is the 2-methyl-1,4-naphthoquinone core used to design potent antimalarial redox-cyclers to affect the redox equilibrium of Plasmodium-infected red blood cells. Exploring the reactivity of fluoromethyl-1,4-naphthoquinones, in particular trifluoromenadione, under quasi-physiological conditions in NADPH-dependent glutathione reductase reactions, is discussed in terms of chemical synthesis, electrochemistry, enzyme kinetics, and antimalarial activities. Multitarget-directed drug discovery is an emerging approach to the design of new antimalarial drugs. Combining in one single 1,4-naphthoquinone molecule, the trifluoromenadione core with the alkyl chain at C-3 of the known antimalarial drug atovaquone, revealed a mechanism for CF(3) as a leaving group. The resulting trifluoromethyl derivative 5 showed a potent antimalarial activity per se against malarial parasites in culture.     

Synthesis of cis- and trans-5,8-dihydroxy-5,6,7,8-tetrahydro-1,4-naphthoquinone

Cis- and trans-5,8-dihydroxy-5,6,7,8-tetrahydro-1,4-naphthoquinone (1a, 1b) were for the first time synthesized from 5,8-dihydroxy-1,4-naphthoquinone (naphthazazine) (6) as a starting material and racemic triol (3) was first synthesized from 7. The configuration of 1a was determined by X-ray analysis.     

A new type of palladium(0) complex having both electron-withdrawing and -donating sites in a ligand: 5,8-dihydro- and 5,8,9,10-tetrahydro-1,4-naphthoquinone complexes

A new type of palladium(0) complex, (5,8-dihydro-1,4-naphthoquinone)Pd(PPh₃)₂ and (5,8,9,10-tetrahydro-1,4-naphthoquinone)Pd(PPh₃)₂, having both olefin and quinone or dihydro-quinone sites in a ligand molecule was prepared. IR and ¹H NMR spectroscopic studies of these complexes suggested that it is the quinone or dihydro-quinone CC bond which is complexed to Pd. Ligand exchange reactions showed that the stability order of the olefinic quinone complexes was as follows: (1,4-naphthoquinone)Pd(PPh₃)₂ > (5,8-dihydro-1,4-naphthoquinone) Pd(PPh₃)₂>(5,8,9,10-tetrahydro-1,4-naphthoquinone)Pd(PPh₃)₂.     

Synthesis of lomazarin and norlomazarin, pigments from Lomandra hastilis

5,8-Dihydroxy-2,3,6-trimethoxy-7-ethyl-1,4-naphthoquinone (1) was used to synthesize in high yield 5,8-dihydroxy-7(1′-hydroxyethyl)-2,3,6-trimethoxy-1,4-naphthoquinone (lomazarin, 3), a pigment from Lomandra hastilis. Alkaline hydrolysis of lomazarin produced mainly 5,6,8-trihydroxy-2,3-dimethoxy-1,4-naphthoquinone (9) through a retro-aldol decomposition of the 6-keto-form of 5,6,8-trihydroxy-7(1′-hydroxyethyl)-2,3-dimethoxy-1,4-naphthoquinone (13b) formed during the reaction. 2,5,8-Trihydroxy-7(1′-hydroxyethyl)-3,6-dimethoxy-1,4-naphthoquinone (norlomazarin, 4a), a pigment of L. hastilis, and its 3,5,8-trihydroxy-7(1′-hydroxyethyl)-2,6-dimethoxy isomer 4b were formed as a difficultly separable mixture in addition to quinone 9. Translated from Khimiya Prirodnykh Soedinenii, No. 6, pp. 581–584, November–December, 2008.     

Systematic investigation of Saccharomyces cerevisiae enzymes catalyzing carbonyl reductions

Eighteen key reductases from baker's yeast (Saccharomyces cerevisiae) have been overproduced in Escherichia coli as glutathione S-transferase fusion proteins. A representative set of alpha- and beta-keto esters was tested as substrates (11 total) for each purified fusion protein. The stereoselectivities of beta-keto ester reductions depended both on the identity of the enzyme and the substrate structure, and some reductases yielded both L- and D-alcohols with high stereoselectivities. While alpha-keto esters were generally reduced with lower enantioselectivities, it was possible in all but one case to identify pairs of yeast reductases that delivered both alcohol antipodes in optically pure form. Taken together, the results demonstrate not only that individual yeast reductases can be used to supply important chiral building blocks, but that GST-fusion proteins allow rapid identification of synthetically useful biocatalysts (along with their corresponding genes).     

Synthesis and absorption spectra of 2-substituted 5,8-dimethoxy-4H-1-benzothiopyran-4-one 1,1-dioxides

2,3-Dibromo-5,8-dimethoxy-4H-1-benzothiopyran-4-one (thiochromone) 1,1-dioxide which was a starting material to prepare sulfone analogues of 1,4-naphthoquinone dyes was easily prepared from 5,8-dimethoxythiochroman-4-one by oxidation and bromination. The reactions of 2,3-dibromo-5,8-dimethoxythiochromone 1,1-dioxide 4 with aliphatic and aromatic amines in ethanol below 20° gave 2-substituted derivatives 12a-e and at higher reaction temperature the amination gave 2-arylamino derivatives 13c-e debrominated at C -3. The visible absorption spectra of these derivatives were investigated by the PPP MO method.     

Ab initio and semiempirical study of structure and electronic spectra of hydroxy substituted naphthoquinones

The geometries of hydroxy derivatives of 1,4-naphthoquinone (NQ), viz., 2-hydroxy-1,4-naphthoquinone (2HNQ), 5-hydroxy-1,4-naphthoquinone (5HNQ), and 5,8-dihydroxy-1,4-naphthoquinone (DHNQ), have been optimized using the semiempirical and ab initio theoretical methods. Semiempirical methods used for the optimization are Austin Model 1 (AM1) and Zerner's Intermediate Neglect of Differential Overlap/1(ZINDO/1). For ab initio calculations the 6-31G* basis set is used. The electronic spectra of 1,4-naphthoquinone and its hydroxy derivatives are calculated using the semiempirical Zerner's Intermediate Neglect of Differential Overlap/Spectroscopy (ZINDO/S) method employing the geometries optimized at AM1, ZINDO/1 and ab initio levels and compared with their electronic absorption spectra measured by us. For hydroxy substituted systems, such calculations for spectral assignments are made for the first time. It is found that though the predictions of the three theoretical methods for the geometries are similar, the predictions of the ZINDO/S method using the ZINDO/1 optimized geometries, are better for the transition wavelengths in the visible region of the hydroxy substituted naphthoquinones, especially for 5HNQ and DHNQ.     

Preparation and electrochemical properties of palladium(0) complexes coordinated by quinones and 1,5-cyclooctadiene

The complexes Pd(quinone)(COD) (COD = 1,5-cyclooctadiene) are prepared by a ligand substitution reaction of Pd₂(DBA)₃ (DBA = dibenzylideneacetone) in the presence of both quinone and COD. Palladium(0) complexes coordinated by quinones only are formed in the reaction in the absence of COD. The cyclic voltammetric behavior of Pd(quinone)(COD) has been studied. The reduction potentials for quinones shifted toward negative values on coordination to palladium(0). The oxidation potentials for the central palladium(0) in Pd(quinone)(COD) depend on the electron-withdrawing ability of the free quinones, and are in the following series: quinone = p-benzoquinone < 5,8-dihydro-1,4-naphthoquinone ～ 1,4-naphthoquinone < duroquinone. The shift of oxidation potentials for Pd(quinone)(COD) on changing the quinones as ligands is in contrast to that of Pd(quinone)(triphenylphosphine)₂.     

Polyazomethines derived from polynuclear dihydroxyquinones and siloxane diamines

New polyazomethines have been synthesized based on polynuclear dihydroxy quinones (5,8-dihydroxy-1,4-naphthoquinone and 1,4-dihydroxyanthraquinone) and siloxane diamines differing by the siloxane sequence length (1,3-bis(3-aminopropyl)tetramethyldisiloxane and α,ω-bis(3-aminopropyl)oligodimethylsiloxane having about 12 siloxane units/sequence). The structures were verified by spectral analyses. Solubility tests, GPC and viscosity measurements were performed. Some properties of the resulted polymers were investigated by thermal (TGA and DSC), electrical, spectral (UV-Vis) and electrochemical (differential pulse voltammetry) methods.     

Catalytic activity of sorbents containing metals, and nucleophilicity of alcohols activated with fluoride anion in reaction of nucleophilic substitution in 2,3-dichloronaphthazarines

In reaction of 5, 8-dihydroxy-2, 3-dichloro-6-ethyl-7-ethoxy-1,4-naphthoquinone and 6-tert-butyl-5,8-dihydroxy-2,3-dichloro-l,4-naphthoquinone proceeding on the surface of molecular sieves, calcium phosphate and carbonate, neutral alumina, or magnesium silicate with nucleophilic reagents (methanol, 2-methoxyethanol, monomethyl ethers of di- and triethylene glycols) activated with fluoride anion the yield of products decreased in this nucleophiles series. The most active catalysts among sorbents are alumina and magnesium silicate. All the sorbents are also efficient catalysts of alkoxy groups interchange.     

Design of a new electrogenerated polyquinone film substituted with glutathione. Towards direct electrochemical biosensors

We developed a method to graft a tripeptide (glutathione) onto 5-hydroxy-1,4-naphthoquinone, an electropolymerizable molecule. The resulting thin conducting polymer presents a well-defined and stable electroactivity in neutral buffered solution, due to the embedded quinone group, and is able to covalently graft amino-modified DNA probe strands. It is shown that the bioelectrode presents positive current change following DNA hybridization. This makes a “signal-on” direct electrochemical DNA sensor. The results were obtained with low target concentration (50 nM) and the selectivity is excellent as a single-mismatch sequence can be discriminated from the full-complementary target.     

Valence-state analysis through spectroelectrochemistry in a series of quinonoid-bridged diruthenium complexes [(acac)(2)Ru(mu-L)Ru(acac)(2)](n) (n=+2, +1, 0, -1, -2)

The quinonoid ligand-bridged diruthenium compounds [(acac)(2)Ru(mu-L(2-))Ru(acac)(2)] (acac(-)=acetylacetonato=2,4-pentanedionato; L(2-)=2,5-dioxido-1,4-benzoquinone, 1; 3,6-dichloro-2,5-dioxido-1,4-benzoquinone, 2; 5,8-dioxido-1,4-naphthoquinone, 3; 2,3-dichloro-5,8-dioxido-1,4-naphthoquinone, 4; 1,5-dioxido-9,10-anthraquinone, 5; and 1,5-diimido-9,10-anthraquinone, 6) were prepared and characterized analytically. The crystal structure analysis of 5 in the rac configuration reveals two tris(2,4-pentanedionato)ruthenium moieties with an extended anthracenedione-derived bis(ketoenolate) pi-conjugated bridging ligand. The weakly antiferromagnetically coupled {Ru(III)(mu-L(2-))Ru(III)} configuration in 1-6 exhibits complicated overall magnetic and EPR responses. The simultaneous presence of highly redox-active quinonoid-bridging ligands and of two ruthenium centers capable of adopting the oxidation states +2, +3, and +4 creates a large variety of possible oxidation state combinations. Accordingly, the complexes 1-6 exhibit two reversible one-electron oxidation steps and at least two reversible reduction processes. Shifts to positive potentials were observed on introduction of Cl substituents (1-->2, 3-->4) or through replacement of NH by O (6-->5). The ligand-to-metal charge transfer (LMCT) absorptions in the visible region of the neutral molecules become more intense and shifted to lower energies on stepwise reduction with two electrons. On oxidation, the para-substituted systems 1-4 exhibit monocation intermediates with intervalence charge transfer (IVCT) transitions of Ru(III)Ru(IV) mixed-valent species. In contrast, the differently substituted systems 5 and 6 show no such near infrared (NIR) absorption. While the first reduction steps are thus assigned to largely ligand-centered processes, the oxidation appears to involve metal-ligand delocalized molecular orbitals with variable degrees of mixing.     

Structural analysis of naphthoquinone protein adducts with liquid chromatography/tandem mass spectrometry and the scoring algorithm for spectral analysis (SALSA)

The relative reactivities of various naphthoquinone isomers (1,4-, 1,2- and 2-methyl-1,4-naphthoquinone) to two test proteins, apomyoglobin and human hemoglobin, were evaluated via liquid chromatography/electrospray ionization mass spectrometry (LC/ESI-MS). The structural characterization of the resulting adducts was also obtained by LC/ESI-MS analysis of the intact proteins. The reactive sites of apomyoglobin and human hemoglobin with 1,4-naphthoquinone and 1,2-naphthoquinone were also identified through characterization of adducted tryptic peptides by use of high-pressure liquid chromatography/electrospray ionization with tandem mass spectrometry (HPLC/ESI-MS/MS), TurboSEQUEST, and the scoring algorithm for spectral analysis (SALSA). Four adducted peptides, which were formed by nucleophilic addition of a lysine amino acid residue to 1,4-naphthoquinone, were also identified, as was an adducted peptide from incubation of 1,2-naphthoquinone with apomyoglobin. In the case of incubation of human hemoglobin with the two naphthoquinones, two adducted peptides were identified from the N-terminal valine modification of the alpha and beta chains of human hemoglobin. The adducted protein formation may imply that naphthalene produces its in vivo toxicity through 1,2- and 1,4-naphthoquinone metabolites reacting with biomolecular proteins.     

Synthesis and biological evaluation of 1,4-naphthoquinones and quinoline-5,8-diones as antimalarial and schistosomicidal agents

Improving the solubility of polysubstituted 1,4-naphthoquinone derivatives was achieved by introducing nitrogen in two different positions of the naphthoquinone core, at C-5 and at C-8 of menadione through a two-step, straightforward synthesis based on the regioselective hetero-Diels-Alder reaction. The antimalarial and the antischistosomal activities of these polysubstituted aza-1,4-naphthoquinone derivatives were evaluated and led to the selection of distinct compounds for antimalarial versus antischistosomal action. The Ag(II)-assisted oxidative radical decarboxylation of the phenyl acetic acids using AgNO(3) and ammonium peroxodisulfate was modified to generate the 3-picolinyl-menadione with improved pharmacokinetic parameters, high antimalarial effects and capacity to inhibit the formation of β-hematin.     

Electrochemical properties of palladium(0) complexes coordinated by quinone derivatives

The polagrophic and cyclic voltammetric behavior of quinone derivatives (Q) and their palladium(0) complexes, (Q)₁ or ²Pd(PPh₃)₂, has been studied. All free quinone derivatives except 5,8,9,10-tetrahydro-1,4-naphthoquinone (THNQ) showed two reversible waves, and all palladium(0) complexes showed irreversible waves. The reduction half-wave potentials for free quinone derivatives lie in the following order:7,7,8,8-tetracyanoquinodimethane (TCNQ) ? p-benzoquinone (BQ) ? 5,8-dihydro-1,4-naphthoquinone (DHNQ) ? 1,4-naphthoquinone (NQ) ? THNQ. The reduction potentials for quinone derivatives shifted toward the negative or coordination to palladium(0). The extents of the shifts depended on the electron-withdrawing ability of the free quinone derivatives. On the other hand, the oxidation potentials for the central palladium(0) in their complexes showed more positive values in comparison with the potential for Pd(PPh₃)₄. However, the oxidation potentials were almost constant for all complexes of the quinone derivatives. On the basis of these facts, the phenomena of charge transfer in the complexes are discussed.     

Infrared spectra of the polymorphs of naphthazarin: Microscopy and low temperature studies

The infrared microscope spectra of theA,B, andC polymorphs of naphthazarin (5,8-dihydroxy-1,4-naphthoquinone) can be distinguished clearly. When naphthazarin is dispersed in KBr, such a distinction can only be made when experimental precautions are taken during the preparation of the pellet. Low temperature infrared studies indicate that a phase transition takes place in naphthazarin around 110 K.     

Preparation of Vitamin K3 in Mo–V–P Heteropoly Acid Solutions by Diene Synthesis

Kinetics and Catalysis - The possibility of obtaining vitamin K3 (2-methyl-1,4-naphthoquinone, menadione) by diene synthesis from accessible substrates such as 2-methylphenol (o-cresol) and...     

Photoreactions of 1,4-Naphthoquinones: effects of substituents and water on the intermediates and reactivity

The photochemistry of lapachol and other 1,4-naphthoquinone (NQ) derivatives, e.g. 2-methoxy-1,4-naphthoquinone (MeONQ), 2-hydroxy-1,4-naphthoquinone (2-HONQ) or 5-hydroxy-1,4-naphthoquinone (5-HONQ) and 2-methyl-5-hydroxy-1,4-naphthoquinone (P-NQ) in solution at room temperature was studied by ultraviolet-visible spectroscopy after nanosecond laser pulses at 248 nm. The triplet state and semiquinone radicals were observed for MeONQ, HONQ and P-NQ, whereas for lapachol, intramolecular H-atom and charge transfer processes take place, as in the case of vitamin K1. The photoinduced reaction of NQ into HONQ is initiated by nucleophilic water addition to the triplet state, and for the secondary reactions, a modified mechanism is proposed.     

7-Amino-5-imino-8(5H)-quinolones, 6-Amino-8-imino-5(8H)-quinolones and 7-Alkyl-4,6-dihydroxy-5,8-quinolinediones as potential antiprotozoal agents

Oxidation of 7-amino-8-hydroxyquinoline-5-sulfonic acid with silver oxide in dimethylformamide and in the presence of arylamines provided a series of 7-amino-5-arylimino-8(5H)-quinolones (VIIIb). Reaction of 8-dialkylamino-5,6-quinolinediones with triethyloxonium tetrafluoborate gave a series of unstable but synthetically useful enol ethers. These reacted with amines to give 6-amino-8-imino-5(8H)-quinolones, isolated and characterized as tetrafluoborate salts (XIa). Proton magnetic resonance studies showed these to be vinylogous amidinium salts, analogous to those previously obtained with 2-amino-1,4-naphthoquinone imines. 4,6-Dihydroxy-5,8-quinolinedione underwent free radical alkylation to give a 7-alkyl-4,6-dihydroxy-5,8-quinolinedione. Evaluation of the new compounds against various Plasmodium species in rodents, birds and mosquitoes revealed no significant antimalarial activity.