Characterization of adducts formed in reactions of acrolein with thymidine and calf thymus DNA

Acrolein, an important industrial chemical and environmental contaminant, has been shown to interact with nucleic acids in vitro and in vivo. In this study, we examined the reactivity of acrolein towards thymidine and calf-thymus double- and single-stranded DNA in aqueous buffered solutions. LC-MS Analyses of the reaction mixture of acrolein with thymidine showed the formation of five structurally different adducts. The structures of the products were determined on the basis of mass spectrometry, UV absorbance, and (1)H- and (13)C-NMR spectroscopy. The adducts were identified as 3-(3-oxopropyl)thymidine (dT1), 3-[(tetrahydro-2,4-dihydroxypyran-3-yl)methyl]thymidine (dT2), 2-(hydroxymethyl)-5-(thymidin-3-yl)pent-2-enal (dT3), 3-hydroxy-2-methylidene-5-(thymidin-3-yl)pentanal (dT4), and 2-[(thymidin-3-yl)methyl]penta-2,4-dienal (dT5). The adducts dT2-dT5 were formed in reaction of dT1 with acrolein. In the reaction of acrolein with calf-thymus DNA, dT1 was the only adduct detected in the DNA hydrolysate.     

Synthesis of the four 1-(1-deoxy-D-pentitol-1-yl)thymines and conformational properties of the acyclic sugar chain

Acetylated D-pentose diethyl dithioacetals were coupled by way of 1-bromo-1-ethylthio derivatives with 2,4-bis(trimethylsilyl)thymine to afford diastereomeric pairs of acyclic-sugar nucleoside analogues bearing a thymin-1-yl and an ethylthio group at C-1. Free-radical desulfurization by the action of tributylstannane removed the ethylthio group to afford the corresponding acetylated 1-(1-deoxy-d-pentitol-1-yl)thymines and subsequently the free title compounds in the arabino, lyxo, ribo, and xylo series. Conformations of the intermediates and products were studied in detail and the final products were evaluated for their potential as agents active against plant viruses and rice blast fungus.     

Synthesis of new isoxazoles and dihydroisoxazoles and in vitro evaluation of their antifungal activity

New 2-(2,4-dihalogenophenyl)-1-(1H-imidazol-1-yl)-3-(isoxazol-5-yl)propan-2-ols and 2-(2,4-dihalogenophenyl)-1-(1H-imidazol-1-yl)-3-(4,5-dihydroisoxazol-5-yl)propan-2-ols were synthesized by 1,3-dipolar cycloaddition between homopropargylic or homoallylic alcohols and in-situ generated nitrile oxide. Their antifungal activity was evaluated against Candida albicans, C. glabrata, Aspergillus fumigatus and an azole-resistant petite mutant of C. glabrata. Preliminary SAR results are discussed.     

New pyrrolopyrimidin-6-yl benzenesulfonamides: potent A2B adenosine receptor antagonists

A new series of 4-(1,3-dialkyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl)benzenesulfonamides has been identified as potent A2B adenosine receptor antagonists. The products have been evaluated for their binding affinities for the human A2B, A1 and A3 adenosine receptors. 6-(4-{[4-(4-Bromobenzyl)piperazin-1-yl]sulfonyl}phenyl)-1,3-dimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione (16) showed a high affinity for the A2B adenosine receptor (IC50=1 nM) and selectivity (A1: 183x; A3: 12660x). Synthesis and SAR of this novel class of compounds showing improved absorption properties is presented herein.     

Geranyl flavonoids from the leaves of Artocarpus altilis

Five geranyl dihydrochalcones, 1-(2,4-dihydroxyphenyl)-3-{4-hydroxy-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-dibenzo[b,d]pyran-5-yl}-1-propanone (2), 1-(2,4-dihydroxyphenyl)-3-[3,4-dihydro-3,8-dihydroxy-2-methyl-2-(4-methyl-3-pentenyl)-2H-1-benzopyran-5-yl]-1-propanone (4), 1-(2,4-dihydroxyphenyl)-3-[8-hydroxy-2-methyl-2-(3,4-epoxy-4-methyl-1-pentenyl)-2H-1-benzopyran-5-yl]-1-propanone (5), 1-(2,4-dihydroxyphenyl)-3-[8-hydroxy-2-methyl-2-(4-hydroxy-4-methyl-2-pentenyl)-2H-1-benzopyran-5-yl]-1-propanone (8), and 2-[6-hydroxy-3,7-dimethylocta-2(E),7-dienyl]-2',3,4,4'-tetrahydroxydihydrochalcone (9), along with four known geranyl flavonoids (1, 3, 6, 7), were isolated from the leaves of Artocarpus altilis. Their structures were established by spectroscopic means and by comparison with the literature values. Compounds 2, 4, and 9 exhibited moderate cytotoxicity against SPC-A-1, SW-480, and SMMC-7721 human cancer cells.     

Metabolism of 2,2'-dihydroxybiphenyl by Pseudomonas sp. strain HBP1: production and consumption of 2,2',3-trihydroxybiphenyl.

Cells of Pseudomonas sp. strain HBP1 grown on 2-hydroxy- or 2,2'-dihydroxybiphenyl contain NADH-dependent monooxygenase activity that hydroxylates 2,2'-dihydroxybiphenyl. The product of this reaction was identified as 2,2',3-trihydroxybiphenyl by 1H nuclear magnetic resonance and mass spectrometry. Furthermore, the monooxygenase activity also hydroxylates 2,2',3-trihydroxybiphenyl at the C-3' position, yielding 2,2',3,3'-tetrahydroxybiphenyl as a product. An estradiol ring cleavage dioxygenase activity that acts on both 2,2',3-tri- and 2,2',3,3'-tetrahydroxybiphenyl was partially purified. Both substrates yielded yellow meta-cleavage compounds that were identified as 2-hydroxy-6-(2-hydroxyphenyl)-6-oxo-2,4-hexadienoic acid and 2-hydroxy-6-(2,3-dihydroxyphenyl)-6-oxo-2,4-hexadienoic acid, respectively, by gas chromatography-mass spectrometry analysis of their respective trimethylsilyl derivatives. The meta-cleavage products were not stable in aqueous incubation mixtures but gave rise to their cyclization products, 3-(chroman-4-on-2-yl)pyruvate and 3-(8-hydroxychroman-4-on-2-yl)pyruvate, respectively. In contrast to the meta-cleavage compounds, which were turned over to salicylic acid and 2,3-dihydroxybenzoic acid, the cyclization products are not substrates to the meta-cleavage product hydrolase activity. NADH-dependent salicylate monooxygenase activity catalyzed the conversions of salicylic acid and 2,3-dihydroxybenzoic acid to catechol and pyrogallol, respectively. The partially purified estradiol ring cleavage dioxygenase activity that acted on the hydroxybiphenyls also produced 2-hydroxymuconic semialdehyde and 2-hydroxymuconic acid from catechol and pyrogallol, respectively.     

Environmental fate of the triazole fungicide propiconazole in a rice-paddy-soil lysimeter

Environmental fate of the triazole fungicide propiconazole, 1-[[2(2,4-dichlorophenyl)-4-propyl-1,3-diox olane-2-yl]methyl]1H-1,2,4-triazole, in soil was investigated using lysimeters simulating a rice-paddy-soil conditions. Two lysimeters composed of different soil types, a sandy loam (lysimeter A) and silty clay (lysimeter B), were used. Propiconazole (Tilt 250^R EC) plus [U-¹⁴C]-propiconazole was applied over a two-year period to the soil surface of the lysimeters. Propiconazole fate in the lysimeters was assessed by measuring total radioactivity in the leachate, evolved ¹⁴CO₂, and ¹⁴C-residues in the soil and rice plants. The amounts of applied ¹⁴C in the leachate from lysimeter A were 4.4 and 5.2% in the first and second year, respectively. A background level of (0.00005% of applied) ¹⁴C in the leachate from lysimeter B was detected, suggesting negligible movement of the fungicide to groundwater in the silty clay soil. The amount of ¹⁴CO₂ evolved from lysimeter A accounted for 7.8 and 12.2% of applied ¹⁴C in the first and second year, respectively, whereas those from lysimeter B were 5.7 and 7.1%. Total ¹⁴C detected in the rice plants grown in lysimeter A were 7.3 and 9.8% of applied ¹⁴C in the first and second year, respectively, which compared to 3.0 and 7.6% in lysimeter B. Most of the applied ¹⁴C was detected in the top 10 cm soil layer, suggesting that propiconazole remains close to the soil surface after application in soil. Degradation products of propiconazole identified in the lysimeter soils were 1-[[2(2,4-dichlorophenyl)-2-(1,2,4-triazole -1-yl) ketone (DP-1), 1-(2,4-dichlorophenyl)-2-(1,2,4-triazole-1- yl) ethanol (DP-2) and 1-[[2(2,4-dichlorophenyl)-4-hydroxypropyl-1,3-dioxolane-2-yl]methyl]1H-1,2,4-triazole (DP-3 and DP-4).     

Synthesis and antimetabolite properties of 5-substituted 2'-deoxyuridines. Anomeric 5-(2-aminohexafluoroprop-2-yl)- and 5-(2-trifluoroacetylaminohexafluoroprop-2-yl)-2'-deoxyuridine

Alkylation of 2,4-bis-O-(trimethylsilyl)uracil with hexafluoroacetone trifluoroacetylimine gave 5-(2-trifluoroacelylaminohexafluoroprop-2-yl)uracil, which was transformed by alkaline hydrolysis to 5-(2-aminohexafluoroprop-2-yl)uracil. The latter was glycosytated with 2-deoxy-3,5-di-O-p-toluoyl-alpha-D-ribofyranosyl chloride by means of various modifications of the silyl method leading to the predominant formation of beta-deoxynucleoside; after deacylation 1-(2-deoxy-beta-D-ribofuranosyl)-5-(2-aminohexafluoroprop-2-yl)ura cil was obtained. Interaction of silylated 5-(2-trifluoroacetylaminohexafluoroprop-2-yl)uracil with acylgalogenose gave anomeric O-substitutet deoxynucleosides, which were deblocked to give 5-(2-trifluoroacetylaminohexafluoroprop-2-yl)-2'-deoxyuridine and corresponding alpha-anomer. Alkaline hydrolysis of N-trifluoroacetyl group in both individual anomers produced 1-(2-deoxy-alpha-D-ribofuranosyl)-5-(2-aminohexafluoroprop-2-yl)ur acil and the abovementioned beta-anomer. Of all compounds synthesised only 1-(2-deoxy-beta-D-ribofuranosyl)-5-(2-aminohexafluoroprop-2-yl)ura cil has a moderate inhibitory effect on replication of vaccinia virus in vitro.     

Tunable Photophysical Behavior of a Novel Fluorescent Probe by Silver/Gold and Core–Shell NPs

Plasmonics - The photophysical and photochemical behaviors of a novel fluorescent probe, namely 5-(4-(dimethylamino)phenyl)-1-(thiophen-2-yl)penta-2,4-dien-1-one (DMATP), were tuned by solvent...     

RNA RECOGNITION BY FLUOR-AROMATIC SUBSTITUTED

RNA exhibits a higher structural diversity than DNA and is an important molecule in the biology of life. It shows a number of secondary structures such as duplexes, hairpin loops, bulges, internal loops, etc. However, in natural RNA, bases are limited to the four predominant structures U, C, A, and G and so the number of compounds that can be used for investigation of parameters of base stacking, base pairing, and hydrogen bond is limited. We synthesized different fluoromodifications of RNA building blocks: 1′-deoxy-1′-phenyl-β-d-ribofuranose (B), 1′-deoxy-1′-(4-fluorophenyl)-β-d-ribofuranose (4 FB), 1′-deoxy-1′-(2,4-difluorophenyl)-β-d-ribofuranose (2,4 DFB), 1′-deoxy-1′-(2,4,5-trifluorophenyl)-β-d-ribofuranose (2,4,5 TFB), 1′-deoxy-1′-(2,4,6-trifluorophenyl)-β-d-ribofuranose, 1′-deoxy-1′-(pentafluorophenyl)-β-d-ribofuranose (PFB), 1′-deoxy-1′-(benzimidazol-1-yl)-β-d-ribofuranose (BI), 1′-deoxy-1′-(4-fluoro-1H-benzimidazol-1-yl)-β-d-ribofuranose (4 FBI), 1′-deoxy-1′-(6-fluoro-1H-benzimidazol-1-yl)-β-d-ribofuranose (6 FBI), 1′-deoxy-1′-(4,6-difluoro-1H-benzimidazol-1-yl)-β-d-ribofuranose (4,6 DFBI), 1′-deoxy-1′-(4-trifluoromethyl-1H-benzimidazol-1-yl)-β-d-ribofuranose (4 TFM), 1′-deoxy-1′-(5-trifluoromethyl-1H-benzimidazol-1-yl)-β-d-ribofuranose (5 TFM), and 1′-deoxy-1′-(6-trifluoromethyl-1H-benzimidazol-1-yl)-β-d-ribofuranose (6 TFM). These amidites were incorporated and tested in a defined A, U-rich RNA sequence (12-mer, 5′-CUU UUC XUU CUU-3′ paired with 3′-GAA AAG YAA GAA-5′). Only one position was modified, marked as X and Y, respectively. UV melting profiles of those oligonucleotides were measured.     

Studies on the 1,1-diphenyl-2-picrylhydrazyl radical scavenging mechanism for a 2-pyrone compound

The radical scavenging mechanisms for the 2-pyrone compound, 4-hydroxy-3,6-dimethyl-2H-pyrane-2-one (1), and the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical (4) in several solvent systems were evaluated by the quantitative change in compounds detected at 270 nm and subsequent HPLC analyses. The HPLC profile for each condition suggested that the reaction proceeded by a different mechanism in each solvent system. In organic solvents (CHCl3, iso-propanol, and EtOH), 1-[4-(3,4-dihydro-3,6-dimethyl-2,4-dioxo-2H-pyran-3-yl) phenyl]-1-phenyl-2-picrylhydrazine (2) was produced as an adduct of the DPPH radical and 1. On the other hand, the reaction in a buffer solution (an acetate buffer at pH 5.5) gave several degradation products with 1[4-(2,3-dihydro-2,5-dimethyl-3-oxo-fur-2-yl) phenyl]-1-phenyl-2-picrylhydrazine (5), this being structurally elucidated by spectroscopic analyses. The decrease of the DPPH radical in each reaction system suggests that compound 1 could scavenge about 1.5-1.8 equivalents of the radical in organic solvents and about 3.5-3.9 in the buffer solution.     

Two biflavonoids from Ouratea flava stem bark

In a chemical investigation on the stem bark of Ouratea flava, two biflavonoids: 1-[3-(2,4-dihydroxy-benzoyl)-4,5,6-trihydroxy-2-(4-hydroxy-phenyl)-benzofuran-7-yl] -3-(4-hydroxy-phenyl) -propenone (flavumone A) and 3-(2,4-dihydroxy-benzoyl)-4-hydroxy-2,7-bis-(4-hydroxy-phenyl) -7,8- dihydro-furo[2,3-f]chromen-9-on (flavumone B) were isolated along with five known flavonoids. Their structures were established by various analyses including 2D-NMR spectroscopy.     

RNA recognition by fluor-aromatic substituted

RNA exhibits a higher structural diversity than DNA and is an important molecule in the biology of life. It shows a number of secondary structures such as duplexes, hairpin loops, bulges, internal loops, etc. However, in natural RNA, bases are limited to the four predominant structures U, C, A, and G and so the number of compounds that can be used for investigation of parameters of base stacking, base pairing, and hydrogen bond is limited. We synthesized different fluoromodifications of RNA building blocks: 1'-deoxy-1'-phenyl-beta-D-ribofuranose (B), 1'-deoxy-1'-(4-fluorophenyl)-beta-D-ribofuranose (4 FB), 1'-deoxy-1'-(2,4-difluorophenyl)-beta-D-ribofuranose (2,4 DFB), 1'-deoxy- 1'-(2,4,5-trifluorophenyl)-beta-D-ribofuranose (2,4,5 TFB), 1'-deoxy- 1'-(2,4, 6-trifluorophenyl)-beta-D-ribofuranose, 1'-deoxy- 1'-(pentafluorophenyl)-beta-D-ribofuranose (PFB), 1'-deoxy-1'-(benzimidazol-1-yl)-beta-D-ribofuranose (BI), 1'-deoxy-1'-(4-fluoro-1H-benzimidazol-1-yl)-1-beta-ribofuranose (4 FBI), 1'-deoxy- 1'-(6-fluoro- 1H-benzimidazol-1-yl)-beta-D-ribofuranose (6FBI), 1'-deoxy- 1'-(4, 6-difluoro- 1H-benzimidazol- 1-yl)-beta-D-ribofuranose (4,6 DFBI), 1'-deoxy- 1'-(4-trifluoromnethyl- H-benzimidazol-1-yl)-beta-D-ribofuranose (4 TFM), 1'-deoxy-1'-(5-trifluoromnethyl-1H-benzimidazol-1-yl)-beta-D-ribofuranose (5 TFM), and 1'-deoxy-1'-(6-trifluoromethyl-1H-benzimidazol-1-yl)-beta-D-ribofuranose (6 TFM). These amidites were incorporated and tested in a defined A, U-rich RNA sequence (12-mer, 5-CUU UUCXUU CUU-3' paired with 3'-GAA AAG YAA GAA-5'). Only one position was modified, marked as X and Y, respectively. UV melting profiles of those oligonucleotides were measured.     

Copper(II) assisted hydrolysis of 2,4,6-tris(pyrazol-1-yl)-1,3,5-triazine. Crystal and molecular structure of catena-[CuL(H2O)Cl]n (L = 2,4-dione-1,3,5-(1H)-triazin-1-amido)

This article describes the partial hydrolysis of the multidentate ligand 2,4,6-tris(pyrazol-1-yl)-1,3,5-triazine in the presence of copper(II), to give the anionic ligand 2,4-dione-1,3,5-(1H)-triazin-1-amido, which was isolated as the cupric complex catena-[CuL(H₂O)Cl]_n, where L is the amido ligand. No other hydrolysis products were isolated or identified.The complex defines a zigzag 1D covalent chain, along the b cell axis, through apical copper-oxygen bonds (Cu-N-C-O···Cu bridges).     

Optically active antifungal azoles: synthesis and antifungal activity of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-[2-[4-aryl-piperazin-1-yl]-ethyl]-tetrazol-2-yl/1-yl)-1-[1,2,4]-triazol-1-yl-butan-2-ol

A series of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-[2-[4-aryl-piperazin-1-yl]-ethyl]-tetrazol-2-yl)-1-[1,2,4]-triazol-1-yl-butan-2-ol (11a-n) and (2R,3S)-2-(2,4-difluorophenyl)-3-(5-[2-[4-aryl-piperazin-1-yl]-ethyl]-tetrazole-1-yl)-1-[1,2,4]-triazol-1-yl-butan-2-ol (12a-n) has been synthesized. The antifungal activity of compounds was evaluated by in vitro agar diffusion and broth dilution assay. Compounds 11d and its positional isomer 12d having 3-trifluoromethyl substitution on the phenyl ring of piperazine demonstrated significant antifungal activity against variety of fungal cultures (Candida spp. C. neoformans and Aspergillus spp.). The compound 12d showed MIC value of 0.12 microg/mL for C. albicans, C. albicans V-01-191A-261 (resistant strain); 0.25 microg/mL for C. tropicalis, C. parapsilosis ATCC 22019 and C. krusei and MIC value of 0.5 microg/mL for C. glabrata, C. krusei ATCC 6258, which is comparable to itraconazole and better than fluconazole. Further, compound 11d showed significant activity (MIC; 0.25-0.5 microg/mL) against Candida spp. and strong anticryptococcal activity (MIC; 0.25 microg/mL) against C. neoformans.     

(3-substituted benzyl)thiazolidine-2,4-diones as structurally new antihyperglycemic agents

A series of 3-[(2,4-dioxothiazolidin-5-yl)methyl]benzamide derivatives was prepared as part of a search for antidiabetic agents. A structure-activity relationship study of these compounds led to the identification of 5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[4-(trifluorome thyl)-phenyl]methyl]benzamide (KRP-297) as a candidate drug for the treatment of diabetes mellitus.     

Solid-phase synthesis of chiral stationary phases based on 2,4,5,6-tetrachloro-1,3-dicyanobenzene derivatives spaced from N-3,5-dinitrobenzoyl alpha-amino acids: comparative study of their resolution efficacy

Two new chiral stationary phases, 3-[5-chloro-1,3-dicyano-2,4-[2'-(N'-1,3-dinitrobenzoyl-D-phenylglycinyl) aminoethyl]aminophen-1-yl] aminopropyl silica (CSP-1) and 3-[5-chloro-1,3-dicyano-2,4-[2'-(N'-1,3-dinitrobenzoyl-L-leucinyl) aminoethyl] aminophen-1-yl] aminopropyl silica (CSP-2), were prepared by solid-phase synthesis. They comprise chiral unit, 3,5-dinitrobenzoyl derivative of the amino acid, D-PhGly or L-Leu, bound via spacer 1,2-diaminoethane to 2,4-positions of the persubstituted benzene ring, derived from compound 1, and possess pseudo-C2 symmetry. Preparation of model compounds 6 and 7 confirmed the structure of chiral selectors, which comprise pi-donor persubsituted aromatic ring and two strong pi-acceptor 3,5-dinitrobenzoyl amido units. CD spectra of model selectors 6 and 7, run in DMSO above 250 nm, exhibit negative exciton coupling (EC) between pi-acceptor and pi-donor chromophores, C(1) symmetric model compound 8 exhibited much weaker EC and 9, devoid of pi-donor unit, does not exhibit any significant CD. Combined pi-donor and pi-acceptor properties enable the new CSPs to separate a broad range of racemates. The columns with CSP-1 and CSP-2 were tested for the separation of 22 racemates by HPLC with two different mobile phase systems and the results are compared with those obtained by using a structurally related commercial column.     

New azoles with antifungal activity: Design, synthesis, and molecular docking

In order to search for many target compounds with excellent activities, a series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluoro-phenyl)-3-[(4-substituted phenyl)-piperazin-1-yl]-propan-2-ols were designed, synthesized, and evaluated as antifungal agents. Results of preliminary antifungal tests against eight human pathogenic fungi in vitro showed that all the title compounds exhibited excellent activities with broad spectrum. Moreover, a molecular model for the binding between 5a and the active site of CACYP51 was provided based on the computational docking results.     

Synthesis and SAR studies of biaryloxy-substituted triazoles as antifungal agents

A series of 1-(substituted biaryloxy)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl) propan-2-ol were synthesized and their antifungal activities were evaluated against eight human pathogenic fungi in vitro. Seventeen compounds showed activity 4- to 64-fold higher than voriconazole against Candida albicans. SAR clearly suggested that introduction of a biaryloxy side chain greatly enhanced the antifungal activity of triazole analogs against Candida species.