The synthesis of some methy 4,6-O-Benzylidene-α-D-erythro-Hexopyranosid-2,3-Diulose derivatives

Methyl 4,6-O-benzylidene-3-deoxy-3-phenylazo-α-D-glucopyranoside (1) has been oxidised with the Pfitzner—Moffat reagent to the 2,3-diulose 3-phenylhydrazone derivative (2) which has been characterised as the phenylosazone (3) and oxime (4). An unstable 2-imino derivative (10) of the same diulose has been produced by base-catalysed elimination of nitrogen from methyl 2-azido-4,6-O-benzylidene-2-deoxy-α-D-ribo-hexopyranosid-3-ulose (8). The imino intermediate was trapped as a quinoxaline derivative (9). The base-catalysed reactions of certain other hydrazone derivatives of methyl hexosiduloses have also been examined.     

2-aryl-8-chloro-1,2,4-triazolo[1,5-a]quinoxalin-4-amines as highly potent A1 and A3 adenosine receptor antagonists

Some 2-aryl-8-chloro-1,2,4-triazolo[1,5-a]quinoxaline derivatives 2-18, obtained by introducing different substituents on either the 4-amino moiety (acyl or carbamoyl groups) or the 2-phenyl ring (4-OCH3) of previously reported 8-chloro-2-phenyl-1,2,4-triazolo[1,5-a]quinoxalin-4-amine (1), have been synthesized and tested in radioligand binding assays at bovine A1 and A(2A) and at cloned human A1 and A3 adenosine receptors. The rationally designed 8-chloro-2-(4-methoxy-phenyl)-1,2,4-triazolo[1,5-a]quinoxalin-4-acetylamine (14) can be considered one of the most potent and hA3 versus hA1 selective AR antagonists reported till now. The structure-activity relationships of compounds 2-18 are in agreement with those of previously reported 2-aryl-1,2,4-triazolo[4,3-a]quinoxalines (series A) and 2-arylpyrazolo[3,4-c]quinolines (series B), thus suggesting a similar AR binding mode. In fact, the importance for the A3 receptor-ligand interaction of both a strong acidic NH proton donor and a C=O proton acceptor at position-4, able to engage hydrogen-bonding interactions with specific sites on the A3 AR, has been confirmed. Using our recently published hA3 receptor model, to better elucidate our experimental results, we decided to theoretically depict the putative TM binding motif of the herein reported 1,2,4-triazolo[1,5-a]quinoxaline derivatives on human A3 receptor. Structure-activity relationships have been explained analyzing the three-dimensional structure of the antagonist-receptor models obtained by molecular docking simulation.     

Convenient preparation of L-arabino-hexos-5-ulose derivatives from lactose

2,6-di-O-benzyl- (9), 2-O-benzyl-3,4-O-isopropylidene- (19), and 2-O-benzyl-6-O-m-chlorobenzoyl-L-arabino-hexos-5-ulose (20) have been prepared using 4'-deoxy-4'-eno- and 6'-deoxy-5'-eno lactose dimethyl acetal derivatives 7 and 14 as key intermediates. The synthesis of enol ethers 7 and 14 has been performed with good yields by base-promoted elimination of acetone or p-toluenesulfonic acid from 2',6'-di-O-benzyl-, and 6'-O-p-toluenesulfonyl-2,3:5,6:3',4'-tri-O-isopropylidenelactose dimethyl acetal, respectively. The epoxidation with MCPBA of 7 and 14 in methanol or dichloromethane furnishes C-5'-methoxy and C-5'-m-chlorobenzoyloxy derivatives, easily transformed with good yields into L-arabino 5-ketoaldohexoses 9, 19 and 20.     

Isolation and identification of the intermediates during pyrazole formation of some carbohydrate hydrazone derivatives

Reaction of the oxidation product of L-ascorbic acid, dehydro-L-ascorbic acid, with o-phenylenediamine, followed by 2,4,6-trichlorophenylhydrazine (3) afforded 3-[1-(2,4,6-trichlorophenylhydrazono)-L-threo-2,3,4-trihydroxybut-1-yl]quinoxalin-2(1H)one (4), whose structure was deduced from studying its periodate oxidation, which gave the glyoxal derivative 3-[1-(2,4,6-trichlorophenylhydrazono)glyoxal-1-yl]quinoxalin-2(1H)one (5) that upon reduction afforded 3-[1-(2,4,6-trichlorophenylhydrazono)-2-hydroxyethy-1-yl]quinoxalin-2(1H)one (6). The reaction of 5 with 3 afforded the bishydrazone 3-[1,2-bis(2,4,6-trichlorophenylhydrazono)glyoxal-1-yl]quinoxalin-2(1H)one. The reaction of 5 with acetic anhydride in pyridine afforded the 2,3-dihydrofuro[2,3-b]quinoxaline derivative 2-acetoxy-3-[2-acetyl-2-(2,4,6-trichlorophenyl)hydrazono)]-2,3-dihydrofuro[2,3-b]quinoxaline. Acetylation of 4 with acetic anhydride in pyridine afforded the acyclic diacetate intermediate 3-[3,4-di-O-acetyl-2-deoxy-1-(2,4,6-trichlorophenylhydra-zono)but-2-en-1-yl]quinoxalin-2(1H)one (12), which was also obtained from the reaction of 4 with boiling acetic anhydride. Compound 12 rearranged under the reaction conditions to give the pyrazole derivatives 3-[5-(ace-toxymethyl)-1-(2,4,6-trichlorophenyl)pyrazol-3-yl]quinoxalin-2(1H)one (14) and 2-acetoxy-3-[5-(acetoxymethyl)-1-(2,4,6-trichlorophenyl)pyrazol-3-yl)]quinoxaline (15), as well as the 2,3-dihydrofuro[2,3-b]quinoxaline derivative 2-(2-acetoxyethen-2-yl)-3-[2-(2,4,6-trichlorophenyl)hydrazono]-2,3-dihydrofuro[2,3-b]quinoxaline. Acetylation of 3-[5-(hydroxymethyl)-l-(2,4,6-trichlorophenyl)pyrazol-3-yl]quinoxalin-2(1H)one (16) with acetic anhydride in pyridine or 12 with boiling acetic anhydride afforded 15 and 16, respectively. Treatment of 4 with diluted sodium hydroxide afforded the pyrazolo[2,3-b]quinoxaline (flavazole) derivative 1-(2,4,6-trichlorophenyl)-3-(L-threo-glycerol-1-yl)pyrazolo[2,3-b]quinoxaline whose acetylation afforded the acetyl derivative 3-(2,3,4-tri-O-acetyl-L-threo-glycerol-1-yl)-1-(2,4,6-trichlorophenyl)pyrazolo[2,3-b]quinoxaline. The assigned structures were based on spectral analysis. The activity of compound 4 against hepatitis B virus has been studied.     

Gamma-radiolysis of D-glucose in aerated, aqueous solution.

Gamma-Radiolysis of D-glucose in aerated, aqueous solution gives mainly D-glucono-1,5-lactone, D-arabino-hexosulose, and D-ribo-hexos-3-ulose, together with D-xylo-hexos-4-ulose, D-xylo-hexos-5-ulose, and other pentose, tetrose, and triose derivatives as minor products, which were estimated by mass spectrometry of their alditol-d acetates. These hexose derivatives appear to be produced by the decomposition of D-glucose peroxy-radicals which are formed by the reaction of the primary radicals of D-glucose with oxygen. Bond scission of the peroxy-radicals yields triose, tetrose, and pentose. A radiolysis mechanism for the degradation of D-glucose in aerated, aqueous solution is proposed, based on the reaction of several kinds of D-glucose radical with oxygen.     

Iminoalditol-amino acid hybrids: synthesis and evaluation as glycosidase inhibitors

Cyclization by double reductive amination of D-xylo-hexos-5-ulose with the terminal amino group of alpha-N-Boc-lysine methyl ester gave a 4:1-mixture of (1'R)-N-methoxycarbonyl-(1-N-Boc-amino)pentyl-1-deoxynojirimycin and the corresponding L-ido epimer whereas D-lyxo-hexos-5-ulose furnished the desired N-alkylated 1-deoxymannojirimycin derivative without any observable epimer formation at C-5. By subsequent modification of the lysine moiety, additional chain-extended derivatives as well as fluorescent compounds were obtained. All fluorescent iminoalditol-amino acid hybrids prepared in this study exhibited glycosidase inhibitory activities better than or comparable to the parent compounds'.     

The reaction of some dicarbonyl sugars with aminoguanidine.

The reactions of aminoguanidine (guanylhydrazine) with 3-deoxy-D-erythro-hexos-2-ulose (1a), 3-deoxy-D-glycero-pentose-2-ulose (1b), D-erythro-hexos-2-ulose (1c), and D-glycero-pentose-2-ulose (1d) were examined at 37 degrees at a solution pH of 7.0 (phosphate buffer). For 1a and 1b, two major products were observed and shown respectively to be the 5- and 6-substituted 3-amino-1,2,4-triazine derivatives. The ratios of the products were independent of the amount of aminoguanidine present or the order of mixing the reagents prior to the experiments. For 1c and 1d, only the 5-substituted triazine derivatives were formed. No evidence for hydrazone or bishydrazone formation was observed.     

A new and efficient entry to D-xylo-hexos-4-ulose and some derivatives thereof through epoxidation of the 3,4-hexeno derivative of diacetone-D-glucose

A new preparation of D-xylo-hexos-4-ulose (1) and of its 3-m-chlorobenzoate (2) has been devised using the epoxidation of 3-deoxy-1,2:5,6-di-O-isopropylidene-D-erythro-hex-3-enofuranose (6) as the key step. The epoxidation of 6 in CH2Cl2 furnished with high yield 1,2:5,6-di-O-isopropylidene-3-O-m-chlorobenzoyl-4-C-hydroxy-D-xylo-hexos-4-ulo-1,4-furanose as a mixture of C-4 hemiacetal anomers (7a,b), which, on acid hydrolysis, gave a tautomeric mixture of 3-O-m-chlorobenzoyl-D-xylo-hexos-4-ulose (2) with an overall 60% yield from 6. The formation of 4-C-methoxy-diacetone-D-glucose derivatives (11a,b) through epoxidation-methanolysis of 6, took place with reduced yield because of the competition between m-chlorobenzoic acid (MCBA) and methanol to the opening by attack at C-4 of the intermediate epoxide and the formation of acyclic products arising from the alternative nucleophilic attack at C-1. Acid hydrolysis of derivatives 11 gave D-xylo-hexos-4-ulose (1) with a 35% overall yield from 6. NMR analysis showed that 2 is composed, in CD3CN, mainly by a 7:3 mixture of 4-keto-alpha- and beta-pyranose forms, while 1, in D2O, is present as a more complex mixture constituted mainly by 4-keto-alpha- and beta-pyranoses and their respective hydrates in a 17:15:34:34 ratio.     

Synthesis of phosphono-pyrimidine and -purine ribonucleosides

The reaction of the lithiated species of 2', 3', 5'-tri-O-protected uridines and 6-chloropurine ribonucleoside with diethyl chlorophosphate provided the corresponding diethyl phosphonate derivatives (III, IV and VIII). The Arbuzov-reaction of 2', 3', 5'-tri-O-protected 4-chloro-2(1H)-pyrimidinone ribonucleoside with triethyl phosphite afforded the diethyl phosphonate derivative (VI).     

Chemical and enzymatic synthesis of 4'-thio-beta-D-arabinofuranosylcytosine monophosphate and triphosphate

N4-Acetyl-1-(2, 3-di-O-acetyl-4-thio-beta-D-arabinofuranosyl) cytosine (2) was synthesized in three steps from 1-(4-thio-beta-D-arabinofuranosyl) cytosine (1). The reaction of this partially blocked 4'-thio-ara-C derivative 2 with 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one gave the 5-phosphitylate derivative 3, which on reaction with pyrophosphate gave the 5'-nucleosidylcyclotriphosphite 4. Product 4 was then oxidized with iodine/pyridine/water and deblocked with concentrated ammonium hydroxide to provide the desired 4'-thio-ara-C-5'-triphosphate 5. This triphosphate 5 was converted to 4'-thio-ara-C -5'-monophosphate 6 by treatment with snake venom phosphodiesterase I. The details of the synthesis, purification, and characterization of both nucleotides are described.     

Cytotoxicity and detection of damage to DNA by 3-(5-nitro-2-thienyl)-9-chloro-5-morpholin-4-yl[1,2,4]triazolo[4,3-c] quinazoline on human cancer cell line HeLa

Quinazolines - 1,3-benzodiazines are biological active compounds, which are used in the phamaceutical industry, in agriculture and in the medicine. As documented in the literature, many derivatives demonstrated anticancer activity and they act as multitarget agents. 3-(5-Nitro-2-thienyl)-9-chloro-5-morpholin-4-yl[1,2,4]triazolo[4,3-c] quinazoline (NTCHMTQ) - a new synthetically prepared quinazoline derivative was the most effective derivative in our primary cytotoxic screening. In this study, we evaluated cytotoxic/antiproliferative activity of NTCHMTQ using human tumor cell line HeLa. Possible interaction of 3-(5-nitro-2-thienyl)-9-chloro-5-morpholin-4-yl[1,2,4]triazolo[4,3-c] quinazoline with calf thymus DNA was tested by the DNA - modified screen - printed electrode. Quinazoline derivative acted cytotoxically on tumor cell line HeLa. The IC(100) value was 10 microg/ml. The IC(50) values was found to be less than 4 microg/ml, a limit put forward by the National Cancer Institute (NCI) for classification of he compound as a potential anticancer drug. Quinazoline at micromolar concentrations induced morphological changes and necrosis of HeLa cells. Using the DNA based electrochemical biosensor, we have not found damage to DNA under in vitro conditions at an incubation of the biosensor in mixture with quinazoline.     

Synthesis of glycosides of 3-deoxy-4-thiopentopyranosid-2-uloses and their reduction products: 3-deoxy-4-thiopentopyranosides

Michael addition of common thiols to the enone system of (2S)-2-benzyloxy-2H-pyran-3(6H)-one (1) afforded the corresponding 3-deoxy-4-thiopentopyranosid-2-ulose derivatives (2-4). The reaction was highly diastereoselective, and the addition was governed by the quasiaxially disposed 2-benzyloxy substituent of the starting pyranone. As expected from the enantiomeric excess of 1 (ee > 86%) the corresponding thiouloses 2-4 exhibited the same optical purity. However, the enantiomerically pure thioulose 5 was obtained by reaction of 1 with the chiral thiol, N-(tert-butoxycarbonyl)-L-cysteine methyl ester. The thio derivative 7 was also synthesized by reaction of 6 (enantiomer of 1) with the same chiral thiol. Alternatively, 4-thiopent-2-uloses 9-12 were prepared in high optical purity by 1,4-addition of thiols to (2S)-[(S)-2'-octyloxy]dihydropyranone 8. Similarly, reaction of 13 (enantiomer of 8) with benzenemethanethiol afforded 14 (enantiomer of 10). This way, the stereocontrol exerted by the anomeric center on the starting dihydropyranone led to 4-thiopentuloses of the D and L series. Sodium borohydride reduction of the carbonyl function of uloses 10 and 12 gave the corresponding 3-deoxy-4-thiopentopyranosid-2-uloses (16-19). The diastereomers having the beta-D-threo configuration (16, 18) slightly predominated over the beta-D-erythro (17, 19) analogues. However, the reduction of the enantiomeric pyranones 10 and 14 with K-Selectride was highly diastereofacial selective in favor of the beta-D- and beta-L-threo isomers 16 and 20, respectively.     

Cu, Pt, and Pd complexes of the 3-deoxy-1,2-bis(thiosemicarbazone) derived from D-glucose

3-Deoxy-D-erythro-hexos-2-ulose bis(thiosemicarbazone) (1) acts as a tetradentate ligand of the N2S2 type which forms stable coordination complexes with metal(II) cations. The Cu(II), Pt(II), and Pd(II) chelates (2, 4, and 6, respectively) of 1 were synthesized and characterized by elemental analysis and NMR spectroscopy. The NMR spectra of the Pt complex (4) showed the coupling of H-1 and C-1, C-2 of the bis(thiosemicarbazone) with 195Pt (33.7% naturally occurring), which supports the structure proposed for the chelate. The complexes 2, 4, and 6 were acetylated to give the corresponding tri-O-acetyl derivatives 3, 5, and 7. Elimination of Cu(II) from 3 with hydrogen sulfide afforded 8, the tri-O-acetyl derivative of 1. Preliminary studies have shown antiviral activity of chelates 2, 4, and 6 against poliovirus type 1.     

Isolation and Identification of l-Menthyl-β-d-glucoside from Shubi

Quinoxalines derived from d-galactose with o-phenylenediamine (OPD) in acidic media under reflux were studied by using GLC and NMR measurements. Four quinoxaline derivatives were obtained from the reaction mixture, and were identical with those derived from d-glucose. The yields of 2-(D-lyxo-tetrahydroxybutyl)quinoxaline (GA-III), and the stereoisomeric derivative of GA-III, i.e., 2-(D-arabino-tetrahydroxybutyl)quinoxaline (ATBQ), were 13.2 and 5.3–, respectively. The ratio of GA-III to ATBQ derived from d-galactose was reciprocally coincident with that from d-glucose. Some proposals are made on the relationship between the isomerization of these sugars and the formation of quinoxaline derivatives.     

Chemiluminescent assay of various enzymes using indoxyl derivatives as substrate and its applications to enzyme immunoassay and DNA probe assay.

Chemiluminescent assays of various enzymes have been developed using indoxyl derivatives as substrates. The principle of the method is as follows: an enzyme causes hydrolysis of an indoxyl derivative to an intermediate indoxyl that is readily oxidized to indigo dye and simultaneously produces hydrogen peroxide (H2O2). Hydrogen peroxide is detected chemiluminescently using isoluminol-microperoxidase. Alkaline phosphatase (ALP), beta-D-galactosidase (beta-gal), and beta-glucosidase were assayed by this method using 5-bromo-4-chloro-3-indolyl phosphate (BCIP), 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-Gal), and 5-bromo-4-chloro-3-indolyl-beta-D-glucoside, respectively, as substrates. Using BCIP and X-Gal substrates, we have been able to detect 10(-19) mol of ALP and beta-gal, respectively. This assay system can be applied to enzyme immunoassay and DNA probe assay.     

Intramolecular aldol cyclization of L-lyxo-hexos-5-ulose derivatives: a new diastereoselective synthesis of D-chiro-inositol

The DBU-promoted intramolecular aldol condensation of two partially protected L-lyxo-hexos-5-ulose derivatives (8 and 9), in turn obtained starting from methyl beta-D-galactopyranoside, takes place with fairly good yield and complete diastereoselectivity to give 2L-(2,3,6/4,5)-pentahydroxycyclohexanone derivatives, 10 and 11. The stereoselective reduction of inosose 10 with sodium triacetoxyborohydride leads, after catalytic debenzylation, to D-chiro-inositol (1), while the sodium borohydride reduction furnishes, with opposite stereoselectivity, a derivative of allo-inositol.     

Mutagenic activity of the methyl and phenyl derivatives of the food mutagen 2-amino-3-methylimidazo[4,5-f]quinoxaline (IQx) in the Ames test

The mutagenic activity of 15 different mono-, di-, tri-, and tetramethyl derivatives of the food mutagen IQx (2-amino-3-methylimidazo[4,5-f]quinoxaline), one diphenyl derivative of IQx and two phenyl derivatives of 5-MeIQx (2-amino-3,5-dimethylimidazo[4,5-f]quinoxaline) were studied in the Ames test with Salmonella typhimurium TA98 and enzymatic activation (S9). The number and positioning of the methyl groups strongly affected the mutagenic activity. The phenylated compounds showed weak mutagenic potency. It seems that both resonance stabilization of the nitrenium ion and steric effects are important in determining mutagenic potency.     

Isolation of Permethylated Dicarbonyl Sugar Derivatives from Polysaccharides

Oxidation of methyl trimethyl glucopyranosides which were obtained by methanolysis of permethylated cellulose, laminarin, and dextran, was performed with dimethyl sulfoxide (DMSO)-phosphorus pentoxide to afford the corresponding ulose derivatives, methyl 2,3,6-tri-O-methyl-d-xylo-hexopyranosid-4-ulose, methyl 2,4,6-tri-O-methyl-d-ribo-hexopyranosid-3-ulose, and methyl 2,3,4-tri-O-methyl-d-gluco-hexodialdo-l,5-pyranoside, respectively, in good or moderate yields. As a new type of derivatives for the linkage analysis of polysaccharides the chromatographic and spectrometric properties of 2,4-dinitrophenylhydrazone of the ulose derivatives were investigated.     

The synthesis of -xylo-hexos-4-ulose and some derivatives

D-xylo-Hexos-4-ulose has been synthesised, characterised chromatographically, and methyl α- -xylo-hexopyranosid-4-ulose has been shown to be stable in neutral aqueous solution, contrary to a previous report. Glycosyl phosphate derivatives are also reported.     

Synthesis and evaluation of novel 2-butyl-4-chloro-1-methylimidazole embedded chalcones and pyrazoles as angiotensin converting enzyme (ACE) inhibitors

A series of novel 2-butyl-4-chloro-1-methylimidazole embedded aryl and heteroaryl derived chalcones and pyrazoles were synthesized and evaluated for their angiotensin converting enzyme (ACE) inhibitory activity. The condensation of 2-butyl-4-chloro-1-methylimidazole-5-carboxaldehyde with various aryl and heteroaryl methyl ketones in the presence of 10% aqueous NaOH in methanol proceeded efficiently to give the respective chalcones in very good yields. Further, the reaction of chalcones with hydrazine hydrate in acetic acid gave substituted pyrazole analogues. Screening all 36 new compounds using ACE inhibition assay, resulted chalcones with better ACE inhibitory activity compared to the respective pyrazole analogues. Among the chalcones 4a-r, three compounds, (E)-3-(2-butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-(5-chlorothiophen-2-yl)prop-2-enone 4i, (E)-3-(2-butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-(1H-pyrrol-2-yl)prop-2-enone 4l, (E)-3-(2-butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-(dibenzo[b,d] thiophen-2-yl)prop-2-enone 4q were resulted as most active ACE inhibitors with IC(50) of 3.60 μM, 2.24 μM, and 2.68 μM, respectively.