Synthesis of furanosyl alpha-C-glycosides derived from 4-chloro-4-deoxy-alpha-D-galactose and their cytotoxic activities

Condensation of a new unnatural sugar 1 with 1,3-dicarbonyl compounds in the presence of anhydrous zinc chloride gave the polyhydroxyalkyl-furans in excellent yields. Further modification afforded the corresponding furanosyl alpha-C-glycoside derivatives. The absolute configuration of 3-acetyl-2-methyl-5-(2'-chloro-D-galacto-tetritol-1-yl)-furan was confirmed by single-crystal X-ray analysis. The in vitro cytotoxic activities of these furanosyl C-glycosides were also investigated.     

The reduction of alpha-ketocarboxylic acids and alpha-dicarbonyl compounds with titanium(III) chloride

Thirteen model alpha-ketocarboxylic acids and alpha-dicarbonyl compounds have been observed to be reduced by titanium(III) chloride. The products of these reactions were shown by melting (boiling) points, mixed melting points, derivatives, refractive indices, infrared, and NMR comparisons with authentic compounds or literature information to be the corresponding alpha-hydroxycarboxylic acids or alpha-hydroxyketones.     

The reduction of aliphatic and aromatic N-oxides to the corresponding amines with titanium(III) chloride

Amine N-oxides have been observed to be reduced by titanium(III) chloride. To study this reaction, 24 model amine N-oxides were reacted with titanium(III) chloride. The products of these reactions were shown by melting (boiling) points, mixed melting points, derivatives, refractive indices, infrared, and NMR comparisons with authentic compounds to be the corresponding amines. The reductions were found to require 2 moles of titanium(III) per mole of amine N-oxide.     

Pyrimidine arabinofuranosyl nucleosides with 5-substituted long, branched and unsaturated chains: synthesis and antiherpes properties

Several procedures have been applied to the preparation of 5-alkyl analogues of araU and araC via condensation of the appropriate 2,4-bis-O-(trimethylsilyl)-5-alkylpyrimidine with 2,3,5-tri-O-benzyl-alpha-D-arabinofuranosyl chloride. The resulting O'-benzylated nucleosides were deblocked with the aid of BF3 . Et2O in C2H5SH. The araC analogues were also prepared by conversions of the corresponding 5-alkyl-araU derivatives. The chloromercuri derivatives of araU and araC, were reacted with allyl chloride in the presence of Li2PdCl4. The resulting 5-allyl derivatives were catalytically reduced to the corresponding 5-propyl analogues. Catalysed condensation of 2,4-bis-O-(trimethylsilyl)-5-vinyluracil with 2,3,5-tri-O-benzyl-alpha-D-arabinosyl chloride, as well as with 1-O-acetyl-2,3,5-tri-O-benzoylarabinofuranose, was carried out under a variety of different conditions. Deblocking of the benzylated nucleosides with various reagents led invariably to addition to the vinyl substituent. In the case of benzoylated nucleosides, deblocking yielded largely the alpha-anomers. The antiherpes activities of the 5-alkyl compounds have been evaluated, as well as the susceptibility of the araC analogues to enzymatic deamination.     

As-Triazine Derivatives with Potential Therapeutic Action XXVII. Synthesis of 5-[Alkyl-(ethoxycarbonyl)methyl]mercapto-6-azauridines

Abstract

5-Mercapto-6-azauracil (I) reacted in aqueous medium with ethyl α-haloalkanoates giving 5-[alkyl-(ethoxycarbonyl)methyl]mercapto-6-azauracils (II). Their 2,4-bis(trimethylsilyloxy) derivatives (III) were condensed with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose in the presence of anhydrous stannic chloride to afford the corresponding blocked nucleosides (IV). Under the action of sodium methoxide, the derivatives IV were debenzoylated with the formation of the title compounds (V).     

Biochemical studies of toxic agents. The metabolic formation of 1- and 2-menaphthylmercapturic acid

1. Various derivatives of 1- and 2-methylnaphthalene, of the type C(10)H(7).CH(2)X, were administered to rats and the urines of the dosed animals were examined for the presence of 1- and 2-menaphthylmercapturic acid by chromatographic and isolation procedures. A similar, but more limited, series of experiments was carried out with rabbits. 2. All the compounds were administered by subcutaneous injection with the exception of S-(1- and 2-menaphthyl)-l-cysteine, which were added to the food. 3. 1-Menaphthylmercapturic acid was isolated from the urine of rats after the administration of 1-menaphthyl chloride, bromide, alcohol, acetate and benzoate, S-(1-menaphthyl)-l-cysteine and S-(1-menaphthyl)glutathione. 4. 2-Menaphthylmercapturic acid was isolated from rat urine after administration of 2-menaphthyl chloride, S-(2-menaphthyl)-l-cysteine and S-(2-menaphthyl)-glutathione, and was detected chromatographically after injecting 2-menaphthyl bromide. 5. The corresponding mercapturic acids were isolated after administering 1- and 2-menaphthyl chloride and 1-menaphthyl acetate to rabbits, but not after giving 1- and 2-menaphthyl bromide and 1-menaphthyl alcohol, although chromatographic evidence of mercapturic acid excretion was obtained after injecting these compounds.     

Synthesis of novel steroidal heterocyclic derivatives as antibacterial agents

This study aimed at the synthesis of novel structurally promising steroidal heterocycles and to elucidate the potential role of these compounds as antibacterial agents. Epi-androsterone 1 reacted with CS2 and sodium hydride in dimethylsulfoxide to yield alpha-oxoketene dithiodisodium salt 2. The non-isolable salt 2 reacted with acetyl chloride, benzoyl chloride, phenacyl bromide and iodomethane to afford the corresponding alpha-oxodithioacetal derivatives 4a,b, 6 and 7, respectively. Interaction of 2 with the alkyl halide reagents 8a-d yielded the corresponding thiophene derivatives 10a-d. Alpha-oxoketene dithioacetal 7 reacted with urea and thiourea to furnish the pyrimidinoandrostane derivatives 12a,b. Compound 7 also reacted with ortho-phenylene diamine and ortho-aminophenol 13a,b to produce the dinucleophilic adducts 15a,b. The in vitro antibacterial evaluation of some newly prepared compounds showed that all compounds have high significant antibacterial activity against the used strains of gram positive and gram negative bacteria.     

Synthesis of some new hybride molecules containing several azole moieties and investigation of their biological activities

1,2,4-Triazole-3-one prepared from tryptamine was converted to the corresponding carbothioamides by several steps. Their treatment with ethyl bromoacetate or 4-chlorophenacyl bromide produced the corresponding 5-oxo-1,3-thiazolidine or 3-(4-chlorophenyl)-1,3-thiazole derivatives. Acetohydrazide derivative that was obtained starting from tryptamine, was converted to the corresponding Schiff basis and sulfonamide by the treatment with suitable aldehydes and benzensulphonyl chloride, respectively. 2-[(4-Amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)methyl]-4-[2-(1H-indole-3-yl)ethyl]-5-methyl-2,4-dihydro-3H-1,2,4-triazole-3-one was synthesized starting from hydrazide via the formation of the corresponding 1,3,4-oxadiazole compound, while the other bitriazole compounds were obtained by intramolecular cyclisation of carbothioamides in basic media. The treatment of 1,2,4-triazole or 1,3,4-oxadiazole compound with several amines generated the corresponding Mannich bases. Ethyl (2-amino-1,3-thiazole-4-yl)acetate was converted to the corresponding 1,3,4-oxadiazole derivative, arylidenehydrazides, 1,2,4-triazole-3-one and 5-oxo-1,3-oxazolidine derivatives by several steps. The structural assignments of new compounds were based on their elemental analysis and spectral (FT IR, ¹H NMR, ¹³C NMR and LC-MS) data. The antimicrobial, antilipase and antiurease activity studies revealed that some of the synthesized compounds showed antimicrobial, antilipase and/or antiurease activity.     

Novel and regiospecific synthesis of 2-amino estrogens via Zincke nitration

An efficient synthesis of 2-aminoestrone (14), 2 aminoestradiol (15), 2-amino-16 alpha-hydroxyestrone (16) and 2-aminoestriol (17) is described. 2,4-Dibromo estrogens 1 - 4 were regiospecifically converted to the corresponding 2-nitro-4-bromo derivatives 5 - 8 in quantitative yields, with Zincke nitration using sodium nitrite. Catalytic hydrogenation of the 2-nitro-4-bromides 5 - 8 over palladium-on-charcoal gave directly the desired 2-amino estrogens 14 - 17 in high yields. The 2-amino compounds 15 and 17 were also obtained by the reduction of the corresponding 2-nitro-4-bromides 6 and 8 with sodium borohydride in the presence of palladium chloride.     

Synthesis of 2-(aminocarbonylmethylthio)-1H-imidazoles as novel Capravirine analogues

Different analogues of Capravirine (AG-1549) or S-1153 were prepared by synthesis of 2-(5-benzyl-4-isopropyl-1-methyl-2,3-dihydro-1H-imidazol-2-ylthio)acetamide (3a-c), ethyl [5-benzyl-1-(ethoxymethyl)-4-ethyl-1H-imidazol-2-ylthio]acetate (10), 2-[5-alkyl-4-substituted 1-(pyridin-4-ylmethyl)-1H-imidazol-2-ylthio]acetamides (12a-f), and 2-[5-benzyl-1-(benzyloxymethyl)-4-isopropyl-1H-imidazol-2-ylthio]acetamides (14a-l) from their corresponding amino acids through a sequence of reactions: Dakin-West reaction, hydrolysis, condensation with thiocyanate derivatives, alkylation with 2-iodoacetamide and ethyl chloroacetate, and coupling with 4-pyridylmethyl chloride, ethoxymethyl chloride and benzyloxymethyl chloride. All the synthesized compounds were screened for their activity against HIV-1 (wild type) and some of them (especially Capravirine like structures) were found active.     

Synthesis of new arylalkoxy amido derivatives as melatoninergic ligands

Amido derivatives 10-18 of the corresponding oxyamines were synthesised as melatoninergic ligands by the reaction of hydroxyphtalimide with the halogeno derivatives or the corresponding alcohols using Mitsunobu reaction conditions. The affinity of the compounds for chicken brain melatonin receptors and recombinant human MT(1) and MT(2) receptors was evaluated using 2-[125I]-iodomelatonin as the radioligand. Overall, the introduction of an oxygen atom in the amido chain was not a favourable parameter as the compounds were less potent than the corresponding deoxy derivatives. However, nanomolar compounds were obtained with the arylethyloxy derivatives (13c (R'=nPr), chicken brain, hMT(1), hMT(2), K(i) values: 4.8, 3.86, 2.4 nM, respectively) and the 2,7-dimethoxynaphthalene derivatives (17c (R'=nPr), chicken brain, hMT(1), hMT(2), K(i) values: 0.04, 0.13, 0.1 nM, respectively). The functional activity of these compounds was evaluated by the aggregation of melanophores in Xenopus laevis tadpoles and the potency was related to the affinity of the molecules for melatonin receptors. The compounds were found to be full agonists and compound 17a was 20-fold more potent than melatonin in this bioassay.     

Synthesis, antimicrobial, and anti-HIV-1 activity of certain 5-(1-adamantyl)-2-substituted thio-1,3,4-oxadiazoles and 5-(1-adamantyl)-3-substituted aminomethyl-1,3,4-oxadiazoline-2-thiones

The reaction of 5-(1-adamantyl)-1,3,4-oxadiazoline-2-thione 2 with iodoethane, 2-dimethylaminoethyl chloride hydrochloride or 2-piperidinoethyl chloride hydrochloride in ethanolic potassium hydroxide yielded the corresponding 5-(1-adamantyl)-2-ethyl or substituted ethylthio-1,3,4-oxadiazoles 3a-c. Interaction of 2 with formaldehyde solution and primary aromatic amines or 1-substituted piperazines, in ethanol at room temperature yielded the corresponding 5-(1-adamantyl)-3-arylaminomethyl-1,3,4-oxadiazoline-2-thiones 4a-m or 5-(1-adamantyl)-3-(4-substituted-1-piperazinylmethyl)-1,3,4-oxadiazoline-2-thiones 5a-h, respectively. All the synthesized compounds were tested for in vitro activities against certain strains of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Compounds 2, 5a, and 5e were found as the most active derivatives, particularly against the Gram-positive bacteria. In addition, the antiviral activity of compounds 2, 4a-m, and 5a-h against HIV-1 using the XTT assay was carried out. Compound 2 produced 100%, 43%, and 37% reduction of viral replication at 50, 10, and 2microg/mL concentrations, respectively.     

N-methyl-2-anilino-6-naphthalenesulfonyl hydrazine (2,6-mansyl hydrazine): A new sensitive fluorometric reagent for carbonyl compounds

An almost quantitative synthesis of N-methyl-2-anilino-6-naphthalenesulfonyl hydrazine (2,6-mansyl hydrazine) from sulfonyl chloride and hydrazinlum hydroxide is described. The 2,6-mansyl chloride was prepared by different methods from 6-hydroxynaphthalene-2-sulfonic acid (overall yield: 69%). The N- and the O-mansylation of suitable compounds (e.g., amines, amino acids, and phenolic steroids) with 2,6-mansyl chloride and the preparation of oxosteroid-2,6-mansyl hydrazones are deseribed, and the derivatives obtained, their uv spectra, and methods for their thin-layer chromatographic separation are compared with the corresponding data for dansylated compounds.     

Aliphatic analogues of nucleotides: synthesis and affinity towards nucleases

DL-1-(2,3-Dihydroxypropyl)thymine was prepared by Hilbert-Johnson reaction of 2,4-dinethoxy-5-methylpyrimidine with allyl bromide followed by the osmium tetroxide catalyzed hydroxylation of the l-allyl-4-methoxy-5-methylpyrimidin-2-one obtained as an intermediate. The D-glycero enantiomer, R-1-(2,3-dihydroxypropyl)thymine and the corresponding 1-substituted uracil derivative were prepared from 3-O-p-toluenesulfonyl-1, 2-O-isopropylidene-D-glycerine and sodium salt of 4-methoxy-5-methylpyrimidin-2-one or 4-methoxypyrimidin-2-one followed by treatment with hydrogen chloride in ethanol. The phosphorylation of the above 2,3-dihydroxypropyl derivatives with phosphoryl chloride in triethyl phosphate afforded the corresponding 3-phosphates which were transformed into the 2′,3′-cyclic phosphates by the condensation with N,N′-dicyclohexylcarbodiimide. The latter compounds of the D-glycero configuration are split by some microbial RNases to the 3-phosphates.     

Spiro-annulation of barbituric acid derivatives and its analogs by ring-closing metathesis reaction

Barbituric acid 1 and related beta-dicarbonyl compounds were dialkenylated under the phase-transfer catalyst [e.g., benzyltriethylammonium chloride (BTEAC)] conditions to generate the diallylated products. These diallylated products were subjected to the ring-closing metathesis (RCM) reaction to deliver the corresponding spiro-annulated derivatives.     

A simple liquid chromatographic method based on intramolecular excimer-forming derivatization and fluorescence detection for the determination of tyrosine and tyramine in urine

A liquid chromatographic (LC) method for sensitive and selective fluorometric determination of p-hydroxyphenylethylamino group containing compounds is described. This method is based on an intramolecular excimer-forming fluorescence derivatization with a pyrene reagent, 4-(1-pyrene)butanoyl chloride, followed by reversed-phase LC. The analytes, containing an amino moiety and a phenolic hydroxyl moiety in a molecule, were converted to the corresponding dipyrene-labeled derivatives by one-step derivatization. The dipyrene-labeled derivatives afforded intramolecular excimer fluorescence (440-540 nm), which can clearly be discriminated from the normal fluorescence (360-420 nm) emitted from reagent blanks. The derivatives of tyrosine and tyramine could be separated by reversed-phase LC on ODS column under conditions of isocratic elution. The detection limits (signal-to-noise ratio = 3) for tyrosine and tyramine were 4.5 and 2.6 fmol per 20 microL injection, which corresponded to analyte concentrations of 0.9 and 0.5 nM, respectively.     

Protease inhibitors: Synthesis of L-alanine hydroxamate sulfonylated derivatives as inhibitors of clostridium histolyticum collagenase

L-alanine hydroxamate derivatives were obtained by reaction of alkyl/arylsulfonyl halides with L-alanine, followed by treatment with benzyl chloride, and conversion of the COOH moiety to the CONHOH group with hydroxylamine in the presence of carbodiimides. Other derivatives were obtained by reaction of N-benzyl-alanine with aryl isocyanates, arylsulfonyl isocyanates or benzoyl isothiocyanate, followed by a similar conversion of the COOH to the CONHOH moiety. The obtained compounds were assayed as inhibitors of Clostridium histolyticum collagenase, ChC (EC 3.4.24.3), a zinc enzyme which degrades triple helical collagen. The hydroxamate derivatives were generally 100-500 times more active than the corresponding carboxylates. In the series of synthesized derivatives, substitution patterns leading to the most potent ChC inhibitors were those involving perfluoroalkylsulfonyl- and substituted-arylsulfonyl moieties, such as pentafluorophenylsulfonyl, 3- and 4-protected-aminophenylsulfonyl-, 3- and 4-carboxy-phenylsulfonyl-, 3-trifluoromethyl-phenylsulfonyl-, or 1- and 2-naphthylsulfonyl among others. Similarly to the matrix metalloproteinase (MMP) hydroxamate inhibitors, ChC inhibitors of the type reported here must incorporate hydrophobic moieties at the P(2') and P(3') sites, in order to achieve tight binding to the enzyme.     

Synthesis of N6-substituted 9-[3-(phosphonomethoxy)propyl]adenine derivatives as possible antiviral agents

A number of N6-substituted 9-[3-(phosphonomethoxy)propyl]adenine derivatives having hydroxymethyl at C-1' position were prepared from the appropriate 6-chloroadenine derivative. The syntheses of the corresponding prodrugs of these compounds are also reported. These compounds showed poor activity against HCV in replicon assay.     

Synthesis and antimicrobial activity of new adamantane derivatives I

A series of fourteen derivatives of adamantane was synthesised. The new compound 4-(adamant-1-ylmethoxycarbonyl)phthalanhydride obtained from 1-adamantane-methanol and trimellitic anhydride chloride appeared very useful for preparation of a number of N-substituted phthalimides. Antimicrobial activity of the newly obtained derivatives such as, for example, 4-(adamant-1-ylmethoxycarbonyl)-N-(5-carboxypentamethylene)p hthalimide or 4-(adamant-1-ylmethoxycarbonyl)-N-(L-alanyl)phthalimide was tested against Staphylococcus aureus, Bacillus sp., Micrococcus flavus and Enterococcus faecium. The minimal inhibitory concentration (MIC) for these compounds against S. aureus were 0.022 and 0.05 microg/ml, respectively.     

Synthesis of benzothiophene carboxamide derivatives and their pharmacological evaluation as potent antihypertriglyceridemic agents in rats

Benzothiophene carboxamide derivatives of aminobenzophenone, aminopyridine, aminobenzimidazole, and aniline derivatives (compounds 1-9) were synthesized and compounds 3, 6, 7, 8, and 9 tested in vivo for their hypolipidemic activity. Compounds 1-8 were prepared adopting the fusion process at 130-150 degrees C between benzothiophene-2-carbonyl chloride and aminobenzophenones, aminopyridine, and anilines, respectively, and were obtained in high yield, while compound 9 was obtained from the reaction of benzothiophene acyl chloride with aminobenzimidazole in DMF at 160 degrees C. At a dose of 15 mg/kg body weight compounds 6, 7, and 9 significantly reduced plasma triglyceride levels in Triton WR-1339-induced hyperlipidemic rats in comparison to control rats. Furthermore, they significantly increased high-density lipoprotein levels. It is therefore reasonable to assume that compounds 6, 7, and 9 may have a promising potential in the treatment of hyperlipidemia and atherosclerosis.