Heterocyclic Nucleosede Analogues by Cycloaddition Reactions of 1-Vinylthymine with 1,3-Depoles

Abstract

1,3-Dipolar cycloaddition of 1-vinylthymine to azides, nitrile oxides, nitrones and nitronates has been investigated as a route to heterocyclic nucleoside analogues in which the nucleoside ribose moiety has been replaced by an alternative heterocycle. Reaction of 1-vinylthymine with highly reactive nitrile oxides affords 1-(isoxazolin-5-yl)thymine products in excellent yield at room temperature. The less reactive nitrone dipoles undergo cycloaddition to 1-vinylthymine at elevated temperature to afford l-(isoxazolidin-5-yl)thymine cycloadducts in good-to-moderate yields, but show a tendency to eliminate thymine from the cycloaddition products over long reaction times. Azide cycloadditions to 1-vinylthymine proceed only under forcing conditions to which the fragile triazollne products are unstable.     

A novel synthesis of acyclonucleosides via allylation of 3-[1-(phenylhydrazono)-L-threo-2,3,4-trihydroxybut-1-yl]quinoxalin-2(1H)one

The allylation of 3-[1-(phenylhydrazono)-L-threo-2,3,4-trihydroxybut-1-yl]quinoxalin-2(1H)one (1) gave, in addition to the anticipated 1-N-allyl derivative (2), a dehydrative cyclized product, 1-N-allyl-3-[5-(hydroxymethyl)-1-phenylpyrazol-3-yl]quinoxalin-2-one (4) and its isomeric O-allyl derivative 3. The O-allyl group in 3 underwent acetolysis under acetylation conditions, in addition to the acetylation of the hydroxyl group, to afford 2-acetoxy-3-[5-(acetoxymethyl)-1-phenylpyrazol-3-yl]quinoxaline (8) instead of the O-acetyl derivative of 3. Allylation of the tri-O-acetyl derivative of 1 caused the elimination of a molecule of acetic acid in addition to N-allylation to give 1-N-allyl-3-[3,4-di-O-acetyl-2-deoxy-1-(phenylhydrazono)but-2-en-1-yl]quinoxalin-2-one (11). Hydroxylation of the allyl group gave a glycerol-1-yl acyclonucleoside which can be alternatively obtained by a displacement reaction of the tosyloxy group in 2,3-O-isopropylidene-1-O-(p-tolylsulfonyl)glycerol (14), followed by deisopropylidenation. 1-N-(2,3-Dibromopropyl)-3-[5-(hydroxymethyl)-1-(4-bromophenyl)pyrazol-3-yl]quinoxalin-2-one (15) underwent azidolysis to give a 2,3-diazido derivative. The assigned structures were based on spectral analysis. The activity of compounds 2, 4, 6, and 15 against hepatitis B virus was studied.     

Synthesis and biological evaluation of some acyclic alpha-(1H-pyrazolo-[3,4-d]pyrimidin-4-yl)thioalkylamide nucleosides

The chemical synthesis of some acyclic alpha-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)thioalkylamide nucleosides (10-12)a-c is described. The treatment of IH-pyrazolo[3,4-d]pyrimidin-4-thione 1 with compounds 2a-c gave, regioselectively, ethyl alpha-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)thioalkylates 3a-c, respectively. These heterocycles were alkylated, separately, with alkylating agents 4, 5 and 6 to give, regioselectively, the N1-acyclic nucleosides (7-9)a-c which were deprotected to afford the desired products (10-12)a-c. All synthetic compounds were characterized on the basis of their physical and spectroscopic properties. The products (10-12)a-c were evaluated for their inhibitory effects against the replication of HIV-1 (III(B)), HIV-2 (ROD), various DNA viruses, a variety of tumor-cell lines and M. tuberculosis. No marked biological activity was found.     

The application of safe for humans and the environment Polyversum antifungal agent containing living cells of Pythium oligandrum for biotransformation of prochiral ketones

This report presents the whole-cell biotransformation of benzofuranyl-methyl ketone derivatives with the application of Polyversum antifungal agent containing Pythium oligandrum microorganism. Stereochemistry of the reduction of prochiral substrates was modified by the bioconversion conditions (concentration of reagents, a source of the carbon atom, biotransformation medium). In optimized conditions enantioselective process was noted. Secondary alcohols with excellent enantiomeric purity and high yields were obtained. The enantiomeric excess and conversion degree of 1-(benzofuran-2-yl)ethanol, 1-(7-ethylbenzofuran-2-yl)ethanol and 1-(3,7-dimethylbenzofuran-2-yl)ethanol were 99%/98.1%, 94%/94.4% and 99%/72.6%, respectively. In the presence of P. oligandrum, one of the enantiotopic hydrides of the dihydropyridine ring coenzyme is selectively transferred to a re side of the prochiral carbonyl group to give products with S configuration. This study demonstrates an inexpensive, eco-friendly approach in synthesis of optically pure benzofuran derivatives and can be an interesting alternative to organocatalysis. Furthermore, this method can be used in biotechnology processes due to its good chemical performance and a high degree of product isolation.     

Synthesis and biological evaluation of some alpha-[6-(1'-carbamoylalkylthio)-1 H-pyrazolo[3,4-D]pyrimidin-4-yl]thioalkylcarboxamide acyclonucleosides

The reaction of 1H-pyrazolo[3,4-d]pyrimidin-4,6-dithione 11 with compounds 12a-c produces ethyl alpha-[6-(1'-carboethoxyalkylthio)-1 H-pyrazolo[3,4-d]pyrimidin-4-yl]thioalkylates 13a-c, respectively. These heterocycles were alkylated, separately, with alkylating agents 14, 15, and 16 to afford, predominately, the N(1)-acyclic nucleosides (17-19)a-c, which were deprotected to give the desired products (20-22)a-c. All synthetic compounds were characterized on the basis of their physical and spectroscopic properties. The acyclic nucleosides (20-22)a-c were evaluated for their inhibitory effects against the replication of varicella-zoster virus, human cytomegalovirus and M. tuberculosis. No marked biological activity was found.     

Use of a phenyl 1-selenogalactofuranoside as a glycosyl donor for the synthesis of galactofuranosyl-containing disaccharides.

The use of acetylated phenyl 1-seleno-beta-D-galactofuranoside as a glycosyl donor for the synthesis of protected D-Galf-beta-(1-->3)-alpha-D-Manp as its methyl or ethylthio glycoside has been demonstrated. Activation of the selenoglycoside over a thioglycoside acceptor by NIS/TfOH is extremely selective and gives the ethylthio disaccharide in 91% yield. The parent disaccharide is found as a terminal and branched unit in the lipopeptidophosphoglycan oligosaccharides of the protozoan Trypanosoma cruzi, the causative agent of Chagas' disease.     

Synthesis of some novel pyrazolo[3,4-d]pyrimidine derivatives as potential antimicrobial agents

The reaction of 4-hydrazino-8-(trifluoromethyl)quinoline (2) with ethoxymethylenecyanoacetate afforded ethyl 5-amino-1-[8-(trifluoromethyl)quinolin-4-yl]-1H-pyrazole-4-carboxylate (3) and that with ethoxymethylenemalononitrile afforded 5-amino-1-[8-(trifluoromethyl)quinolin-4-yl]-1H-pyrazole-4-carbonitrile (5). Compounds 3 and 5 were hydrolyzed to get 5-amino-1-[8-(trifluoromethyl)quinolin-4-yl]-1H-pyrazole-4-carboxylic acid and then reacted with acetic anhydride to afford 6-methyl-1-[8-(trifluoromethyl)quinolin-4-yl]pyrazolo[3,4-d]oxazin-4-one (6), which was condensed with different aromatic amines to give a series of 5-substituted 6-methyl-1-[8-(trifluoromethyl)quinolin-4-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-ones (7). Compounds 3 and 5 also reacted with formamide, urea, and thiourea affording the corresponding pyrazolo[3,4-d]pyrimidines (8-13), respectively. Structures of the products have been determined by chemical reactions and spectral studies. All compounds of the series have been screened for their antibacterial and antifungal activity studies. The results are summarized in Tables 1 and 2.     

Acyclic-sugar purine nucleosides derived from -glucose: stereochemical correlations in acyclic-sugar derivatives unequally substituted at c-1

Condensation of 2,3,4,5,6-penta-O-acetyl-l-bromo-1-s-methyl-l-thio- -glucito (1) with 6-chloro-9-(chloromercuri)purine gave 49% of crystalline, levorotatory (1s)-2,3,4,5,6-penta-O-acetyl-1-(6-chloropurin-9-yl)-1- -methyl-1-thio- -glucitol (3), together with a smaller proportion of the syrupy, dextrorotatory (1R) isomer. Thiourea converted 3 into its 6-mercaptopurine analog, whose O-deacetylated derivative could be s-methylated to the corresponding -(methylthio)purin-9-yl analog; all compounds in this sequence were crystalline and were the pure (1s) isomers, as were the corresponding 1′-s-ethyl derivatives prepared by a similar route. Crystal-structure analysis of the O-deacetylated derivative of the 1 s-ethyl analog of 3 established the relative stereochemistry of the ethylthio group, permitting assignment of the (1s) absolute stereochemistry to this compound and thus to all compounds in the sequence starting from 1, including the previously described, crystalline, levorotatory 1-(1,6-dihydro-6-thioxopurin-9-yl)-1-s-ethyl-1-thio- -glucitol, whose chirality at C-1 had not hitherto been established. The close similarity of the chiroptical properties of the crystalline 1′-s-methyl derivatives to those of their 1′-s-ethyl counterparts permitted firm attribution of (1s) chirality to the former series also. Conformational studies showed that all of the derivatives have the sugar chain in a non-extended (sickle) conformation.     

Access to tetrachlorophthalimide-protected ethyl 2-amino-2-deoxy-1-thio-beta-D-glucopyranosides.

Ethyl 2-deoxy-2-tetrachlorophthalimido-1-thio-beta-D-glucopyranoside (7) was prepared from glucosamine hydrochloride in four steps with a 20-25% overall yield. Formation of 1,3,4,6-tetra-O-acetyl-2-deoxy-2-tetrachlorophthalimido-beta-D- glucopyranoside (5) was found to be crucial for this reaction sequence since the corresponding alpha-1-acetate did not react in Lewis-acid-catalyzed ethylthio glycosidations. Formation of the beta-1-acetate (5) was achieved by treatment of 3,4,6-tri-O-acetyl-2-deoxy-2-tetrachlorophthalimido-alpha-D-glucop yranosyl bromide (4) with acetic acid under silver zeolite promotion. This was necessary because conditions normally used for beta-1-acetate formation were not tolerated by the tetrachlorophthalimido (TCP) group.     

Acyclic-sugar purine nucleosides derived from d-glucose: stereochemical correlations in acyclic-sugar derivatives unequally substituted at c-1

Condensation of 2,3,4,5,6-penta-O-acetyl-l-bromo-1-s-methyl-l-thio-d-glucito (1) with 6-chloro-9-(chloromercuri)purine gave 49% of crystalline, levorotatory (1s)-2,3,4,5,6-penta-O-acetyl-1-(6-chloropurin-9-yl)-1-s-methyl-1-thio-d-glucitol (3), together with a smaller proportion of the syrupy, dextrorotatory (1R) isomer. Thiourea converted 3 into its 6-mercaptopurine analog, whose O-deacetylated derivative could be s-methylated to the corresponding 6-(methylthio)purin-9-yl analog; all compounds in this sequence were crystalline and were the pure (1s) isomers, as were the corresponding 1′-s-ethyl derivatives prepared by a similar route. Crystal-structure analysis of the O-deacetylated derivative of the 1$\text{-}\text{?}$s-ethyl analog of 3 established the relative stereochemistry of the ethylthio group, permitting assignment of the (1s) absolute stereochemistry to this compound and thus to all compounds in the sequence starting from 1, including the previously described, crystalline, levorotatory 1-(1,6-dihydro-6-thioxopurin-9-yl)-1-s-ethyl-1-thio-d-glucitol, whose chirality at C-1 had not hitherto been established. The close similarity of the chiroptical properties of the crystalline 1′-s-methyl derivatives to those of their 1′-s-ethyl counterparts permitted firm attribution of (1s) chirality to the former series also. Conformational studies showed that all of the derivatives have the sugar chain in a non-extended (sickle) conformation.     

Photodegradation of Fleroxacin Injection: Different Products with Different Concentration Levels

Photodegradation of fleroxacin is investigated in different injections and solutions. After UV irradiation, fleroxacin was degraded to afford two major products in large-volume injection (specification, 200 mg:100 ml), while degraded to afford another major product in small-volume injection (specification, 200 mg:2 ml). The photodegradation products were detected and isolated by reversed-phase HPLC. Based on the spectral data (FT-IR, MSⁿ, TOF-MS, ¹H/¹³C, DEPT, and 2D NMR), the structures of these products were: 8-fluoro-9-(4-methyl-piperazin-1-yl)-6-oxo-2,3-dihydro-6H-1-oxa-3a-aza-phenalene-5-carboxylic acid (impurity-I); 6-fluoro-1-(2-fluoro-ethyl)-7-(2-methylamino-ethylamino)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (impurity-II); and 6,8-difluoro-1-(2-fluoro-ethyl)-7-(2-methylamino-ethylamino)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (impurity-III), respectively. Different photodegradation pathways of fleroxacin were proposed, which led to the different stability characteristics of fleroxacin in the injections. The fluorine atom at C8 is more photolabile in dilute injection, so defluorination and cyclization reactions are prone to take place, whereas photo irradiation only cause ring-opening oxidation reaction of piperazine side chain in concentrated injection.     

抗肿瘤药物帕玛度胺类似物的合成

目的：设计并合成抗肿瘤药物帕玛度胺的3位N取代的新型类似物。方法：从3-硝基邻苯二甲酸（2）和N-（叔丁氧羰基）．L-谷氨酰胺（4）出发,经过六步反应得到目标化合物。3-硝基邻苯二甲酸（2）经脱水制得3-硝基邻苯二甲酸酐（3）。用N-（叔丁氧羰基）-L-谷氨酰胺（4）经闭环、脱保护制得3-氨基-2,6-哌啶二酮三氟乙酸盐（6）。4与6经缩合、钯碳催化氢化制得免疫调节剂Pomalidomide（8）,（8）经过酰化得到3-乙酰氨基-N-（2,6-二氧代-3-哌啶基）邻苯二甲酰亚胺（1）。以（4）计总收率约34．9％。结果：得到3-乙酰氨基-N-（2,6-二氧代-3-哌啶基）-邻苯二甲酰亚胺（1）,应用于细胞活性测试。结论：改进了帕玛度胺的合成工艺,得到了3位N乙酰化的新型帕玛度胺类似物（1）,初步研究显示（1）的生物活性与帕玛度胺接近。     

Synthesis of 3-aminoimidazo[4,5-c]pyrazole nucleoside via the N-N bond formation strategy as a [5:5] fused analog of adenosine

3-Amino-6-(beta-D-ribofuranosyl)imidazo[4,5-c]pyrazole (2) was synthesized via an N-N bond formation strategy by a mononuclear heterocyclic rearrangement (MHR). A series of 5-amino-1-(5-O-tert-butyldimethylsilysilyl-2,3-O-isopropylidene-beta-D-ribofuranosyl)-4-(1,2,4-oxadiazol-3-yl)imidazoles (6a-d), with different substituents at the 5-position of the 1,2,4-oxadiazole, were synthesized from 5-amino-1-(beta-D-ribofuranosyl)imidazole-4-carboxamide (AICA Ribose, 3). It was found that 5-amino-1-(5-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-beta-D-ribofuranosyl)-4-(5-methyl-1,2,4-oxadiazol-3-yl)imidazole (6a) underwent the MHR with sodium hydride in DMF or DMSO to afford the corresponding 3-acetamidoimidazo[4,5-c]pyrazole nucleoside(s) (7b and/or 7a) in good yields. A direct removal of the acetyl group from 3-acetamidoimidazo[4,5-c]pyrazoles under numerous conditions was unsuccessful. Subsequent protecting group manipulations afforded the desired 3-amino-6-(beta-D-ribofuranosyl)imidazo[4,5-c]pyrazole (2) as a 5:5 fused analog of adenosine (1).     

4-Substituted 4-(1H-1,2,3-triazol-1-yl)piperidine: Novel C7 moieties of fluoroquinolones as antibacterial agents

A series of 4-substituted 4-(1H-1,2,3-triazol-1-yl)piperidine building blocks was synthesized and introduced to the C7 position of the quinolone core, 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, to afford the corresponding fluoroquinolones in 40–83% yield. The antibacterial activity of these new fluoroquinolones was evaluated using a standard broth microdilution technique. Among them, the quinolone 1-cyclopropyl-6-fluoro-7-(4-(4-formyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (34.15) exhibited comparable antibacterial activity against quinolone-susceptible and multidrug-resistant strains, especially to Staphylococcus aureus and Staphylococcus epidermidis, in comparison with ciprofloxacin and vancomycin.     

Synthesis of Six-Membered Nucleoside Analogs. Part 1: Pyrimidine Nucleosides Based on the 1,3-Dioxane Ring System

Abstract

The synthesis of pyrimidine nucleosides, cis-N-1-[(2-hydroxymethyl)-1,3-dioxan-5-yl]uracil (4) cis-N-1-[(2-hydroxymethyl)-1,3-dioxan-5-yl]thymine (5) and cis-N-1-[(2-hydroxymethyl)-1,3-dioxan-5-yl]cytosine (6) and their corresponding trans isomers is described. Compound 4 showed modest, selective activity against human immunodeficiency virus in acutely infected primary human lymphocytes.     

Synthesis of imidazol-2-yl amino acids by using cells from alkane-oxidizing bacteria

Sixty-one strains of alkane-oxidizing bacteria were tested for their ability to oxidize N-(2-hexylamino-4-phenylimidazol-1-yl)-acetamide to imidazol-2-yl amino acids applicable for pharmaceutical purposes. After growth with n-alkane, 15 strains formed different imidazol-2-yl amino acids identified by chemical structure analysis (mass and nuclear magnetic resonance spectrometry). High yields of imidazol-2-yl amino acids were produced by the strains Gordonia rubropertincta SBUG 105, Gordonia terrae SBUG 253, Nocardia asteroides SBUG 175, Rhodococcus erythropolis SBUG 251, and Rhodococcus erythropolis SBUG 254. Biotransformation occurred via oxidation of the alkyl side chain and produced 1-acetylamino-4-phenylimidazol-2-yl-6-aminohexanoic acid and the butanoic acid derivative. In addition, the acetylamino group of these products and of the substrate was transformed to an amino group. The product pattern as well as the transformation pathway of N-(2-hexylamino-4-phenylimidazol-1-yl)-acetamide differed in the various strains used.     

The interaction of per-O-acetylated acyclic 1-(1-butylindol-3-yl)-1-deoxy-ketoses with silylated uracil

The per-O-acetylated open chain derivatives of 1-(1-butylindol-3-yl)-1-deoxy-1-L-sorbose and 1-(1-butylindol-3-yl)-1-deoxy-L-tagatose, which are readily available by alkaline degradation of 1-butylascorbigen followed by acetylation, were used in a nucleoside-type synthesis. The interaction of these ketoses derivatives with bis-(trimethylsilyl)-uracil yielded in each case a mixture of (E)-2,4,5,6-tetra-O-acetyl-1-(1-butylindol-3-yl)-1,3-dideoxy-3-(uracil-1-yl)-L-xylo-hexa-1-enitol and (E)-2,4,5,6-tetra-O-acetyl-1-(1-butylindol-3-yl)-1,3-dideoxy-3-(uracil-1-yl)-L-lyxo-hexa-1-enitol, which were separated by preparative HPLC. The deacetylation of each of these compounds by MeONa in MeOH produced a mixture of 1-(1-butylindol-3-yl)-1,3-dideoxy-4-O-methyl-3-(uracil-1-yl)-alpha-L-sorbopyranose and 1-(1-butylindol-3-yl)-1,3-dideoxy-4-O-methyl-3-(uracil-1-yl)-beta-D-fructopyranose, which were also separated by HPLC, the structures were confirmed by NMR.     

Synthesis of N-(1-deoxyhexitol-1-yl)amino acids, reference compounds for the nonenzymic glycosylation of proteins

The N-(1-deoxy-D-mannitol-1-yl) and N-(1-deoxy-D-glucitol-1-yl) derivatives of L-valine, L-alanine, L-threonine, and L-leucine were prepared by reductive amination of D-mannose and D-glucose with the appropriate amino acids, in the presence of sodium cyanoborohydride. N epsilon-(1-Deoxy-D-mannitol-1-yl)- and N epsilon-(1-deoxy-D-glucitol-1-yl)-L-lysine were prepared by similar reactions of hexoses with N alpha-tert-butoxycarbonyl and N alpha-benzyloxycarbonyl-L-lysine, followed by removal of the protecting groups. The structures were confirmed by 1H-n.m.r. spectroscopy, which showed that each compound was completely free of its C-2 epimer. The synthetic compounds may be used as reference compounds for the identification of N-(1-deoxyhexitol-1-yl)amino acids formed when N-(1-deoxy-D-fructose-1-yl) groups of nonenzymically glycosylated proteins, of the hemoglobin A1c type, are reduced with sodium borohydride, and the protein is subjected to acid-catalyzed hydrolysis.     

Novobiocin-related compounds: synthesis of 3-benzoylamino-2-oxo-2H-1-benzopyran-7-yl D-glycopyranosides by the trichloroacetimidate methodology

A general stereoselective method for the synthesis of 4-deoxynovobiocin-related glycosides is described. 3-Benzoylamino-2H-1-benzopyran-7-yl 2,3,4,6-tetra-O-acetyl-D-glycopyranosides of glucose, galactose and mannose were synthesised from appropriate O-glycosyltrichloroacetimidates and N-(7-hydroxy-2-oxo-2H-1-benzopyran-3-yl)benzamides in boiling methylene chloride in the presence of boron trifluoride etherate. Heating of these products in a mixture of triethylamine and methanol gave the corresponding deprotected 3-benzoylamino-2-oxo-2H-1-benzopyran-7-yl beta-D-glycopyranosides.     

Iodine-catalyzed conjugate addition of indoles onto en-1,4-dione: a novel synthesis of 3-(1-(1H-indol-3-yl)-2-oxo-2-phenylethyl)indolin-2-ones as antibacterial and antifungal agents

Indole and its derivatives undergo smooth conjugate addition onto en-1,4-dione derived from isatin and acetophenone, in the presence of a catalytic amount of molecular iodine in acetonitrile under mild conditions to afford a novel class of 3-(1-(1H-indol-3-yl)-2-oxo-2-phenylethyl)indolin-2-one derivatives in good yields with high degree of 1,4-selectivity. Some of these compounds are found to exhibit modest antibacterial and antifungal properties.