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.     

柯拉斯那沉香的生物活性成分研究

为了解柯拉斯那(Aquilaria crassna)的化学成分,从其所产沉香中分离得到10个化合物,经波谱分析分别鉴定为:6,8-羟基-2-(2-苯乙基)色酮(1),6,8-二羟基-2-[2-(4-甲氧基苯)乙基]色酮(2),rel-(1a R,2R,3R,7b S)-1a,2,3,7b-tetrahydro-2,3-dihydroxy-5-(2-phenylethyl)-7H-oxireno[f][1]benzopyran-7-one(3),rel-(1a R,2R,3R,7b S)-1a,2,3,7b-tetrahydro-2,3-dihydroxy-[2-(4-methoxyphenyl)-ethyl]-7H-oxireno[f][1]benzopyran-7-one(4),rel-(1a R,2R,3R,7b S)-1a,2,3,7b-tetrahydro-2,3-dihydroxy-5-[2-(3-hydroxy-4-methoxyphenyl)-ethyl]-7H-oxireno[f][1]benzopyran-7-one(5),oxidoagarochromone B(6),oxidoagarochromone C(7),(5S,6R,7S,8R)-2-[2-(3′-hydroxy-4′-methoxyphenyl)ethyl]-5,6,7,8-tetrahydroxy-5,6,7,8-tetrahydrochromone(8),6,7-cis-dihydroxy-2-(2-phenylethyl)-5,6,7,8-tetrahydrochromone(9),N-trans-feruloyltyramine(10)。化合物3~5和8~10为首次从柯拉斯那沉香中分离得到。化合物1,3,6,7,9和10对乙酰胆碱酯酶具有一定的抑制活性,化合物4对人慢性髓原白血病细胞株K-562和人胃癌细胞株SGC-7901均具有较小的抑制作用,化合物1和3对人肝癌细胞株BEL-7402也有抑制活性。     

红树林源白骨壤链霉菌中多环稠合大环内酰胺类化合物的结构多样性研究

【目的】通过基因组挖掘的方法,研究红树林来源白骨壤链霉菌Streptomyces avicenniae 9-9中多环稠合大环内酰胺(PTMs)类化合物的结构多样性。【方法】通过生物信息学分析白骨壤链霉菌基因组序列,寻找PTMs类化合物的生物合成相关基因;利用UPLC-MS/MS技术对该菌的次级代谢产物进行分析。【结果】在白骨壤链霉菌基因组中发现PTMs生物合成基因簇(aviA-D);从菌液提取物中鉴定出5个PTMs类化合物,其中包括ikarugamycin(化合物1)和capsimycin B(化合物2);基于PTMs类化合物5-6-5环类型的MS/MS碎裂规律,对化合物3–5的结构进行了推测。【结论】红树林来源白骨壤链霉菌S.avicenniae 9-9具有产生5-6-5环类型的PTMs类化合物的能力。     

Synthesis of novel selenium containing sulfa drugs and their antibacterial activities

Synthesis of 3-[4-(N-substituted sulfamoyl)phenyl]-3,4-dihydro-4-oxo-7,9-dimethylpyri-do[3′,2′:4,5]selenolo[3,2-d]pyrimidines,7-[4-(N-substituted sulfamoyl)phenyl]-7,8-dihydro-8-oxo-3,4-diphenylpyrimido[4′,5′:4,5]selenolo [2,3-c]pyridazines and 1-[4-(N-substituted sulfamoyl)phenyl]-1,11-dihydro 11-oxo-4-methylpyrimido[4′,5′:4,5]selenolo[2,3-b]quinolines is reported. 4-Amino-N-pyrimidine-2-ylbenzene sulfonamide (a), 4-amino-N-(2,6-dimethylpyrimidin-4-yl)benzene sulfonamide (b), N-[(4-aminophenyl)sulfonyl] acetamide (c) with N-ethoxymethyleneamino of selenolo pyridine, selenolo pyridazine and selenolo quinoline derivatives respectively were obtained starting from 1-amino-N ⁴-substituted sulfanilamides. Spectroscopic data (IR, ¹H NMR, ¹³C NMR and Mass spectral) confirmed the structure of the newly synthesized compounds. Substituted pyrimidines, pyridazines and quinolines were screened for antibacterial activity against gram-positive and gram-negative bacteria. Selenolo derivative of N-[(4-aminophenyl)sulfonyl] acetamide (substitutent of sulfacetamide c) showed strong bactericidal effect against all the tested organisms. Selenolo[3,2-d]pyrimidin (substitutent a) showed a good bactericidal effect against Serratia marcescens, Staphylococcus aureus and Escherichia coli. Compounds selenolo[2,3-c]pyridazine (substitutent b), selenolo[2,3-b]quinoline(substitutents c)) exhibited a moderate bactericidal effect against Serratia marcescens. None of the synthesized seleno pyridazines has a considerable antimicrobial activity against the tested organisms. The minimum inhibitory concentration (MIC) of the most active compound-3-[4-(N-acetyl sulfamoyl)phenyl]-3,4-dihydro-4-oxo-7,9-dimethylpyrido[3′,2′:4,5]selenolo [3,2-d]pyrimidine was 10 mg ml⁻¹.     

EFFICIENT METHODS FOR THE SYNTHESIS OF [2-15N]GUANOSINE AND 2′-DEOXY[2-15N]GUANOSINE DERIVATIVES

The nucleophilic addition–elimination reaction of 2′,3′,5′-tri-O-acetyl-2-fluoro-O ⁶-[2-(4-nitrophenyl)ethyl]inosine (8) with [¹⁵N]benzylamine in the presence of triethylamine afforded the N ²-benzyl[2-¹⁵N]guanosine derivative (13) in a high yield, which was further converted into the N ²-benzoyl[2-¹⁵N] guanosine derivative by treatment with ruthenium trichloride and tetrabutyl-ammonium periodate. A similar sequence of reactions of 2′,3′,5′-tri-O-acetyl-2-fluoro-O ⁶-[2-(methylthio)ethyl]inosine (9) and the 6-chloro-2-fluoro-9-(β-D-ribofuranosyl)-9H-purine derivative (11), which were respectively prepared from guanosine, with potassium [¹⁵N]phthalimide afforded the N ²-phthaloyl [2-¹⁵N]guanosine derivative (15; 62%) and 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-2-[¹⁵N]phthalimido-9H-purine (17; 64%), respectively. Compounds 15 and 17 were then efficiently converted into 2′,3′,5′-tri-O-acetyl[2-¹⁵N]guanosine. The corresponding 2′-deoxy derivatives (16 and 18) were also synthesized through similar procedures.     

Synthesis and Biological Evaluation of 1,3-Oxathiolane 5-Azapyrimidine, 6-Azapyrimidine,and Fluorosubstituted 3-Deazapyrimidine Nucleosides

Abstract

(2R,5S)-5-Amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,2,4-triazine-3(2H)-one (8) and (2R,5R)-5-amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,2,4-triazine-3(2H)-one (9) have been synthesized via a multi-step procedure from 6-azauridine. (2R,5S)-4-Amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,3,5-triazine-2(1H)-one (11) and (2R,5R)-4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,3,5-triazine-2(1H)-one (12), and the fluorosubstituted 3-deazanucleosides (19–24) have been synthesized by the transglycosylation of (2R,5S)-1-{2-[[(tert-butyldiphenylsilyl) oxy]methyl]-1,3-oxathiolan-5-y1} cytosine (2) with silylated 5-azacytosine and the corresponding silylated fluorosubstituted 3-deazacytosines, respectively, in the presence of trimethylsilyl trifluoromethanesulfonate as the catalyst in anhydrous dichloroethane, followed by deprotection of the blocking groups. These compounds were tested in vitro for cytotoxicity against L1210, B₁₆F₁₀, and CCRF-CEM tumor cell lines and for antiviral activity against HIV-1 and HBV.     

A comparison of the enantioselective reduction potential of five strains of Saccharomyces cerevisiae towards a selected ketone

The enantioselectivity potential of five strains of Saccharomyces cerevisiae was studied for the reduction of ethyl N-{2-{4-[(2-oxocyclohexyl)methyl]phenoxy}ethyl} carbamate (1), an insect juvenile hormone bioanalog. The products of the reaction, the cis and trans isomers of ethyl N-{2-{4-[(2-hydroxycyclohexyl)methyl]phenoxy}ethyl} carbamate (2 and 3), were obtained in 45–49% (w/w) chemical yields and with 79 to > 99% enantiomeric purity values. The absolute configurations of the major products were assigned as ethyl (1S,2S)-N-{2-{4-[(2-hydroxycyclohexyl)methyl]phenoxy}ethyl} carbamate (2) and ethyl (1S,2R)-N-{2-{4-[(2-hydroxycyclohexyl)methyl]phenoxy}ethyl} carbamate (3). The products 2 and 3 belong to the series of the chiral insect juvenile hormone analogs.     

真菌Talaromyces stipitatus WH4-2中的抗菌活性成分

【目的】对真菌菌株WH4-2进行鉴定并分离鉴定具有抗菌活性的天然产物。【方法】综合菌落形态和ITS全序列分析,鉴定菌株种属。以抗菌活性分析为导向对其中的活性组分进行分离纯化,波谱分析鉴定结构。采用微量稀释法对化合物进行活性复筛,得最小抑菌浓度MIC值。【结果】真菌菌株WH4-2鉴定为Talaromyces stipitatus。从其土豆发酵液中分离鉴定化合物1 (5S-arugosin K)、2 (5R-arugosin K)、3 (5S-arugosin M)、4 (5R-arugosin M)和5 (Chrysophanol),其中1–4为含异戊烯基的dibenzo[b,e]oxepinone类化合物,5为蒽醌类化合物。1–4对Staphylococcus aureus ATCC43300、ATCC33591,Enterococcus faecium ATCC35667和Bacillussubtilis ATCC6633具有抗菌活性。【结论】含异戊烯基的Dibenzo[b,e]oxepinone类化合物是真菌T. stipitatus中抗菌活性成分。     

SYNTHESES OF 2′,3′-DIDEOXY-D-C-NUCLEOSIDES FROM γ-LACTONE

Abstract

Abstract: 2′,3′-Dideoxy-D-C-nucleosides, 2,4-diamino-5-(2,3-dideoxy-D-glycero-pentofuranosyl)pyrimidine.s (11 and 12), 4-amino-8-(2,3-dideoxy-D-glyceropentofuranosyl)pyrazolo[1,5-a]-1,3,5-triazines (17 and 18), 4-amino-7-(2,3-dideoxy-D-glyceropentofuranosyl)-5H-pyrrolo[3,2-d]pyrimidines (2 and 25), 7-(2,3-dideoxy-D-glyceropentofuranosyl)-4-oxo-3H,5H-pyrrolo[3,2-d]pyrimidines (30 and 31) have been synthesized from γ-lactone 4. These 2′, 3′-dideoxy-nucleosides were evaluated against HBV and HIV. No significant antiviral activities were found up to 100 μM.     

Insights into biological activity of ureidoamides with primaquine and amino acid moieties

Primaquine (PQ) ureidoamides 5a–f were screened for antimicrobial, biofilm eradication and antioxidative activities. Susceptibility of the tested microbial species towards tested compounds showed species- and compound-dependent activity. N-(diphenylmethyl)-2-[({4-[(6-methoxyquinolin-8-yl)amino]pentyl}carbamoyl)amino]-4-methylpentanamide (5a) and 2-(4-chlorophenyl)-N-(diphenylmethyl)-2-[({4-[(6-methoxyquinolin-8-yl)amino]pentyl}carbamoyl)amino]acetamide (5d) showed antibacterial activity against S. aureus strains (MIC?=?6.5?µg/ml). Further, compounds 5c and 5d had weak antibacterial activity against Escherichia coli and Pseudomonas aeruginosa. None of the tested compounds showed a wide spectrum of antifungal activity. In contrast, most of the compounds exerted strong activity in a biofilm eradication assay against E. coli, P. aeruginosa and Candida albicans, comparable to or even higher than gentamycin, amphotericin B or parent PQ. The most active compounds were 5a and 5b. Tested compounds were inactive against biofilm formation by C. parapsylosis, Enterococcus faecalis, C. tropicalis and C. krusei. Compounds 5b–f significantly inhibited lipid peroxidation (80–99%), whereas compound 5c presented interesting LOX inhibition.     

Synthesis of New 5″-Sulfonylamido Derivatives of 3″-Azido-3″-Deoxythymidine (AZT)

Abstract

A series of 5′-N-methanesulfonyl derivatives of 3′-azido-5′-(alkylamino)-3′,5′-dideoxythymidine was synthesised. The first step of the synthesis involved the reaction of 1-(2,5-dideoxy-5-O-tosyl-β-D-threo-pentofuranosyl)thymine 1 with an appropriate amine to give 1-[5-(alkylamino)-2,5-dideoxy-β-D-threo-pentofuranosyl]thymines 2a-e and 1-(2,5-dideoxy-β-threo-pent-4-enofuranosyl)thymine 3 as a by-product. Compounds 2a-e were treated with an excess of methanesulfonyl chloride to yield intermediates 1-[5-(dimethylamino)-3-O-methanesulfonyl-2,3,5-trideoxy-β-D-threo-pentofuranosyl]-thymine 4a and 1-[5-(N-alkyl-N-methanesulfonyl)-3-O-methanesulfonyl-2,3,5-trideoxy-β-D-threo-penfuranosyl]thymines 4b-e. The reaction of 4a-e with lithium azide in dimethyl-formamide afforded the final compounds 1-[3-azido-5-(N-methyl-N-methanesulfonyl)-2,3,5-trideoxy-β-D-erythro-penofuranosyl]thymine 5a and 1-[3-azido-5-(N-alkyl-N-methanesulfonyl)-2,3,5-trideoxy-β-D-erythro-penofuranosyl]thymines 5b-e. The independent synthesis of 4′,5′-unsaturated product 3 was also described.     

Synthesis of 2-Bromomethyl-3-Hydroxy-2-Hydroxymethyl-Propyl Pyrimidine and Theophylline Nucleosides Under Microwave Irradiation. Evaluation of Their Activity Against Hepatitis B Virus

Alkylation of 2-methylthiopyrimidin-4(1H)-one (1a) and its 5(6)-alkyl derivatives 1b–d as well as theophylline (7) with 2,2-bis(bromomethyl)-1,3-diacetoxypropane (2) under microwave irradia-tion gave the corresponding acyclonucleosides 1-[(3-acetoxy-2-acetoxymethyl-2-bromomethyl)prop-1-yl]-2-methyl-thio pyrmidin-4(1H)-ones 3a–d and 7-[(3-acetoxy-2-acetoxymethyl-2-bromomethyl)prop-1-yl]theophylline (8), which upon further irradiation gave the double-headed acyclonucleosides 1,1 ′-[(2,2-diacetoxymethyl)-1,3-propylidene]-bis[(2-(methylthio)-pyrimidin-4(1H)-ones] 4a–c, and 7,7 ′-[(2,2-diacetoxymethyl)-1,3-propylidene]-bis(theophylline) (9). The deacetylated derivatives were obtained by the action of sodium methoxide. The activity of deacetylated nucleosides against Hepatitis B virus was evaluated. Compound 5b showed moderate inhibition activity against HBV with mild cytotoxicity.     

SYNTHESIS OF 3′-THIOAMIDO-MODIFIED 3′-DEOXYTHYMIDINE-5′-TRIPHOSPHATES AND THEIR USE AS CHAIN TERMINATORS IN SANGER-DNA SEQUENCING

The thioamide derivatives 3′-deoxy-5′-O-(4,4′-dimethoxytrityl)-3′-[(2-methyl-1-thioxo-propyl)amino]thymidine 1 and 3′-deoxy-5′-O-(4,4′-dimethoxytrityl)-3′-{{6-{[(9H-(fluo-ren-9-ylmethoxy)carbonyl]-amino}-1-thioxohexyl}amino} thymidine 2 were synthesized by regioselective thionation of their corresponding amides 7 and 8 with 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphet-ane-2,4-disulfide (Lawesson's reagent). The thioamides were converted into the corresponding 5′-triphosphates 3 and 4. Compound 3 was chosen for DNA sequencing experiments and 4 was further labelled with fluorescein.     

Synthesis,structure, and antifungal evaluation of some novel 1,2,4-triazolylmercaptoacetylthiosemicarbazide and 1,2,4-triazolylmercaptomethyl-1,3,4-thiadiazole analogs

Novel 1-[[4-(4-bromophenyl)-5-(2-furyl)-4H-1,2,4-triazole-3-yl]mercaptoacetyl]-4-alkyl/aryl-3-thiosemicarbazides (5–12) were synthesized by the reaction of 4-(4-bromophenyl)-5-(2-furyl)-4H-1,2,4-triazole-3-ylmercaptoacetylhydrazide (4) with substituted isothiocyanates. Cyclodehydration of thiosemicarbazides with concentrated sulfuric acid yielded 2-[4-(4-bromophenyl)-5-(2-furyl)-4H-1,2,4-triazole-3-yl]mercaptomethyl-5-alkyl/arylamino-1,3, 4-thiadiazoles (13–17). The new compounds were evaluated for in vitro antifungal activity using the microdilution method. The tested compounds showed varying degrees of activity against Microsporum gypseum NCPF-580, Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum, and Candida albicans ATCC 10231 (MIC 8–4 μg/mL).     

Comparison of Soybean Tissue Extracted with Different Solvents

The enantioselective hydrolysis of (R,S)-3-acetoxymethyl-7,8-difluoro-2,3-dihydro-4H-[1,4]benzoxazine (I) with enzymes was investigated. Optically active I and its hydrolyzate, 7,8-difluoro-2,3-dihydro-3-hydroxymethyl-4H-[1,4]benzoxazine (II), are the intermediates for preparing optically active ofloxacins, whose racemate is known to be an excellent antibacterial agent. Lipoprotein lipase from Pseudomonas fluorescens (LPL Amano 3) was found to predominantly hydrolyze (S)-I, giving (R)-I in 54% e.e. and (R)-II in 44% e.e. On the other hand, lipase from Candida cylindracea was found to predominantly hydrolyze (R)-I, giving (S)-I in 24% e.e. and (S)-II in 20% e.e. Since, the optical purities of I and II thus obtained were not particularly high, these optically active I and II were converted into 3-acetoxymethyl-7,8-difluoro-2,3-dihydro-4-(3,5-dinitrobenzoyl)-4H-[1,4]benzoxazine (IV). After recrystallizing IV from ethyl acetate-hexane, (S)- and (R)-II were obtained with high enantiomeric excess by removing the crystallized racemic IV and subsequently hydrolyzing the resulting optically active IV with alkali. The reduction of II afforded 7,8-difluoro-2,3-dihydro-3-methyl-4H-[1,4]benzoxazine (III), for which the optical purity was estimated to be >96%e.e. by HPLC analysis. (R)- and (S)-ofloxacin were prepared from (R)- and (S)-III with retention of their configuration.     

Minor diterpenoid glycosides from the leaves of Stevia rebaudiana

From the commercial extract of the leaves of Stevia rebaudiana, three new diterpenoid glycosides were isolated besides eight known steviol glycosides including stevioside, rebaudiosides A–F and dulcoside A. The structures of the three compounds were identified as 13-[(2-O-β-d-glucopyranosyl-β-d-glucopyranosyl) oxy]-kaur-16-en-18-oic acid-(6-O-β-d-xylopyranosyl-β-d-glucopyranosyl) ester (1), 13-[(2-O-β-d-glucopyranosyl-β-d-glucopyranosyl) oxy]-17-hydroxy-kaur-15-en-18-oic acid β-d-glucopyranosyl ester (2), and 13-[(2-O-β-d-glucopyranosyl-β-d-glucopyranosyl) oxy]-17-oxo-kaur-15-en-18-oic acid β-d-glucopyranosyl ester (3) on the basis of extensive NMR and MS spectral studies. Another known diterpenoid glycoside, 13-[(2-O-β-d-glucopyranosyl-β-d-glucopyranosyl) oxy]-kaur-15-en-18-oic acid β-d-glucopyranosyl ester (4) was also isolated and its complete NMR spectral assignments were made on the basis of COSY, HSQC and HMBC spectral data.     

假单胞菌T1-3-2的抑菌特性及其对杉木的抗病促生作用

【背景】生物防治是“基于自然的解决方案”,有利于生态文明和可持续发展,开展生物防治技术研究的基础是明确菌株的生防作用和抑菌特性。【目的】探究杉木内生菌株T1-3-2的抑菌促生特性,为研制该菌株生防菌剂、防治杉木炭疽病(Cunninghamia lanceolata anthracnose)奠定基础。【方法】通过形态学特征、生理生化特性及16S rRNA基因序列分析,确定菌株T1-3-2的分类地位;通过平板对峙、菌落径向生长抑制率和平板倒扣等方法测定细菌及其挥发性气体和次级代谢产物的抑菌作用;同时,测定其促生作用和室内防效。【结果】菌株T1-3-2与桉生假单胞菌(Pseudomonas eucalypticola)亲缘性较近,属于假单胞菌属。该菌株对分属于6个属的10株靶标菌株具有较强的拮抗作用,尤其对炭疽菌属、拟盘多毛孢属、黑孢霉属和葡萄座腔菌属的6株靶标菌株抑制率高达80%以上。室内盆栽试验显示：菌株T1-3-2用Kings Medium B液体培养基的发酵菌液对杉木炭疽病的防效可达74.20%,同时能有效改善杉木幼苗的生长状况、增加生物量。【结论】菌株T1-3-2隶属于假单胞菌属,对杉木具有良好的抗病促生作用,是一株具有开发潜力的生防菌株。     

A Convenient Approach to N-3 Alkylation of 9-Substituted Guanines

Abstract

Aryl or tert-butyl substituent in the 6 position of 3,9-dihydro-3-[(2-hydroxy-ethoxy)methyl]-9-oxo-6-R-5H-imidazo[1,2-α]purine 1 directs the benzylation reaction partly into N-4 position to give 3. Cleavage of the third ring of 3 gives 3-benzylacycloguanosine 5, a first 3-aralkilo-9-substituted guanine.     

苏云金芽胞杆菌等离子复合体诱变提高抗鳞翅目害虫的杀虫毒力

[目的]苏云金芽胞杆菌(Bacillus thuringiensis,Bt)D18对鳞翅目、鞘翅目等农业害虫具有杀虫毒力,本研究拟通过复合诱变育种,筛选出杀虫毒力更高的突变菌.[方法]经四轮室温常压等离子体(ARTP)诱变和一轮ARTP-NTG复合诱变后,镜检形态观察与生物毒力测定筛选高毒力菌株,SDS-PAGE检测C...     

A Facile Synthesis of cis-9-[4-(1,2-Dihydroxyethyl)-cyclopent-2-enyl]guanine and Its Derivative

Abstract

The synthesis of carbocyclic nucleosides, cis-9-[4-(1,2-dihydroxyethyl)-cyclopent-2-enyl]guanine (3) and cis-2-amino-6-cyclopropylamino-9-[4-(1,2-dihydroxyethyl)-cyclopent-2-enyl]guanine (4), was achieved from cyclopentadiene (5) in five and six steps, respectively. This route involves a hetero Diels-Alder reaction and a Pd(0)-catalyzed coupling reaction.