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Influenza viruses belong to the Orthomyxoviridae family and cause acute respiratory distress in humans. The developed drug resistance toward existing drugs and the emergence of viral mutants that can escape vaccines mandate the search for novel antiviral drugs. Herein, the synthesis of epimeric 4'-methyl-4'-phosphonomethoxy [4'-C-Me-4'-C-(O-CH2 PâO)] pyrimidine ribonucleosides, their phosphonothioate [4'-C-Me-4'-C-(O-CH2 PâS)] derivatives, and their evaluation against an RNA viral panel are described. Selective formation of the α- l-lyxo epimer, [4'-C-(α)-Me-4'-C-(ß)-(O-CH2 -P(âO)(OEt)2 )] over the ß- d-ribo epimer [4'-C-(ß)-Me-4'-C-(α)-(O-CH2 -P(âO)(OEt)2 )] was explained by DFT equilibrium geometry optimizations studies. Pyrimidine nucleosides having the [4'-C-(α)-Me-4'-C-(ß)-(O-CH2 -P(âO)(OEt)2 )] framework showed specific activity against influenza A virus. Significant anti-influenza virus A (H1N1 California/07/2009 isolate) was observed with the 4'-C-(α)-Me-4'-C-(ß)-O-CH2 -P(âO)(OEt)2 -uridine derivative 1 (EC50 = 4.56 mM, SI50 > 56), 4-ethoxy-2-oxo-1(2H)-pyrimidin-1-yl derivative 3 (EC50 = 5.44 mM, SI50 > 43) and the cytidine derivative 2 (EC50 = 0.81 mM, SI50 > 13), respectively. The corresponding thiophosphonates 4'-C-(α)-Me-4'-C-(ß)-(O-CH2 -P( S)(OEt)2 ) and thionopyrimidine nucleosides were devoid of any antiviral activity. This study shows that the 4'-C-(α)-Me-4'-(ß)-O-CH2 -P(âO)(OEt)2 ribonucleoside can be further optimized to provide potent antiviral agents.
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Vírus da Influenza A Subtipo H1N1 , Nucleosídeos de Pirimidina , Ribonucleosídeos , Humanos , Relação Estrutura-Atividade , Antivirais/farmacologiaRESUMO
Pathogenic CUG and CCUG RNA repeats have been associated with myotonic dystrophy type 1 and 2 (DM1 and DM2), respectively. Identifying small molecules that can bind these RNA repeats is of great significance to develop potential therapeutics to treat these neurodegenerative diseases. Some studies have shown that aminoglycosides and their derivatives could work as potential lead compounds targeting these RNA repeats. In this work, sisomicin, previously known to bind HIV-1 TAR, is investigated as a possible ligand for CUG RNA repeats. We designed a novel fluorescence-labeled RNA sequence of r(CUG)10 to mimic cellular RNA repeats and improve the detecting sensitivity. The interaction of sisomicin with CUG RNA repeats is characterized by the change of fluorescent signal, which is initially minimized by covalently incorporating the fluorescein into the RNA bases and later increased upon ligand binding. The results show that sisomicin can bind and stabilize the folded RNA structure. We demonstrate that this new fluorescence-based binding characterization assay is consistent with the classic UV Tm technique, indicating its feasibility for high-throughput screening of ligand-RNA binding interactions and wide applications to measure the thermodynamic parameters in addition to binding constants and kinetics when probing such interactions.
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Distrofia Miotônica , RNA , Fluorescência , Humanos , Ligantes , Distrofia Miotônica/genética , RNA/genética , Proteínas de Ligação a RNA/metabolismo , SisomicinaRESUMO
A new series of nicotinonitrile derivatives 2-7 was designed and synthesized from the starting material (E)-3-(4-chlorophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (1) to assess their molluscicidal activity. The newly synthesized nicotinonitrile compounds 2-7 were characterized based on FTIR, 1H-NMR, and 13C-APT NMR spectra as well as elemental microanalyses. The target compounds 2-7 were screened for their toxicity effect against M. cartusiana land snails and were compared to Acetamiprid as a reference compound. The results demonstrated that the nicotinonitrile-2-thiolate salts 4a and 4b had good mortality compared with that of Acetamiprid. The results of the in vivo effect of the prepared nicotinonitrile molecules 2, 4a, and 4b on biochemical parameters, including AChE, ALT, AST, and TSP, indicated a reduction in the level of AChE and TSP as well as an increase in the concentration of transaminases (ALT and AST). A histopathological study of the digestive gland sections of the M. cartusiana land snails was carried out. The nicotinonitrile-2-thiolate salts 4a,b showed vacuolization, causing the digestive gland to lose its function. It could be concluded that the water-soluble nicotinonitrile-2-thiolate salts 4a,b could be adequate molluscicidal molecules against M. cartusiana land snails.
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Moluscocidas , Animais , Moluscocidas/farmacologia , Moluscocidas/química , CaramujosRESUMO
6-Methylpurine (MeP) is cytotoxic adenine analog that does not exhibit selectivity when administered systemically, and could be very useful in a gene therapy approach to cancer treatment involving Escherichia coli PNP. The prototype MeP releasing prodrug, 9-(ß-d-ribofuranosyl)-6-methylpurine, MeP-dR has demonstrated good activity against tumors expressing E. coli PNP, but its antitumor activity is limited due to toxicity resulting from the generation of MeP from gut bacteria. Therefore, we have embarked on a medicinal chemistry program to identify non-toxic MeP prodrugs that could be used in conjunction with E. coli PNP. In this work, we report on the synthesis of 9-(6-deoxy-ß-d-allofuranosyl)-6-methylpurine (3) and 9-(6-deoxy-5-C-methyl-ß-d-ribo-hexofuranosyl)-6-methylpurine (4), and the evaluation of their substrate activity with several phosphorylases. The glycosyl donors; 1,2-di-O-acetyl-3,5-di-O-benzyl-α-d-allofuranose (10) and 1-O-acetyl-3-O-benzyl-2,5-di-O-benzoyl-6-deoxy-5-C-methyl-ß-d-ribohexofuran-ose (15) were prepared from 1,2:5,6-di-O-isopropylidine-α-d-glucofuranose in 9 and 11 steps, respectively. Coupling of 10 and 15 with silylated 6-methylpurine under Vorbrüggen glycosylation conditions followed conventional deprotection of the hydroxyl groups furnished 5'-C-methylated-6-methylpurine nucleosides 3 and 4, respectively. Unlike 9-(6-deoxy-α-l-talo-furanosyl)-6-methylpurine, which showed good substrate activity with E. coli PNP mutant (M64V), the ß-d-allo-furanosyl derivative 3 and the 5'-di-C-methyl derivative 4 were poor substrates for all tested glycosidic bond cleavage enzymes.
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Carboidratos/química , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Purina-Núcleosídeo Fosforilase/metabolismo , Purinas/química , Humanos , Conformação Molecular , Nucleosídeos/química , Purina-Núcleosídeo Fosforilase/química , Especificidade por SubstratoRESUMO
Enrichment of broiler meat with very long-chain omega-3 fatty acids (VLCn-3 FA) is of interest because of their beneficial effects on human health. The ability of Ahiflower® (AHI) oil (Buglossoides arvensis), which naturally contains stearidonic acid (SDA), and a high-alpha-linolenic acid (ALA) flaxseed (FLAX) oil to enrich VLCn-3 FA contents in broilers tissues was investigated. Fifty-five Cobb 500 chicks were fed from days 12 to 35 of life either a control (CON) diet that contained 27.9 g/kg soybean oil or AHI or FLAX oils, each individually at 7.5 or 22.5 g/kg of the diet in substitution for soybean oil (all on an as fed basis). Total VLCn-3 FA contents were greater in breast, thigh, liver, adipose tissue, and plasma of all n-3 treatments compared to CON, with the greatest increase observed at the highest level of AHI and FLAX oils (p < 0.001). AHI oil at 7.5 g/kg promoted the most efficient synthesis and deposition of VLCn-3 in broiler tissues measured as deposition of VLCn-3 FA in tissues relative to intake of n3 FA. In conclusion, both ALA and SDA oils increased VLCn-3 FA deposition in tissues, but there were diminishing returns when increasing dietary levels of the oils.
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Ácidos Graxos Ômega-3 , Óleo de Semente do Linho , Animais , Galinhas , Humanos , Ácido alfa-LinolênicoRESUMO
The syntheses of a series of novel 6-aza-2-hydroxyimino-5-methylpyrimidine and related nucleosides are described. A suitably protected 2-methylthiopyrimidine nucleoside was selected as the precursor for installing a hydroxyimino moiety at the C-2 position. The starting nucleobase 6-aza-5-methyl-2-thiouracil is prepared in two steps from thiosemicarbazone and ethyl pyruvate. This is subjected to coupling with 1-O-acetyl-2,3,5-tri-O-benzoyl-ß-D-ribofuranose under Vorbrüggen glycosylation conditions to provide the corresponding nucleoside in high yield. Activation of the nucleoside to the corresponding 2-methylthio derivative followed by treatment with hydroxylamine hydrochloride in pyridine provides the corresponding 2-hydroxyimino derivative in high yield. Finally, the synthesis of five free modified nucleoside analogs is described. The newly synthesized nucleosides have been evaluated against an RNA viral panel and moderate activity was observed against hepatitis C virus, Zika virus, and human respiratory syncytial virus. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Preparation of 6-aza-5-methyl-2-thiouracil Basic Protocol 2: Preparation of 6-aza-5-methyl-2-thiouridine and 6-aza-5-methyluridine Basic Protocol 3: Preparation of 6-aza-2-hydroxyimino-5-methyluridine Basic Protocol 4: Preparation of 6-aza-2-hydroxyimino-5-methyl-4-thiouridine and 6-aza-2-hydroxyimino-5-methylcytosine.
Assuntos
Infecção por Zika virus , Zika virus , Antivirais , Hepacivirus , Humanos , NucleosídeosRESUMO
Cancer is a multifaceted disease. With the development of multi drug resistance, the need for the arousal of novel targets in order to avoid these drawbacks increased. A new series of acrylamide derivatives was synthesized from starting material 4-(furan-2-ylmethylene)-2-(3,4,5-trimethoxyphenyl)oxazol-5(4H)-one (1), and they are evaluated for their inhibitory activity against ß-tubulin polymerization. The target molecules 2-5 d were screened for their cytotoxic activity against breast cancer MCF-7 cell line. The results of cytotoxicity screening revealed that compounds 4e and 5d showed good cytotoxic profile against MCF-7 cells. Compounds 4e produced significant reduction in cellular tubulin with excellent ß-tubulin polymerization inhibition activity. In addition, compound 4e exhibited cytotoxic activity against MCF-7 cells by cell cycle arrest at pre-G1 and G2/M phases, as shown by DNA flow cytometry assay. Aiming to enhance the limited aqueous solubility and, hence, poor oral bioavailability of the prepared lead acrylamide molecule, 4e-charged PEGylated bilosomes were successfully fabricated via thin film hydration techniques as an attempt to improve these pitfalls. 23 full factorial designs were manipulated to examine the influence of formulation variables: types of bile salt including either sodium deoxy cholate (SDC) or sodium tauro cholate (STC), amount of bile salt (15 mg or 30 mg) and amount of DSPE-mPEG-2000 amount (25 mg or 50 mg) on the characteristics of the nanosystem. The F7 formula of entrapment efficiency (E.E% = 100 ± 5.6%), particle size (PS = 280.3 ± 15.4 nm) and zeta potential (ZP = -22.5 ± 3.4 mv) was picked as an optimum formula with a desirability value of 0.868. Moreover, prominent enhancement was observed at the compound's cytotoxic activity (IC50 = 0.75 ± 0.03 µM) instead of (IC50 = 2.11 ± 0.19 µM) for the unformulated 4e after being included in the nano-PEGylated bilosomal system.
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OBJECTIVE: This work aimed at studying dietary energy supplementation effects during late pregnancy upon the metabolic status of does, as well as on the birth weight (BW), body temperature, and metabolic profile for their kids and the net economic profit. MATERIALS AND METHODS: Eighty pregnant does (Egyptian Nubian) were equally split into four dietary treatments; the control (CON) receiving basal diet, the basal diet with 200 gm corn starch and 100 gm of molasses /h/d added (MS), the basal diet with 300 gm/h/d of corn grains added (CG), and the basal diet with 300 gm/h/d of barley grains added (BG). RESULTS: Body weight and temperature of kids were significantly higher in MS and BG groups, respectively. The serum concentration of albumin (Alb), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels are significantly decreased. At the same time, urea and vitamin A increased dramatically in the BG group before giving birth. After birth, conversely, the serum concentration of albumin, AST, ALT, cholesterol, and vitamin A significantly increased with energy supplementation. Kids in the BG group show the most high level of albumin. Furthermore, all supplemented groups increased dramatically in vitamin A. The economic efficiency of the MS group, followed by the BG group, was significantly higher compared to the other treatments. CONCLUSION: It is beneficial for Egyptian farmers to feed extra concentrate (especially barley) to the does during late gestation stages to produce healthy kids with optimal BW and body temperature, as well as to avoid metabolic disorders that may affect the does at this critical stage. Finally, it can be said that this dietary supplementation may also increases the profit margins of the farmers.
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AIM: This study aimed to investigate the effects of protein reduction with supplementation of limiting amino acids (AA, tryptophan, threonine, and valine) on growth performance, blood biochemical, immunity parameters, and carcass traits in broiler chickens. MATERIALS AND METHODS: Three hundred one-day-old broiler chicks were randomly allotted into three treatment groups, with five replicates per treatment and 20 broiler chickens per replicate. The three experimental diets were formulated with different dietary crude protein (CP) %, (control [CON] and CON with 1% [CP-1%] or 2% [CP-2%] less CP units) during the starter, grower, and finisher phases. The CP of the experimental diets were 22, 21, and 20% for the starting period (day 1-14); 20, 19, and 18% CP for the growing period (day 15-28); and 18, 17, and 16% CP for the finishing period (day 29-35) in CON, CP-1%, and CP-2%, respectively. The low-CP diets (CP-1% and CP-2%) were supplemented with combined AA, threonine+tryptophan+valine, to meet the respective levels of the CON diet. RESULTS: The CP-2% group had greater (p<0.05; linear, p<0.05) final body weight and gain and better feed conversion ratio. The combined AA inclusion in the low-CP diet (CP-1% and CP-2%) increased (p<0.001; linear, p<0.001) carcass and breast meat yield as well as CP% of breast meat. The reduction of CP% with AA supplementation (CP-2%) decreased (p<0.05; linear, p<0.05) serum triglycerides, glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, and alkaline phosphatase, while increased (p<0.01; linear, p<0.01) phagocytic activity and phagocytic index. The mRNA expression of splenic and cecal tonsil interleukin 4 and interferon gamma was upregulated (p<0.001; linear, p<0.001) in the low-CP diets supplemented with AA (CP-1% and CP-2%). Dietary supplementation with AA to low-protein diets improved (p<0.01; linear, p<0.01) the economic returns of broiler chickens. CONCLUSION: A reduction of dietary CP and increased synthetic AA such as threonine, valine, and tryptophan should be considered to improve performance, health, and immunity in broiler chickens.
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6-Methylpurine (MeP) is a cytotoxic adenine analog that does not exhibit selectivity when administered systemically and could be very useful in a gene therapy approach to cancer treatment involving Escherichia coli purine nucleoside phosphorylase (PNP). 9-(6-Deoxy-ß-D-allofuranosyl)-6-methylpurine [methyl(allo)-MePR, 18] and 9-(6-deoxy-α-L-talofuranosyl)-6-methylpurine [methyl(talo)-MePR, 21] were synthesized as potential prodrugs for MeP in the E. coli PNP/prodrug cancer gene therapy approach. The detailed syntheses of [methyl(allo)-MePR] and [methyl(talo)-MePR] are described. The glycosyl donors, 1,2-di-O-acetyl-3,5-di-O-benzyl-α-D-allofuranose (12) and 1-O-acetyl-3-O-benzyl-2,5-di-O-benzoyl-α-L-talofuranose (16) were prepared from 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (4) in nine and eleven steps, respectively. Vorbrüggen coupling of the latter glycosyl donors with 6-methylpurine (3), followed by deprotection of the sugar hydroxyl groups, gave the title compounds in good overall yields. © 2020 by John Wiley & Sons, Inc. Basic Protocol 1: Preparation of 6-methylpurine Basic Protocol 2: Preparation of the D-allofuranose derivative (12) Basic Protocol 3: Preparation of 6-deoxy-α-L-talofuranoside Basic Protocol 4: Preparation of methyl(allo)-MePR (18) Basic Protocol 5: Preparation of methyl(talo)-MePR (21).
Assuntos
Nucleosídeos de Purina/síntese química , Cromatografia em Camada Fina , Espectrometria de Massas , Espectroscopia de Prótons por Ressonância Magnética , Nucleosídeos de Purina/química , Nucleosídeos de Purina/farmacologia , Relação Estrutura-AtividadeRESUMO
This study was conducted to evaluate the effect of three concentrations of the Moringa oleifera seed powder as a feed supplement on the productive performance and egg quality traits of laying Japanese quail (Coturnix japonica) exposed to heat stress. The expression patterns of the genes estrogen receptors (ESR2), follicle-stimulating hormone receptor (FSHR), prolactin receptor (PRLR), and steroidogenic acute regulatory protein (STAR) were estimated in ovaries, using a quantitative real-time polymerase chain reaction. A total of 200 laying quail aged seven weeks were randomly allocated to the following four experimental groups-the control (CNT), T1, T2, and T3 groups; each group comprised 50 quail females with 5 replicates (10 per group). The CNT group was fed a basal diet, whereas the T1, T2, and T3 groups were fed the basal diet supplemented with 0.1%, 0.2%, and 0.3% M. oleifera seed powder, respectively. The results revealed that the T3 group showed the highest hen-day egg production (%) as well as the highest egg yolk index. Feed intake and feed conversion ratio improved significantly (p < 0.05) with increased concentrations of the M. oleifera seed powder supplementation. Furthermore, the mRNA expressions of ESR2, FSHR, and STAR increased significantly in the T3 group, compared to those in the CNT group. Alterations in ovarian gene expressions corresponded to the reproductive patterns of the treated Japanese quail. Thus, it was concluded that the supplementation of the Japanese quail feed with 0.3% M. oleifera seed powder during the laying period might enhance resistance to heat stress and consequently improve egg productivity.
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This study quantifies the effects of extruded linseed and soybean (ELS) dietary supplementation on milk yield, composition, and fatty acid profiles, as well as first-service conception rate in Holstein dairy cows. Seventy-eight open Holstein dairy cows were divided into two groups: (1) a control, which received a basal diet; and (2) a test group, which received a basal diet supplemented with the ELS (650 g/kg of extruded linseed and 150 g/kg of extruded soybean) at a rate of 100 g/kg. In the ELS group, milk yield per day and solid not fat (SNF) yield increased by 3.26% and 0.88%, respectively, in relation to the control. Percentage milk fat decreased significantly by 1.4% in the ELS group when compared with the control. The ELS supplement resulted in a decrease in saturated fatty acids (SFAs) and an increase in monounsaturated (MUFAs) and polyunsaturated fatty acids (PUFAs) in milk. In conclusion, the supplementation of dairy cow feed with 100 g/kg of ELS increases milk yield and milk unsaturated fatty acids (especially MUFAs and PUFAs). ELS supplementation also causes a decrease in percentage fat and SFA levels but does not affect the first-service conception rate or the incidence rate of mastitis.
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Photoexcitation of anthraquinones (AQ) in association with DNA results in DNA damage mainly at guanine residues, with products from thymine oxidation also observed. Studies of adenine oxidation will be aided by systems with an increased driving force for charge transfer, achieved by adding electron-withdrawing groups to the AQ ring. Attaching AQ derivatives to adenine via a bridge with two carbon atoms should enable the intended regiocontrol within the DNA duplex structure. Herein we report the synthesis of conjugates between AQ and adenine in which the AQ moieties have been modified with a formyl, a trifluoroacetyl, and two methyl ester groups. These have been synthesized by palladium coupling of tert-butyldiphenylsilyl 5'-protected 8-ethynyl-2'-deoxyadenosine with the corresponding bromoanthraquinone intermediates. Bromo intermediates bearing formyl or trifluoroacetyl were prepared by monolithiation of 2,6-dibromoanthraquinone, a step that required protection of the anthraquinone carbonyls. A bromo intermediate bearing two methyl ester groups was obtained from 1,2,4-trimethylbenzene by Friedel-Crafts acylation with 4-bromobenzoyl chloride followed by oxidation to the tricarboxylic acid, cyclization to form the anthraquinone ring, and finally esterification. Hydrogenation of the ethynyl linker gave the ethanyl linker. Cyclic voltammetry showed that the conjugate with the two ester groups and ethynyl linker was the most easily reduced of the derivatives synthesized. These derivatives, with reduction potentials favorable for electron transfer, can be used in studies of adenine oxidation in DNA.
Assuntos
Antraquinonas/síntese química , DNA/química , Desoxiadenosinas/síntese química , Antraquinonas/química , Dano ao DNA , Desoxiadenosinas/química , Eletroquímica , Transporte de Elétrons , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Oxidantes Fotoquímicos/química , FotoquímicaRESUMO
Dengue (DENV) viral infection is a global public health problem that infrequently develops life threatening diseases such as dengue hemorrhagic fever (DFS) and dengue shock syndrome (DSS). Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic human corona virus with 38% fatality rate of infected patients. A series of 4-arylhydrazono-5-trifluoromethyl-pyrazolones, their ribofuranosyl, and 5'-deoxyribofuranosyl nucleosides were synthesized, geometry optimized using Density functional theory (DFT), and evaluated for their antiviral activity. 2-Nitrophenylhydrazonopyra-zolone derivative 5 showed significant activity against MERS-CoV (EC50 = 4.6 µM). The nucleoside analog 8 showed moderate activity against DENV-2 (EC50 = 10 µM), while the activity was abolished with the corresponding 5'-deoxyribonucleoside analogs. The identified hits in this study set this category of compounds for further future optimizations.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Pirazolonas/química , Vírus da Dengue/efeitos dos fármacos , Desenho de Fármacos , Hepacivirus/efeitos dos fármacos , Vírus da Hepatite B/efeitos dos fármacos , Humanos , Alphainfluenzavirus/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Estrutura Molecular , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
This study was conducted to evaluate the effects of supplementing laying hen diet with phytogenic additives on laying performance, egg quality, blood constituents and egg lipid peroxidation. Two hundred Lohmann Brown Lite laying hens were randomly allotted to 4 dietary treatments: control (without phytogenic additive), fennel seeds (5 g/kg), black cumin seeds (5 g/kg) and hot red pepper (5 g/kg). Each of the 4 diets was fed to 5 replicates of 10 hens for 8 weeks. No significant differences were observed in body weight or feed intake between the groups. Dietary inclusion of fennel followed by red pepper improved (P < 0.05) egg weight, egg production, egg mass and feed conversion ratio compared with control. Higher yolk shape index, shell and albumen weight percentages and Haugh unit (P < 0.05) were recorded in the fennel supplemented group compared with control. The egg yolk color score increased by the addition of fennel or hot red pepper in laying hen diets compared with control. The inclusion of black cumin or hot red pepper decreased serum and egg yolk cholesterol and malondialdehyde concentrations (P < 0.05) compared with control. Serum aspartate aminotransferase concentration was lower in black cumin group (P < 0.05) than in other treatments. In conclusion, the best laying performance and egg quality were obtained by dietary inclusion of fennel, followed by hot red pepper and black cumin. Dietary supplementation of black cumin or red pepper may lead to the development of low-cholesterol concentration and better antioxidant capacity of eggs.
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Trimethylsilyl-transient protection successfully allowed the use of lithium hexamethyldisilazane to prepare benzimidazole (BI) and 4-azabenzimidazole (azaBI) amidines from nitriles in 58-88% yields. This strategy offers a much better choice to prepare BI/azaBI amidines than the lengthy, low-yielding Pinner reaction. Synthesis of aza/benzimidazole rings from aromatic diamines and aldehydes was affected in dimethyl sulfoxide in 10-15 min, while known procedures require long time and purification. These methods are important for the BI/azaBI-based drug industry and for developing specific DNA binders for expanded therapeutic applications.
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Amidinas/síntese química , Compostos Aza/química , Benzimidazóis/química , Imidazóis/síntese química , Compostos de Lítio/química , Nitrilas/química , Silanos/química , Amidinas/química , Compostos Aza/síntese química , Benzimidazóis/síntese química , Dimetil Sulfóxido/química , Imidazóis/química , Estrutura Molecular , Nitrilas/síntese químicaRESUMO
Impressive antitumor activity has been observed with fludarabine phosphate against tumors that express Escherichia coli purine nucleoside phosphorylase (PNP) due to the liberation of 2-fluoroadenine in the tumor tissue. 6-Methylpurine (MeP) is another cytotoxic adenine analog that does not exhibit selectivity when administered systemically, and could be very useful in a gene therapy approach to cancer treatment involving E. coli PNP. The prototype MeP releasing prodrug 9-(2-deoxy-ß-d-ribofuranosyl)-6-methylpurine (1) [MeP-dR] has demonstrated good activity against tumors expressing E. coli PNP, but its antitumor activity is limited due to toxicity resulting from the generation of MeP from gut bacteria. Therefore, we have embarked on a medicinal chemistry program to identify a combination of non-toxic MeP prodrugs and non-human adenosine glycosidic bond cleaving enzymes. The two best MeP-based substrates with M64V-E coli PNP, a mutant which was engineered to tolerate modification at the 5'-position of adenosine and its analogs, were 9-(6-deoxy-α-l-talofuranosyl)-6-methylpurine (3) [methyl(talo)-MeP-R] and 9-(α-l-lyxofuranosyl)6-methylpurine (4) [lyxo-MeP-R]. The detailed synthesis methyl(talo)-MeP-R and lyxo-MeP-R, and the evaluation of their substrate activity with 4 enzymes not normally associated with cancer patients is described. In addition, we have determined the intraperitoneal pharmacokinetic (ip-PK) properties of methyl(talo)-MeP-R and have determined its in vivo bystander activity in mice bearing D54 tumors that express M64V PNP. The observed good in vivo bystander activity of [methyl(talo)-MeP-R/M64V-E coli PNP combination suggests that these agents could be useful for the treatment of cancer.
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Antineoplásicos/farmacologia , Carboidratos/farmacologia , Inibidores Enzimáticos/farmacologia , Escherichia coli/enzimologia , Nucleosídeos/farmacologia , Purina-Núcleosídeo Fosforilase/antagonistas & inibidores , Purinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Carboidratos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Camundongos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Nucleosídeos/química , Purina-Núcleosídeo Fosforilase/metabolismo , Purinas/síntese química , Purinas/química , Relação Estrutura-AtividadeRESUMO
The challenge in working with anthraquinone-2'-deoxyadenosine (AQ-dA) conjugates is that they are insoluble in water and only sparingly soluble in most organic solvents. However, water-soluble AQ-dA conjugates with short linkers are required for study of their electrochemical and intramolecular electron transfer properties in this solvent prior to their use in laser kinetics investigations of photoinduced hole (cation) transport in DNA. This article first describes the synthesis of a water-soluble, ethynyl-linked AQ-dA conjugate, 8-[(anthraquinone-2-yl)ethynyl]-2'-deoxyadenosine 3'-benzyl hydrogen phosphate, based on initial formation of a 5'-O-(4,4'-dimethoxytrityl) (5'-O-DMTr) intermediate. Because intended H2 over Pd/C reduction of the ethynyl linker in 5'-O-DMTr-protected 2'-deoxyadenosines cleaves the DMTr protecting group and precipitates multiple side products, this work also describes the synthesis of an ethylenyl-linked AQ-dA conjugate, 8-[2-(anthraquinone-2-yl)ethyl]-2'-deoxyadenosine 3'-benzyl hydrogen phosphate, starting with a 5'-O-tert-butyldiphenylsilyl protecting group.
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DNA/química , Nucleotídeos de Desoxiadenina/síntese química , Oxidantes Fotoquímicos/síntese química , Nucleotídeos de Desoxiadenina/química , Estrutura Molecular , Oxidantes Fotoquímicos/químicaRESUMO
Drug resistance and emergence of new pathogens highlight the need for developing new therapeutic agents. We focused on 2-oxonicotinonitrile (2-ONN) as derivative of the natural product 2-pyridinone.(1) Herein, we describe the synthesis of 2-ONNs bearing two aryl groups, which we coupled with organohalides, including three glycosyl bromides, to prepare the nucleoside analogues. Coupling occurred mostly at the 2-ONN ring nitrogen to give the aimed targets, and in a few cases, it happened at the 2-oxo position giving O-alkylation products. Free 2-ONNs and their acetylated nucleosides were tested against a number of viruses. The nucleoside analogue 2a(Ac) showed good anti SARS-CoV and anti influenza A (H5N1) activities. Additionally, 7b had good activity against Gram positive bacterium, Bacillis subtilis.
Assuntos
Nitrilas/síntese química , Nitrilas/farmacologia , Bactérias/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Vírus/efeitos dos fármacosRESUMO
A series of C-6 alkyl, cycloalkyl, and aryl-9-(ß-d-ribofuranosyl)purines were synthesized and their substrate activities with Escherichia coli purine nucleoside phosphorylase (E. coli PNP) were evaluated. (Ph(3)P)(4)Pd-mediated cross-coupling reactions of 6-chloro-9-(2,3,5-tri-O-acetyl-ß-d-ribofuranosyl)-purine (6) with primary alkyl (Me, Et, n-Pr, n-Bu, isoBu) zinc halides followed by treatment with NH(3)/MeOH gave the corresponding 6-alkyl-9-(ß-d-ribofuranosyl)purine derivatives 7-11, respectively, in good yields. Reactions of 6 with cycloalkyl(propyl, butyl, pentyl)zinc halides and aryl (phenyl, 2-thienyl)zinc halides gave under similar conditions the corresponding 6-cyclopropyl, cyclobutyl, cyclopentyl, phenyl, and thienyl -9-(ß-d-ribofuranosyl)purine derivatives 12-16, respectively in high yields. E. coli PNP showed a high tolerance to the steric and hydrophobic environment at the 6-position of the synthesized purine ribonucleosides. Significant cytotoxic activity was observed for 8, 12, 15, and 16. Evaluation of 12 and 16 against human tumor xenografts in mice did not demonstrate any selective antitumor activity. In addition, 6-methyl-9-(ß-d-arabinofuranosyl)purine (18) was prepared and evaluated.