RESUMO
Nucleotide analogs known as acyclic and cyclic nucleoside phosphonates (ANPs and CNPs, respectively) have a variety of biological properties, including antibacterial, antiviral, antiparasitic, antineoplastic, and immunomodulatory. A strong reaction that has emerged in the last several decades has fundamentally changed our knowledge of the chemistry of nucleoside phosphonates. In particular, Olefin cross-metathesis (CM) has been a potent and practical synthesis route to produce functionalized olefins from essential alkene precursors. This review describes recent synthesis examples of ANPs and CNPs analogs using the Ru-catalyzed olefin cross-metathesis reactions. Olefin cross-metathesis reactions are performed in the olefinic parts of nucleoside and phosphonate produced by Grubbs, Hoveyda-Grubbs, and Nolan. This review presents a synthetic overview of a few chosen nucleosides with biological significance. Their biological activity results are briefly discussed.
RESUMO
In an attempt to isolate a biocatalyst able to catalyze biodiesel production from microbial source, Streptomyces sp. CS326 was screened from hundreds of soil isolates collected from various parts of Korea. In 16S rRNA sequence analysis, the strain showed high degree of similarity with Streptomyces xanthocidicus (99.79%); therefore, it is classified as Streptomyces sp. CS326. An extracellular lipase produced by the strain (LP326) was purified using a single step gel permeation chromatography on Sepharose CL-6B. Molecular weight of LP326 was estimated to be 17,000 Da by SDS-PAGE. The activity was optimum at 40 °C and pH 7.0 and was stable at pH 5.0-8.0 and below 50 °C. It preferred p-nitrophenyl palmitate (C16), a long chain substrate; and K (m) and V (max) for the substrate were determined to be 0.24 mM and 4.6 mM/min mg, respectively. First 10 N-terminal amino acid sequences were APDLVALQSE, which are different from so far reported lipases. LP326 catalyzed biodiesel production using methanol and various oils; therefore, the enzyme can be applicable in the field of biofuel.
Assuntos
Biocombustíveis , Lipase/química , Lipase/metabolismo , Metanol/química , Óleos de Plantas/química , Streptomyces/enzimologia , Ativação Enzimática , Estabilidade Enzimática , Lipase/isolamento & purificação , Especificidade da Espécie , Streptomyces/classificação , TemperaturaRESUMO
The synthesis of five series of 4'-truncated nucleoside phosphonic acid analogues is discussed in this review: (1) 4'-truncated furanose nucleoside phosphonic acid analogues; (2) 4'-truncated pyrrolidine nucleoside phosphonic acid analogues; (3) 4'-truncated carbocyclic nucleoside phosphonic acid analogues; (4) 4'-truncated isoxazole nucleoside phosphonic acid analogues; (5) 4'-truncated miscellaneous nucleoside phosphonic acid analogues. Five different ways are used to make the phosphonate moiety: (i) Michaelis-Arbuzov reaction of RX (X = Br, I, OTf) with trialkyl phosphate; (ii) Lewis acid catalyzed Michaelis-Arbuzov reaction of glycoside with trialkyl phosphite; (iii) nucleophilic addition of a dialkyl phosphite to a carbonyl group; (iv) direct coupling reaction with amino alkyl phosphonate; (v) de novo synthesis of phosphonated-isoxazole and 1,3-dioxolane heterocycles from phosphonated starting materials. Their biological activity results are briefly discussed.
Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Enzimas/metabolismo , Nucleosídeos/farmacologia , Ácidos Fosforosos/farmacologia , Vírus/efeitos dos fármacos , Animais , Antivirais/síntese química , Antivirais/química , Configuração de Carboidratos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Testes de Sensibilidade Microbiana , Nucleosídeos/síntese química , Nucleosídeos/química , Ácidos Fosforosos/síntese química , Ácidos Fosforosos/químicaRESUMO
The present review focuses on the synthesis of cyclic 5'-deoxynucleoside phosphonate analogs. The formation of various phosphonate alkyl moieties is accomplished through (i) Wittig (or HWE) type condensation to the nucleoside aldehyde moiety; (ii) nucleophilic displacement reaction using phosphonate anion or Lewis acid; (iii) Arbuzov reaction; (iv) olefin cross-metathesis between vinyl phosphonates and vinylated nucleosides; and (v) radical reaction and Pd catalyzed alkyne. For the coupling of nucleobases with cyclic moieties, the Mitsunobu reaction and Sonogashira-type cross-coupling are usually applied. For the coupling of furanose moieties with nucleobases, Vorbrüggentype condensation is generally applied. Addition reactions mediated by selenium ions are mainly applied for the coupling of carbocyclic moieties. Their biological activity results have been summarized.
Assuntos
Organofosfonatos , Humanos , NucleosídeosRESUMO
The syntheses of acyclic nucleoside phosphonate (ANP) analogs linked with cyclic systems are described in the present review. The purpose of the review is to report the methodology of ANP analogs and to give an idea on the synthesis of a therapeutic structural feature of such analogs. The cyclopropane systems were mainly prepared by diazomethane cyclopropanation catalyzed by Pd(OAc)2, intramolecular alkylation, Kulinkovich cyclopropanation, and use of difluorocyclopropane, and so forth. The preparation of methylenecyclopropane system was made by diazoacetate cyclopropanation catalyzed by Rhodium followed by addition-elimination reactions. For the preparation of a variety of tethered 1,2,3-triazole systems, 1,3-dipolar cycloaddition between azidealkylphosphonates and propargylated nucleobases was mainly applied. The formation of various phosphonate moieties was achieved via phosphonylation of alkoxide, cross-coupling between BrZnCF2P (O)(OEt)2 with iodoalkens catalyzed by CuBr, Michaelis-Arbuzov reaction with phosphite, and Rh(II)-catalyzed O-H insertion, and so forth.
Assuntos
Organofosfonatos/síntese química , Fenômenos Químicos , NucleosídeosRESUMO
This paper reports the synthesis of novel 4'-hydrophobic pocket deoxythreosyl C-nucleosides. The key threose-like intermediates 9 and 14 were constructed from acyclic ketone derivatives, respectively. The antiviral activities of the synthesized compounds against the HIV-1, HSV-1, HSV-2, and HCMV viruses were evaluated. The 9-deaza-adenine derivatives 10 and 20 showed good anti-HIV activity without exhibiting significant cytotoxicity.
Assuntos
Fármacos Anti-HIV/farmacologia , Didesoxiadenosina/farmacologia , HIV-1/efeitos dos fármacos , Fármacos Anti-HIV/síntese química , Linhagem Celular , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/crescimento & desenvolvimento , Didesoxiadenosina/análogos & derivados , Didesoxiadenosina/síntese química , HIV-1/crescimento & desenvolvimento , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 1/crescimento & desenvolvimento , Herpesvirus Humano 2/efeitos dos fármacos , Herpesvirus Humano 2/crescimento & desenvolvimento , Humanos , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The synthesis of a new series of 1beta-methylcarbapenems having pyrrolidine and piperidine moieties is described. Their in-vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of substituents on the pyrrolidine ring was investigated. A particular compound III b having an oxime-pyrrolidine moiety showed the most potent antibacterial activity.
Assuntos
Antibacterianos/síntese química , Carbapenêmicos/síntese química , Antibacterianos/farmacologia , Carbapenêmicos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Piperidinas , Pirrolidinas , Relação Estrutura-AtividadeRESUMO
This paper reports a new method for synthesizing an acyclic version of 6 '-methylene and 6 '(alpha)-methylated carbovir analogues. The introduction of a methylene group to the requisite 6 '-position was carried out employing a Mannich type reaction using Eshenmoser's salt (methylene-N,N-dimethylammonium iodide). Carbonyl enolate alkylation (LiHMDS, CH3I) was used to introduce a methyl group to the 6 '(alpha)-position. The guanine analogues were successfully synthesized from the bromide compound 8 and 14 via a SN2 type reaction and deprotection. When the synthesized compounds 11 and 17 were tested against HIV-1, they showed toxicity that was not related to any anti-HIV activity.
Assuntos
Didesoxinucleosídeos/síntese química , Guanina/síntese química , Fármacos Anti-HIV/farmacologia , Linhagem Celular Tumoral , Didesoxinucleosídeos/farmacologia , Guanina/análogos & derivados , Guanina/farmacologia , Infecções por HIV/tratamento farmacológico , Humanos , Linfócitos T/virologiaRESUMO
This article describes an efficient route for synthesizing novel cyclopropyl homologous PMEA analogues. The condensation of the bromide 8 with nucleosidic bases (A, U, T, C, 5-FU, G) under standard nucleophilic substitution and deprotection conditions, afforded the target phosphonic acid analogues 14 approximately 18 and 21. These compounds were evaluated for their potential antiviral properties against various viruses. Guanine derivative 21 showed significant antiviral activity.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , HIV-1/efeitos dos fármacos , Adenina/síntese química , Adenina/química , Adenina/farmacologia , Fármacos Anti-HIV/química , Infecções por HIV/tratamento farmacológico , HumanosRESUMO
A selective method for synthesizing (E)-fluorovinyl was developed. Novel acyclic (E)-fluorovinyl versions of neplanocin A were designed and selectively synthesized as potential antiviral agents. The condensation of the bromide 7 with the nucleosidic bases (5-FU, C, A, G) and the deprotection afforded the desired acyclic fluorovinyl nucleosides. The synthesized compounds 11, 12, 13, and 16 were evaluated for their antiviral activity. The guanine derivative 16 showed toxicity-dependent anti-HIV-1 activity in MT-4 cells.
Assuntos
Antivirais/síntese química , Nucleosídeos/síntese química , Compostos de Vinila/síntese química , Vírus/efeitos dos fármacos , Antivirais/química , Antivirais/metabolismo , Antivirais/farmacologia , Linhagem Celular , Humanos , Nucleosídeos/química , Nucleosídeos/farmacologia , Compostos de Vinila/química , Compostos de Vinila/farmacologiaRESUMO
Nucleoside phosphonates are isosteric, isopolar, and isoelectronic with phosphates. Nucleoside phosphonates can undergo enzymatic phosphorylation for conversion into the corresponding diphosphoryl phosphonates, which are naturally occurring nucleoside triphosphate analogues. The biological activity, which is mostly antiviral and antitumor but sometimes is as specific enzyme inhibitor, is briefly presented to help discover compounds with increased activity over natural nucleosides to provide structure-activity data. This review focuses on the synthesis of three types of cyclic 5'-nucleoside phosphonate analogues: (1) furanose 5'-nornucleoside phosphonates, (2) carbocyclic 5'-nornucleoside phosphonates, and (3) apiose 5'-nornucleoside phosphonates.
Assuntos
Antineoplásicos/síntese química , Antivirais/síntese química , Nucleosídeos/química , Organofosfonatos/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antivirais/química , Antivirais/farmacologia , Ciclização , Humanos , Estrutura Molecular , Organofosfonatos/química , Organofosfonatos/farmacologiaRESUMO
A series of novel fluorocyclopropyl nucleosides were synthesized starting from acetol using the Simmons-Smith reaction as a key reaction. All the nucleosides synthesized were assayed against several viruses. Among the compounds synthesized, the uracil analogue 22 showed moderate anti-HCMV activity (10.61 microg/mL, in AD-169).
Assuntos
Antivirais/farmacologia , Ciclopropanos/farmacologia , HIV/efeitos dos fármacos , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Nucleosídeos/farmacologia , Antivirais/síntese química , Antivirais/química , Células Cultivadas , Ciclopropanos/síntese química , Ciclopropanos/química , Humanos , Hidrocarbonetos Fluorados/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Nucleosídeos/síntese química , Nucleosídeos/químicaRESUMO
In this study, the synthesis procedures of 2'-branched carbovir analogues were accomplished. The introduction of a methyl group in the requisite 2'-position was carried out by the addition of a carbonyl using isopropenyl magnesium bromide. The desired compound, cyclopentenol 10(beta), was synthesized via ring-closing metathesis using a second-generation Grubbs' catalyst. The nucleosidic bases (adenine, cytosine, thymine, uracil, 5-fluorouracil and 5-iodouracil) were efficiently coupled using a Pd (0) catalyst. When the synthesized compounds were examined for their activity against several viruses, including HIV-1, HSV-1, HSV-2 and HCMV, the 5-iodouracil analogue, 23, exhibited significant anti-HCMV activity.
Assuntos
Antivirais/síntese química , Didesoxinucleosídeos/síntese química , Animais , Antivirais/efeitos adversos , Antivirais/química , Antivirais/farmacologia , Catálise , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citomegalovirus/efeitos dos fármacos , Efeito Citopatogênico Viral/efeitos dos fármacos , Didesoxinucleosídeos/efeitos adversos , Didesoxinucleosídeos/química , Didesoxinucleosídeos/farmacologia , HIV/efeitos dos fármacos , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Humanos , Estrutura MolecularRESUMO
A series of novel fluorocyclopropyl nucleosides were synthesized using the Simmons-Smith reaction as a key reaction starting from 1,3-dihydroxyacetone. All the nucleosides synthesized were assayed against several viruses. Among the compounds synthesized, the 5-fluorouracil analogue 15 showed significant anti-HCMV activity (9.22 microM).
Assuntos
Antivirais/síntese química , HIV-1/crescimento & desenvolvimento , Herpesviridae/crescimento & desenvolvimento , Hidrocarbonetos Fluorados/síntese química , Nucleosídeos/síntese química , Replicação Viral/efeitos dos fármacos , Antivirais/química , Antivirais/farmacologia , Linhagem Celular , Ciclopropanos/síntese química , Ciclopropanos/química , Ciclopropanos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/farmacologia , Nucleosídeos/química , Nucleosídeos/farmacologiaRESUMO
This article reports the novel synthesis of substituted apiosyl nucleosides. The key apiosyl intermediate 9 was constructed by sequential ozonolysis, reductions, and acetylation from the ester derivative 6. The nucleosides of uracil, thymine, cytosine, and adenine were synthesized using the glycosyl condensation procedure (silyated base and TMSOTf). The antiviral activities of the synthesized compounds against the HIV-1, HSV-1, HSV-2, and HCMV viruses were evaluated. The adenine derivative 26 showed weak anti-HIV activity (EC(50) = 10.1 microg/ml) without exhibiting any cytotoxicity up to a concentration of 100 microM.
Assuntos
Antivirais/farmacologia , Química Farmacêutica/métodos , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Di-Hidroxiacetona/análogos & derivados , Di-Hidroxiacetona/síntese química , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Modelos Químicos , Estrutura Molecular , OzônioRESUMO
This study aimed to investigate the gastrointestinal stability and the cellular uptake characteristics of L-valyl-ara-C, a peptidomimetic prodrug of ara-C (cytarabine). After the synthesis of L-valyl-ara-C via the incorporation of L-valine into the N4-amino group of the cytosine ring in araC, the gastrointestinal stability of L-valyl-ara-C was examined using artificial gastric juice and artificial intestinal fluids. The cellular uptake characteristics of L-valyl-ara-C were also examined in Caco-2 cells. The disappearance half-life of L-valyl-ara-C was 2.2 h in artificial gastric juice, while the degradation of L-valyl-ara-C was negligible in artificial intestinal fluid and also in the supernatant above the Caco-2 cell monolayer during the 2-h incubation. The cellular accumulation of L-valyl-ara-C was 5-fold higher than that of ara-C in Caco-2 cells. Furthermore, the cellular uptake of L-valyl-ara-C did not increase proportionally to the increase in drug concentration. The cellular accumulation of L-valyl-ara-C was significantly reduced in the presence of uridine, p-aminohippurate, tetraethylammonium and small dipeptides, while it was not changed in the presence of L-valine and benzoic acid, suggesting that L-valyl-ara-C could interact with multiple uptake transporters, including peptide transporters, organic anion and cation transporters and nucleoside transporters, but might not interact with amino acid transporters. In conclusion, L-valyl-ara-C could be effective to improve the oral absorption of ara-C via the carrier-mediated transport pathway.
Assuntos
Citarabina/análogos & derivados , Peptídeos/química , Pró-Fármacos/farmacocinética , Transporte Biológico , Células CACO-2 , Cromatografia Líquida de Alta Pressão , Citarabina/síntese química , Citarabina/química , Citarabina/farmacocinética , Estabilidade de Medicamentos , Suco Gástrico/química , Meia-Vida , Humanos , Mucosa Intestinal/metabolismo , Secreções Intestinais/química , Pró-Fármacos/síntese química , Pró-Fármacos/químicaRESUMO
Novel phenyl branched apiosyl nucleosides were synthesized in this study. The introduction of phenyl group in the 4'-position was accomplished by a [3,3]-sigmatropic rearrangement. Apiosyl sugar moiety was constructed by sequential ozonolysis and reductions. The natural bases (cytosine and adenine) were efficiently coupled with an apiosyl sugar by classical glycosyl condensation procedure (persilyated base and TMSOTf). The antiviral activities of the synthesized compounds were evaluated against the HIV-1, HSV-1, HSV-2 and HCMV.
Assuntos
Adenina/síntese química , Antivirais/síntese química , Citosina/síntese química , Nucleosídeos/síntese química , Adenina/análogos & derivados , Adenina/farmacologia , Antivirais/farmacologia , Citosina/análogos & derivados , Citosina/farmacologia , Estrutura Molecular , Nucleosídeos/farmacologiaRESUMO
A very simple synthetic route for novel cyclopentene phosphonate nucleosides is described. The characteristic cyclopentene moiety 6 was constructed via a ring-closing metathesis of divinyl 5, which could be readily prepared from diethylmalonate. The condensation of the mesylate 11 with nucleobases (A, C, T, U) under nucleophilic substitution conditions (K2CO3, 18-Crown-6, DMF) afforded the target nucleosides 12, 13, 14, and 15. In addition, the antiviral evaluations against various viruses were performed.
Assuntos
Alcenos/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Nucleosídeos/química , Nucleosídeos/farmacologia , Fármacos Anti-HIV/química , Ciclização , Desenho de Fármacos , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Estrutura Molecular , Nucleosídeos/síntese química , FosforilaçãoRESUMO
Novel 4'-hydroxymethyl branched apiosyl nucleosides were synthesized in this study. The introduction of a hydroxymethyl group in the 4'-position was accomplished by a [3,3]-sigmatropic rearrangement. Apiosyl sugar moiety was constructed by sequential ozonolysis and reductions. The natural bases (uracil, thymine, cytosine, and adenine) were efficiently coupled by a classical glycosyl condensation procedure (persilyated base and TMSOTf). The antiviral activities of the synthesized compounds were evaluated against HIV-1, HSV-1, HSV-2, and HCMV. Compound 18 displayed moderate anti-HCMV activity (EC50 = 20.1 microg/mL) without exhibiting any cytotoxicity up to 100 microM.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Nucleosídeos/química , Nucleosídeos/farmacologia , Acetatos/química , Antivirais/química , Antivirais/toxicidade , Citomegalovirus/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Hidroxilação , Metilação , Estrutura Molecular , Nucleosídeos/síntese química , Nucleosídeos/toxicidade , Simplexvirus/efeitos dos fármacosRESUMO
In these study, novel acyclic (E)-bromovinyl nucleosides were synthesized as potential antiviral agents. The coupling of the allylic bromide 9 with bases (thymine, uracil, 5-fluorouracil, 5-iodouracil, cytosine, adenine) afforded a series of novel acyclic nucleosides. The synthesized compounds were evaluated for their antiviral activity against various viruses such as HIV-1, HSV-1, HSV-2, and HCMV. 5-Iodouracil analogue 19 showed weak anti-HIV-1 activity.