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1.
Org Biomol Chem ; 17(46): 9913-9923, 2019 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-31720670

RESUMO

Nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) inhibitors have been suggested as a potential treatment for calcium pyrophosphate dihydrate (CPPD) deposition disease. Here, we targeted the development of improved NPP1 inhibitors based on acyclic mimics of Pα,α-phosphorodithioate-substituted adenine nucleotides, 7-10. The latter were obtained in a facile two-step synthesis from adenine-(methoxy)ethanol. Among analogs 7-10, adenine-(methoxy)ethoxy-Pα,α-dithio-triphosphate, 8, was the most potent NPP1 inhibitor both with purified enzyme (IC50 0.645 µM) and in osteoarthritic human chondrocytes (IC50 0.033 µM). Furthermore, it efficaciously (10-fold vs. control) inhibited ATP-induced CPPD in human articular chondrocytes. Importantly, 8 was a highly selective NPP1 inhibitor which showed only minor inhibition of NPP3, CD39 and CD73, and did not inhibit TNAP (tissue nonspecific alkaline phosphatase) activity in human chondrocytes. Furthermore, 8 did not activate P2Y1,2,6 receptors. Analog 8 was not toxic to cultured chondrocytes at 100 µM. Therefore, 8 may be suitable for further development as a drug candidate for the treatment of CPPD arthritis and other NPP1-related diseases.


Assuntos
Adenina/farmacologia , Pirofosfato de Cálcio/antagonistas & inibidores , Condrócitos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Osteoartrite do Joelho/tratamento farmacológico , Polifosfatos/farmacologia , Pirofosfatases/antagonistas & inibidores , Compostos de Sulfidrila/farmacologia , Adenina/síntese química , Adenina/química , Pirofosfato de Cálcio/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Condrócitos/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Osteoartrite do Joelho/metabolismo , Osteoartrite do Joelho/patologia , Diester Fosfórico Hidrolases/metabolismo , Polifosfatos/química , Pirofosfatases/metabolismo , Relação Estrutura-Atividade , Compostos de Sulfidrila/química
2.
Nat Commun ; 10(1): 4413, 2019 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-31562325

RESUMO

The synthesis of nucleobases in natural environments, especially in interstellar molecular clouds, is the focus of a long-standing debate regarding prebiotic chemical evolution. Here we report the simultaneous detection of all three pyrimidine (cytosine, uracil and thymine) and three purine nucleobases (adenine, xanthine and hypoxanthine) in interstellar ice analogues composed of simple molecules including H2O, CO, NH3 and CH3OH after exposure to ultraviolet photons followed by thermal processes, that is, in conditions that simulate the chemical processes accompanying star formation from molecular clouds. Photolysis of primitive gas molecules at 10 K might be one of the key steps in the production of nucleobases. The present results strongly suggest that the evolution from molecular clouds to stars and planets provides a suitable environment for nucleobase synthesis in space.


Assuntos
Adenina/química , Citosina/química , Hipoxantina/química , Timina/química , Uracila/química , Xantina/química , Adenina/síntese química , Amônia/química , Monóxido de Carbono/química , Citosina/síntese química , Evolução Química , Meio Ambiente Extraterreno , Hipoxantina/síntese química , Gelo , Metanol/química , Estrutura Molecular , Processos Fotoquímicos/efeitos da radiação , Timina/síntese química , Raios Ultravioleta , Uracila/síntese química , Água/química , Xantina/síntese química
3.
Bioorg Med Chem ; 27(8): 1704-1713, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30879860

RESUMO

Synthetic derivatives of cyclic adenosine monophosphate, such as halogenated or other more hydrophobic analogs, are widely used compounds, to investigate diverse signal transduction pathways of eukaryotic cells. This inspired us to develop cyclic nucleotides, which exhibit chemical structures composed of brominated 7-deazaadenines and the phosphorylated ribosugar. The synthesized 8-bromo- and 7-bromo-7-deazaadenosine-3',5'-cyclic monophosphates rank among the most potent activators of cyclic nucleotide-regulated ion channels as well as cAMP-dependent protein kinase. Moreover, these substances bind tightly to exchange proteins directly activated by cAMP.


Assuntos
AMP Cíclico/análogos & derivados , AMP Cíclico/farmacologia , Adenina/análogos & derivados , Adenina/síntese química , Adenina/química , Adenina/farmacologia , Animais , AMP Cíclico/síntese química , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Canais de Cátion Regulados por Nucleotídeos Cíclicos/agonistas , Canais de Cátion Regulados por Nucleotídeos Cíclicos/metabolismo , Ativação Enzimática/efeitos dos fármacos , Fatores de Troca do Nucleotídeo Guanina/agonistas , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Halogenação , Humanos , Camundongos
4.
Nucleic Acids Res ; 47(3): 1268-1277, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30517733

RESUMO

In addition to DNA cytosine methylation (5-methyl-2'-deoxycytidine, m5dC), DNA adenine methylation (N6-methyl-2'-deoxyadenosine, m6dA) is another DNA modification that has been discovered in eukaryotes. Recent studies demonstrated that the content and distribution of m6dA in genomic DNA of vertebrates and mammals exhibit dynamic regulation, indicating m6dA may function as a potential epigenetic mark in DNA of eukaryotes besides m5dC. Whether m6dA undergoes the further oxidation in a similar way to m5dC remains elusive. Here, we reported the existence of a new DNA modification, N6-hydroxymethyl-2'-deoxyadenosine (hm6dA), in genomic DNA of mammalian cells and tissues. We found that hm6dA can be formed from the hydroxylation of m6dA by the Fe2+- and 2-oxoglutarate-dependent ALKBH1 protein in genomic DNA of mammals. In addition, the content of hm6dA exhibited significant increase in lung carcinoma tissues. The increased expression of ALKBH1 in lung carcinoma tissues may contribute to the increase of hm6dA in DNA. Taken together, our study reported the existence and formation of hm6dA in genomic DNA of mammals.


Assuntos
Adenina/metabolismo , Metilação de DNA/genética , DNA/genética , Epigênese Genética , Adenina/análogos & derivados , Adenina/síntese química , Adenina/farmacologia , Animais , DNA/efeitos dos fármacos , DNA/metabolismo , Genoma/efeitos dos fármacos , Células HeLa , Humanos , Hidroxilação/efeitos dos fármacos , Mamíferos
5.
Artigo em Inglês | MEDLINE | ID: mdl-30188772

RESUMO

A synthesis of cyclobutene nucleoside analogs in which the nucleobase is tethered by a methylene group is described. The coupling of 6-chloropurine with 3-hydroxymethyl-cyclobutanone proceeds via its triflate to give both N-7 and N-9 regioisomers with relative yields corresponding to the calculated charge distribution of the 6-chloropurinyl anion. The stereoselective reduction of the N-alkylated ketones yielded quantitatively one stereoisomer in each case. The structural assignments were based on spectroscopic data and single crystal X-ray diffraction. Attempts to photoexcite the N-7 and N-9 ketones in order to promote ring-expansion did not ensue. Preliminary evidence suggests a photodecarbonylation to cyclopropanes took place.


Assuntos
Ciclobutanos/síntese química , Adenina/análogos & derivados , Adenina/síntese química , Adenina/química , Ciclobutanos/química , Nucleosídeos/síntese química , Nucleosídeos/química , Purinas/química , Estereoisomerismo
6.
ChemMedChem ; 13(17): 1779-1796, 2018 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-29968968

RESUMO

A series of 13 acyclic nucleoside phosphonates (ANPs) as bisamidate prodrugs was prepared. Five compounds were found to be non-cytotoxic and selective inhibitors of Bordetella pertussis adenylate cyclase toxin (ACT) in J774A.1 macrophage cell-based assays. The 8-aza-7-deazapurine derivative of adefovir (PMEA) was found to be the most potent ACT inhibitor in the series (IC50 =16 nm) with substantial selectivity over mammalian adenylate cyclases (mACs). AC inhibitory properties of the most potent analogues were confirmed by direct evaluation of the corresponding phosphonodiphosphates in cell-free assays and were found to be potent inhibitors of both ACT and edema factor (EF) from Bacillus anthracis (IC50 values ranging from 0.5 to 21 nm). Moreover, 7-halo-7-deazapurine analogues of PMEA were discovered to be potent and selective mammalian AC1 inhibitors (no inhibition of AC2 and AC5) with IC50 values ranging from 4.1 to 5.6 µm in HEK293 cell-based assays.


Assuntos
Adenina/análogos & derivados , Adenilil Ciclases/metabolismo , Bacillus anthracis/enzimologia , Bordetella pertussis/enzimologia , Inibidores Enzimáticos/farmacologia , Organofosfonatos/farmacologia , Adenina/síntese química , Adenina/química , Adenina/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estrutura Molecular , Organofosfonatos/síntese química , Organofosfonatos/química , Relação Estrutura-Atividade
7.
Chemistry ; 24(46): 11890-11894, 2018 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-29790604

RESUMO

(3,4-Dihydroxybut-1-ynyl)uracil, -cytosine and -7-deazaadenine 2'-deoxyribonucleoside triphosphates (dNTPs) were prepared by direct aqueous Sonogashira cross-coupling of halogenated dNTPs with dihydroxybut-1-yne and converted to 3,4-dihydroxybutyl dNTPs through catalytic hydrogenation. Sodium periodate oxidative cleavage of dihydroxybutyl-dUTP gave the desired aliphatic aldehyde-linked dUTP, whereas the oxidative cleavage of the corresponding deazaadenine dNTP gave a cyclic aminal. All dihydroxyalkyl or -alkynyl dNTPs and the formylethyl-dUTP were good substrates for DNA polymerases and were used for synthesis of diol- or aldehyde-linked DNA. The aldehyde linked DNA was used for the labelling or bioconjugations through hydrazone formation or reductive aminations.


Assuntos
Adenina/análogos & derivados , Aldeídos/química , Citosina/química , DNA Polimerase Dirigida por DNA/metabolismo , DNA/metabolismo , Nucleotídeos de Desoxiuracil/síntese química , Uracila/metabolismo , Adenina/síntese química , Adenina/química , Aminação , DNA/química , DNA Polimerase Dirigida por DNA/química , Nucleotídeos de Desoxiuracil/química , Estrutura Molecular , Nucleotídeos , Uracila/química
8.
Antivir Chem Chemother ; 26: 2040206618757636, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29436843

RESUMO

Background The replacement of ß,γ-pyrophosphate by ß,γ-phosphonate moieties within the triphosphate chain of 5'-triphosphate nucleoside analogues was previously studied for various antiviral nucleoside analogues such as AZT and 2',3'-dideoxynucleosides. Thus, it has been shown that these chemical modifications could preserve, in some cases, the terminating substrate properties of the triphosphate analogue for HIV-RT. Herein, we aimed to study such 5'-triphosphate mimics based on the scaffold of the well-known antiviral agent 9-[(2-phosphonomethoxy)ethyl]adenine (PMEA, Adefovir). Methods Synthesis involved coupling of a morpholidate derivative of PMEA with appropriate pyrophosphoryl analogues. The relative efficiencies of incorporation of the studied diphosphate phosphonates were measured using subtype B WT HIV-1 RT in an in vitro susceptibility assay, in comparison to the parent nucleotide analogue (PMEApp). Results Searching for nucleoside 5'-triphosphate mimics, we have synthesized and studied a series of diphosphate analogues of PMEA bearing non hydrolysable bonds between the and phosphorus atoms. We also examined their relative inhibitory capacity towards HIV-1 reverse transcriptase in comparison to the parent nucleotide analogue (PMEApp). Only one of them appeared as a weak inhibitor (IC50 = 403.0 ± 75.5 µM) and proved to be less effective than PMEApp (IC50 = 6.4 ± 0.8 µM). Conclusion PMEA diphosphoryl derivatives were designed as potential substrates and/or inhibitors of various viral polymerases. These modifications dramatically affect their ability to inhibit HIV-RT.


Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Inibidores da Transcriptase Reversa/farmacologia , Adenina/síntese química , Adenina/química , Adenina/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
9.
Nucleosides Nucleotides Nucleic Acids ; 37(2): 89-101, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29376769

RESUMO

The title compound is an excellent substrate for E. coli PNP, as well as for its D204N mutant. The main product of the synthetic reaction is N9-riboside, but some amount of N7-riboside is also present. Surprisingly, 1,N6-ethenoadenine is also ribosylated by both wild-type and mutated (N243D) forms of calf PNP, which catalyze the synthesis of a different riboside, tentatively identified as N6-ß-D-ribosyl-1,N6-ethenoadenine. All ribosides are susceptible to phosphorolysis by the E. coli PNP (wild type). All the ribosides are fluorescent and can be utilized as analytical probes.


Assuntos
Adenina/análogos & derivados , Proteínas de Escherichia coli/química , Nucleosídeos de Purina/síntese química , Purina-Núcleosídeo Fosforilase/química , Adenina/síntese química , Adenina/química , Biocatálise , Cinética , Estrutura Molecular , Mutação , Nucleosídeos de Purina/química , Espectrometria de Fluorescência
10.
Pharm Dev Technol ; 23(9): 890-899, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28535125

RESUMO

The objectives of this study were to prepare cocrystal composed of adefovir dipivoxil (AD) and stearic acid (SA) and to investigate the enhanced properties of the cocrystal. The cocrystal was prepared by antisolvent precipitation and characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), X-ray powder diffraction (XRPD), and differential scanning calorimetry (DSC). The enhanced properties were evaluated by dissolution testing, permeability studies, and powder rheology analysis. The AD raw material has a cuboid-like crystal and the cocrystal has a needle shape. In the FT-IR study, there were bathochromic shifts caused by the hydrogen bonding. The melting point of the cocrystal was 52.9 °C, which was lower than that of AD. The XRPD pattern also had distinct differences, supporting the formation of a new crystalline form. The cocrystal showed changes in the lattice energy and the solvation strength, which caused an enhanced dissolution. The permeability was increased due to the SA, which acts as a P-gp inhibitor. The tabletability was enhanced due to the altered crystal habit. In conclusion, cocrystal containing AD and SA was successfully prepared, presenting advantages such as enhanced solubility, tabletability, and permeability. The use of the cocrystal is a desirable approach for the improved physicochemical properties.


Assuntos
Adenina/análogos & derivados , Fenômenos Químicos , Química Farmacêutica/métodos , Organofosfonatos/síntese química , Ácidos Esteáricos/síntese química , Adenina/análise , Adenina/síntese química , Adenina/farmacocinética , Microscopia Eletrônica de Varredura/métodos , Organofosfonatos/análise , Organofosfonatos/farmacocinética , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Ácidos Esteáricos/análise , Ácidos Esteáricos/farmacocinética , Difração de Raios X/métodos
11.
Molecules ; 22(12)2017 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-29240697

RESUMO

The synthesis of four cymantrene-5-fluorouracil derivatives (1-4) and two cymantrene-adenine derivatives (5 and 6) is reported. All of the compounds were characterized by spectroscopic methods and the crystal structure of two derivatives (1 and 6), together with the previously described cymantrene-adenine compound C was determined by X-ray crystallography. While the compounds 1 and 6 crystallized in the triclinic P-1 space group, compound C crystallized in the monoclinic P21/m space group. The newly synthesized compounds 1-6 were tested together with the two previously described cymantrene derivatives B and C for their in vitro antiproliferative activity against seven cancer cell lines (MCF-7, MCF-7/DX, MDA-MB-231, SKOV-3, A549, HepG2m and U-87-MG), five bacterial strains Staphylococcus aureus (methicillin-sensitive, methicillin-resistant and vancomycin-intermediate strains), Staphylococcus epidermidis, and Escherichia coli, including clinical isolates of S. aureus and S. epidermidis, as well as against the protozoan parasite Trypanosoma brucei. The most cytotoxic compounds were derivatives 2 and C for A549 and SKOV-3 cancer cell lines, respectively, with 50% growth inhibition (IC50) values of about 7 µM. The anticancer activity of the cymantrene compounds was determined to be due to their ability to induce oxidative stress and to trigger apoptosis and autophagy in cancer cells. Three derivatives (1, 4 and 5) displayed promising antitrypanosomal activity, with GI50 values in the low micromolar range (3-4 µM). The introduction of the 5-fluorouracil moiety in 1 enhanced the trypanocidal activity when compared to the activity previously reported for the corresponding uracil derivative. The antibacterial activity of cymantrene compounds 1 and C was within the range of 8-64 µg/mL and seemed to be the result of induced cell shrinking.


Assuntos
Adenina/análogos & derivados , Adenina/síntese química , Antibacterianos/síntese química , Antineoplásicos/síntese química , Fluoruracila/análogos & derivados , Fluoruracila/síntese química , Compostos Organometálicos/síntese química , Tripanossomicidas/síntese química , Adenina/farmacologia , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Escherichia coli/efeitos dos fármacos , Fluoruracila/farmacologia , Humanos , Compostos Organometálicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus epidermidis/efeitos dos fármacos , Relação Estrutura-Atividade , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos
12.
Drug Des Devel Ther ; 11: 3197-3204, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29158666

RESUMO

Tenofovir alafenamide (TAF), a novel prodrug of tenofovir (TFV), has been approved for the treatment of chronic hepatitis B virus (HBV) infection. TAF has been shown to be a potent inhibitor of HBV replication at a low dose, with high intracellular concentration and more than 90% lower systemic TFV concentration than tenofovir disoproxil fumarate (TDF). In two randomized, double-blind, multinational, Phase 3, non-inferiority trials for hepatitis B e antigen (HBeAg)-positive and -negative patients (primary analysis: 48 weeks), TAF 25 mg orally once-daily was not inferior to TDF 300 mg in achieving an HBV DNA level <29 IU/mL at week 48. No amino-acid substitutions associated with viral breakthrough were detected by deep sequencing, and no resistance to TAF was found through week 96. In addition, no difference in the frequency of HBeAg or hepatitis B surface antigen loss was observed. However, TAF was associated with a significantly higher ALT normalization rate than was TDF, based on the American Association for the Study of Liver Diseases criteria (male: ALT ≤30 U/L and female: ALT ≤19 U/L). An analysis of renal safety showed that patients treated with TAF had a significantly lower decrease in the estimated glomerular filtration rate level than did patients treated with TDF. Similarly, the declines of hip and spine bone mineral density were significantly less in the TAF group. These trends of efficacy and renal/bone safety continued through week 96. Longer term follow-up and real-world data will be required to determine if the differences in viral/biochemical response and renal/bone safety seen with TAF in comparison with TDF are clinically relevant.


Assuntos
Adenina/análogos & derivados , Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Adenina/síntese química , Adenina/química , Adenina/uso terapêutico , Antivirais/síntese química , Antivirais/química , Ensaios Clínicos como Assunto , Humanos , Conformação Molecular
13.
Bioorg Med Chem ; 25(24): 6388-6397, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29111370

RESUMO

A combination of fluorophore and nucleobase through a π-conjugated rigid linker integrates the base pairing and the fluorescence change into a single event. Such base discriminating fluorophore can change its fluorescence as a direct response to the base pairing event and therefore have advantages over tethered labels or base surrogates lacking the hydrogen-bonding ability. 8-(Pyrene-1-yl)ethynyl-adenine (APyE) has been extensively used as fluorescence labels in DNA and LNA, but it showed little discrimination between different nucleobases. Herein we investigated the synthesis, base pairing ability and optical properties of APyE in pyrrolidinyl peptide nucleic acid - a DNA mimic that shows much stronger affinity and specificity towards DNA than natural oligonucleotides. The APyE in PNA pairs specifically with thymine in the DNA strand, and resulted in 1.5-5.2-fold enhanced and blue-shifted fluorescence emission. Fluorescence quenching was observed in the presence of mismatched base or abasic site directly opposite to the APyE. The behavior of APyE in acpcPNA is distinctively different from DNA whereby a fluorescence was increased selectively upon duplex formation with complementary DNA and therefore emphasizing the unique advantages of using PNA as alternative oligonucleotide probes. Applications as color-shifting probe for detection of trinucleotide repeats in DNA were demonstrated, and the performance of the probe was further improved by combination with reduced graphene oxide as an external nanoquencher.


Assuntos
Adenina/análogos & derivados , Fluorescência , Corantes Fluorescentes/química , Ácidos Nucleicos Peptídicos/química , Pirenos/química , Pirrolidinas/química , Adenina/síntese química , Adenina/química , Estrutura Molecular , Fenômenos Ópticos , Ácidos Nucleicos Peptídicos/síntese química , Pirenos/síntese química , Pirrolidinas/síntese química
14.
Chemphyschem ; 18(24): 3544-3547, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-29028154

RESUMO

Despite the fact that DNA bases have been well-studied on surface, the on-surface synthesis of one-dimensional DNA analogs through in situ reactions is still an interesting topic to be investigated. Herein, from the interplay of high-resolution scanning tunneling microscopy (STM) imaging and density functional theory (DFT) calculations, we have delicately designed a halogenated derivative of adenine as precursor to realize the combination of DNA bases and Ullmann reaction, and then successfully synthesized adenine oligomers on Au(111) via Ullmann coupling. This model system provides a possible bottom-up strategy of fabricating adenine oligomers on surface, which may further give access to man-made DNA strands with multiple bases.


Assuntos
Adenina/síntese química , Adenina/análogos & derivados , Adenina/química , Ouro/química , Microscopia de Tunelamento , Estrutura Molecular , Teoria Quântica , Propriedades de Superfície
15.
Bioorg Med Chem ; 25(20): 5799-5819, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28951094

RESUMO

A series of terminal nonyl chain and nucleobase modified analogues of (+)-EHNA (III) were synthesized and evaluated for their ability to inhibit adenosine deaminase (ADA). The constrained carbon analogues of (+)-EHNA, 7a-7h, 10a-c, 12, 13, 14 and 17a-c appeared very potent with Ki values in the low nanomolar range. Thio-analogues of (+)-EHNA 24a-e wherein 5'C of nonyl chain replaced by sulfur atom found to be less potent compared to (+)-EHNA. Docking of the representative compounds into the active site of ADA was performed to understand structure-activity relationships. Compounds 7a (Ki: 1.1nM) 7b (Ki: 5.2nM) and 26a (Ki: 5.9nM) showed suitable balance of potency, microsomal stability and demonstrated better pharmacokinetic properties as compared to (+)-EHNA and therefore may have therapeutic potential for various inflammatory diseases, hypertension and cancer.


Assuntos
Adenina/análogos & derivados , Inibidores de Adenosina Desaminase/química , Adenina/síntese química , Adenina/química , Adenina/farmacocinética , Adenina/farmacologia , Inibidores de Adenosina Desaminase/síntese química , Inibidores de Adenosina Desaminase/farmacocinética , Inibidores de Adenosina Desaminase/farmacologia , Domínio Catalítico , Ativação Enzimática/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
16.
J Med Chem ; 60(14): 6220-6238, 2017 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-28682067

RESUMO

Acyclic nucleosides containing a 3-fluoro-2-(phosphonomethoxy)propyl (FPMP) side chain are known to be moderately potent antihuman immunodeficiency virus (HIV) agents, while being completely devoid of antiviral activity against a wide range of DNA viruses. The derivatization of the phosphonic acid functionality of FPMPs with a diamyl aspartate phenoxyamidate group led to a novel generation of compounds that not only demonstrate drastically improved antiretroviral potency but also are characterized by an expanded spectrum of activity that also covers hepatitis B and herpes viruses. The best compound, the (S)-FPMPA amidate prodrug, exerts anti-HIV-1 activity in TZM-bl and peripheral blood mononuclear cells at low nanomolar concentrations and displays excellent potency against hepatitis B virus (HBV) and varicella-zoster virus (VZV). This prodrug is stable in acid and human plasma media, but it is efficiently processed in human liver microsomes with a half-life of 2 min. The (R) isomeric guanine derivative emerged as a selectively active anti-HIV and anti-HBV inhibitor, while being nontoxic to human hepatoblastoma cells. Notably, the pyrimidine containing prodrug (S)-Asp-FPMPC is the only congener within this series to demonstrate micromolar antihuman cytomegalovirus (HCMV) potency.


Assuntos
Adenina/análogos & derivados , Antivirais/química , Ácido Aspártico/química , Nucleosídeos/química , Organofosfonatos/química , Pró-Fármacos/química , Adenina/síntese química , Adenina/química , Adenina/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Antivirais/síntese química , Antivirais/farmacologia , Linhagem Celular , Citomegalovirus/efeitos dos fármacos , Farmacorresistência Viral , Estabilidade de Medicamentos , Ésteres/síntese química , Ésteres/química , Ésteres/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Herpesvirus Humano 3/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Microssomos Hepáticos/metabolismo , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Organofosfonatos/síntese química , Organofosfonatos/farmacologia , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
17.
J Nat Prod ; 80(7): 2136-2140, 2017 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-28665127

RESUMO

Discadenine (1), a self-spore germination inhibitor from the cellular slim mold Dictyostelium discoideum, is structurally related to the plant hormone cytokinin. This compound was synthesized from l-aspartic acid, and its activities were confirmed by three classical cytokinin bioassays as well as by using binding and activation assays with the Arabidopsis cytokinin receptors AHK3 and CRE1/AHK4.


Assuntos
Adenina/análogos & derivados , Arabidopsis/metabolismo , Dictyostelium/química , Adenina/síntese química , Adenina/química , Adenina/farmacologia , Ácido Aspártico/química , Citocininas/química , Citocininas/metabolismo , Estrutura Molecular , Estereoisomerismo
18.
Bioorg Med Chem ; 25(14): 3677-3684, 2017 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-28549889

RESUMO

Epigenetic regulation of gene expression via histone acetylation modulates many cellular processes, including apoptosis, the cell cycle, cell growth and differentiation, and inhibitors are promising drug candidates. We have previously developed inhibitors of BRD4, which recognizes acetylated lysine residue on histones and recruits transcription elongation factor to the transcription start site, while inhibitors of histone deacetylase (HDAC), which catalyzes the removal of acetyl groups on histones, are already in clinical use for cancer treatment. Based on the idea that polypharmacological agents with multiple targets would have a more robust action, we set out to develop dual BRD4/HDAC inhibitors. Here, we describe the design and synthesis of N6-[2-(7-hydroxyamino-7-oxoheptyloxy)benzoyl]adenine (5d) as a BRD4/HDAC dual inhibitor. This compound showed HL-60 cell growth-inhibitory and apoptosis-inducing activity, as well as all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation-enhancing activity, and c-MYC production-inhibitory activity. Interestingly, it also showed growth-inhibitory activity towards BRD4 inhibitor-resistant cells.


Assuntos
Inibidores de Histona Desacetilases/síntese química , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Acetilação , Adenina/síntese química , Adenina/química , Adenina/toxicidade , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/toxicidade , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/metabolismo , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo , Tretinoína/farmacologia
19.
Chemistry ; 23(28): 6706-6716, 2017 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-27960050

RESUMO

A description and history of the role that 8-oxo-7,8-dihydroadenine (8-oxoAde) and 8-oxo-7,8-dihydroadenosine (8-oxoA) have in various fields has been compiled. This Review focusses on 1) the formation of this oxidatively generated modification in RNA, its interactions with other biopolymers, and its potential role in the development/progression of disease; 2) the independent synthesis and incorporation of this modified nucleoside into oligonucleotides of RNA to display the progress that has been made in establishing its behavior in biologically relevant systems; 3) reported synthetic routes, which date back to 1890, along with the progress that has been made in the total synthesis of the nucleobase, nucleoside, and their corresponding derivatives; and 4) the isolation, total synthesis, and biological activity of natural products containing these moieties as the backbone. The current state of research regarding this oxidatively generated lesion as well as its importance in the context of RNA, natural products, and potential as drug derivatives is illustrated using all available examples reported to date.


Assuntos
Adenina/análogos & derivados , Adenosina/análogos & derivados , Produtos Biológicos/química , RNA/química , Adenina/síntese química , Adenina/química , Adenosina/síntese química , Adenosina/química , Produtos Biológicos/síntese química , Oxirredução , Nucleotídeos de Purina/química , Espectrofotometria
20.
Org Biomol Chem ; 14(40): 9519-9532, 2016 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-27722393

RESUMO

A new series of photoactivable NADPH mimics bearing one or two O-carboxymethyl groups on the adenosine moiety have been readily synthesized using click chemistry. These compounds display interesting one- or two-photon absorption properties. Their fluorescence emission wavelength and quantum yields (Φ) are dependent on the solvent polarity, with a red-shift in a more polar environment (λmax,em = 460-467 nm, Φ > 0.53 in DMSO, and λmax,em = 475-491 nm, Φ < 0.17 in Tris). These compounds show good binding affinity towards the constitutive nNOS and eNOS, confirming for the first time that the carboxymethyl group can be used as a surrogate of phosphate. Two-photon fluorescence imaging of nanotriggers in living cells showed that the presence of one carboxymethyl group (especially on the 3' position of the ribose) strongly favors the addressing of nanotriggers to eNOS in the cell context.


Assuntos
Adenina/síntese química , Adenina/metabolismo , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/metabolismo , Luz , NADP/metabolismo , Óxido Nítrico Sintase/metabolismo , Adenina/química , Materiais Biomiméticos/química , Química Click , Células HeLa , Humanos , Imagem Molecular
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