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1.
Eur J Med Chem ; 193: 112233, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32199136

RESUMO

Antimicrobial peptides (AMP) with anticancer activity have drawn remarkable attention in modern treatments. However, long peptide length and protease instability are the most addressing factors, which hampers their further development as therapeutic agents. In view of this, herein, we designed and synthesized a series of AZT-based cationic small molecule incorporating a variety of hydrophobic groups and cationic charges, including amine and guanidine groups to mimic the amphipathic structure of AMPs. These compounds were evaluated for their antibacterial activity against Gram-positive and Gram-negative bacteria. Through an extensive structure activity relationship study (SAR), we identified ADG-2e as the most potent antibacterial agent, which exhibited remarkable potency against drug resistant bacterial strains such as MRSA and MDRPA. Further, ADG-2e was examined for their anti-metastatic ability by investigating the cancer cell migration and invasiveness through scratch wound-healing assay and transwell invasive assay, respectively. In addition, time-lapse cell tracking analysis also performed for analyzing the cell movement pattern. Treatment of ADG-2e against metastatic breast cancer cells (MDA-MB-231) suppressed tumor cell migration by multi-directional lamellipodium formation, indicating their anti-metastatic potential. Thus, our cationic AZT based small molecules may evolve as an appealing class of antibacterial agents with anti-metastasis potential.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Zidovudina/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Positivas/crescimento & desenvolvimento , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Cicatrização/efeitos dos fármacos , Zidovudina/síntese química , Zidovudina/química
2.
Colloids Surf B Biointerfaces ; 148: 385-391, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27636322

RESUMO

Anti-HIV prodrugs are recently focused on due to their ability of self-assembly, macrophage targeting, and enhanced antiviral effects. Here, an amphiphilic prodrug of zidovudine, an anti-HIV nucleoside analogue, 5'-cholesteryl-ethyl-phosphoryl zidovudine (CEPZ) was synthesized. CEPZ showed some unique physicochemical properties. The solubility of CEPZ in the noncompetitive solvents chloroform and tetrahydrofuran (THF) was very high based on the hydrogen bonds between zidovudine groups, though CEPZ was sparing soluble in alcohols and almost insoluble in water. The typical amphiphilic property of CEPZ was demonstrated according to the Langmuir monolayers at the air/water interface. The LogP of CEPZ was high to 13.78, indicating the high hydrophobicity of amphiphilic CEPZ similar to phospholipids. Homogenous and stable self-assemblies were formed with the mean size of 128.7nm and the zeta potential of -35.4mV after injecting the CEPZ-in-THF solution into water. Hydrophobic interaction between the cholesteryl moieties of CEPZ could drive molecular self-assembly and lead to the formation of spherical vesicles. CEPZ self-assemblies showed strong stability even under high temperature and gravity probably due to the high surface charge. CEPZ was very slowly degraded in neutral solutions (e.g., pH 7.4), but fast in acid solutions (e.g., pH 5.0) and some tissue homogenates. CEPZ was quickly eliminated from the circulation and distributed into the mononuclear phagocyte system (MPS) including the liver, spleen and lung after bolus intravenous administration of CEPZ self-assemblies to mice. The MPS targeting effect of CEPZ self-assemblies makes them become a promising self-assembled drug delivery system to eradicate the HIV hidden in the macrophages.


Assuntos
Fármacos Anti-HIV/química , Ésteres do Colesterol/química , Pró-Fármacos/química , Zidovudina/análogos & derivados , Zidovudina/química , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Linhagem Celular , Ésteres do Colesterol/síntese química , Ésteres do Colesterol/farmacocinética , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Macaca mulatta , Macrófagos/metabolismo , Masculino , Camundongos , Microscopia Eletrônica de Transmissão , Modelos Químicos , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Ratos Sprague-Dawley , Solubilidade , Solventes/química , Distribuição Tecidual , Zidovudina/síntese química , Zidovudina/farmacocinética
3.
Antivir Chem Chemother ; 24(2): 77-82, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26527820

RESUMO

BACKGROUND: Direct comparison of enzymatic and original blue cell-counting detections with the multinuclear activation of an indicator (MAGI) cells, so far, remains to be performed in parallel. Although inhibitors for reverse transcription solely inhibit the reverse transcription step, those for HIV-1 entry block syncytium formation of HIV-1-infected MAGI cells in addition to the entry (dual inhibition). It raises a concern that reduction of enzymatic activity is artificially influenced by syncytium-blocking activity of inhibitors for entry. METHODS: The MAGI cells with a syncytium inducible strain, HIV-1IIIB, were used for anti-HIV activity determination both with conventional counting with X-Gal staining and measurement of chlorophenol red ß-d-galactopyranoside conversion with a plate reader. RESULTS: Infectivity of HIV-1 in the MAGI cells was highly correlated with both methods. In microscopic observation, small blue cells with single or a couple of nuclei were dominantly observed in the presence of inhibitors for entry, but not in the presence of those for reverse transcription. Actual anti-HIV-1 activities were comparable or moderately sensitive in the chlorophenol red ß-d-galactopyranoside method. CONCLUSIONS: Antiviral activities of inhibitors for entry obtained from both enzymatic and counting methods appear to be comparable, even in infection of a highly syncytia inducible HIV-1IIIB strain.


Assuntos
Fármacos Anti-HIV/farmacologia , Benzoxazinas/farmacologia , Genes Reporter/genética , HIV-1/efeitos dos fármacos , Zidovudina/farmacologia , beta-Galactosidase/metabolismo , Alquinos , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Benzoxazinas/síntese química , Benzoxazinas/química , Ciclopropanos , Relação Dose-Resposta a Droga , HIV-1/genética , HIV-1/metabolismo , Células HeLa , Humanos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Zidovudina/síntese química , Zidovudina/química , beta-Galactosidase/análise , beta-Galactosidase/genética
4.
J Med Chem ; 58(8): 3329-39, 2015 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-25811955

RESUMO

In this article we present the synthesis, characterization, and in vitro biological and biochemical activities of new chalcogenozidovudine derivatives as antioxidant (inhibition of TBARS in brain membranes and thiol peroxidase-like activity) as well as antitumoral agents in bladder carcinoma 5637. A prominent response was obtained for the selected chalcogenonucleosides, showing effective antioxidant and antitumoral activities.


Assuntos
Antineoplásicos/química , Antioxidantes/química , Calcogênios/química , Neoplasias da Bexiga Urinária/tratamento farmacológico , Zidovudina/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Calcogênios/síntese química , Calcogênios/farmacologia , Humanos , Masculino , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Zidovudina/síntese química , Zidovudina/farmacologia
5.
J Pharm Sci ; 104(5): 1691-700, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25676038

RESUMO

A supercritical antisolvent (SAS) process for obtaining zidovudine-poly(L-lactic acid) (PLLA) solid dispersions (SDs) was used to attain a better intestinal permeation of this drug. A 3(2) factorial design was used, having as independent variables the ratio 3'-azido-2'3'-dideoxythymidine (AZT)-PLLA and temperature/pressure conditions, as dependent variables the process yield and particle macroscopic morphology. AZT-PLLA production batches were carried out by the SAS process, and the resulting products evaluated via scanning electron microscope, X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared analyses. From the nine possible combinations of tests performed experimentally, only one combination did not produced a solid. The L3 batch of SD, produced with 1:2 (AZT-PLLA) ratio, resulted in a 91.54% yield, with 40% AZT content. Intestinal permeability studies using the AZT-PLLA from L3 batch led to an AZT permeability of approximately 9.87%, which was higher than that of pure AZT (∼3.84%). AZT remained in crystalline form, whereas PLLA remained in semicrystalline form. AZT release is controlled by a diffusion mechanism. It has been demonstrated that it is possible to use PLLA carrier and SAS process to obtain SD, in a single step.


Assuntos
Cromatografia com Fluido Supercrítico/métodos , Absorção Intestinal/fisiologia , Ácido Láctico/síntese química , Solventes/química , Zidovudina/síntese química , Animais , Absorção Intestinal/efeitos dos fármacos , Ácido Láctico/farmacocinética , Masculino , Permeabilidade/efeitos dos fármacos , Ratos , Ratos Wistar , Zidovudina/farmacocinética
6.
Bioorg Med Chem ; 23(24): 7521-8, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26775541

RESUMO

Novel 3-hydroxy-3-phenylpropanoate ester-azidothymidine (AZT) conjugates have been prepared using Baylis-Hillman methodology, and their potential as dual-action HIV-1 Integrase and Reverse Transcriptase inhibitors has been explored using enzyme inhibition and computer modelling techniques; their activity and HeLa cell toxicity have been compared with those of their cinnamate ester analogues.


Assuntos
Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Zidovudina/química , Zidovudina/farmacologia , Fármacos Anti-HIV , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/síntese química , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Inibidores da Transcriptase Reversa/síntese química , Relação Estrutura-Atividade , Zidovudina/síntese química
7.
Bioorg Med Chem Lett ; 24(22): 5190-4, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25442310

RESUMO

Betulinic acid and analogous naturally occurring triterpenoid acids were transformed into the corresponding propargyl esters and subsequently deployed as substrates for a click chemistry-mediated coupling with azidothymidine (AZT) en route to novel 1,2,3-triazole-tethered triterpenoid-AZT conjugates. Twelve new hybrids were thus prepared and assessed in terms of their cytotoxic activity, revealing an interesting anticancer activity of five triterpenoid-AZT hybrids on KB and Hep-G2 tumor cell lines.


Assuntos
Citotoxinas/síntese química , Extratos Vegetais/síntese química , Triazóis/síntese química , Triterpenos/síntese química , Zidovudina/síntese química , Araliaceae , Citotoxinas/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Eleutherococcus , Ésteres , Células Hep G2 , Humanos , Extratos Vegetais/farmacologia , Triazóis/farmacologia , Triterpenos/farmacologia , Zidovudina/farmacologia
8.
J Labelled Comp Radiopharm ; 57(10): 621-4, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25156931

RESUMO

Previously unreported (15) N labeled Azidothymidine (AZT) was prepared as an equimolar mixture of two isotopomers: 1-(15) N-AZT and 3-(15) N-AZT. Polarization decay of (15) N NMR signal was studied in high (9.4 T) and low (~50 mT) magnetic fields. (15) N T1 values were 45 ± 5 s (1-(15) N-AZT) and 37 ± 2 s (3-(15) N-AZT) at 9.4 T, and 140 ± 16 s (3-(15) N-AZT) at 50 mT. (15) N-AZT can be potentially (15) N hyperpolarized by several methods. These sufficiently long (15) N-AZT T1 values potentially enable hyperpolarized in vivo imaging of (15) N-AZT, because of the known favorable efficient (i.e., of the time scale shorter than the longest reported here (15) N T1 ) kinetics of uptake of injected AZT. Therefore, 3-(15) N-AZT can be potentially used for HIV molecular imaging using hyperpolarized magnetic resonance imaging.


Assuntos
Fármacos Anti-HIV/síntese química , Compostos Radiofarmacêuticos/síntese química , Zidovudina/síntese química , Fármacos Anti-HIV/química , Radioisótopos de Nitrogênio/química , Compostos Radiofarmacêuticos/química , Zidovudina/química
9.
J Labelled Comp Radiopharm ; 57(8): 540-9, 2014 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-24992010

RESUMO

The nucleosides zidovudine (AZT), stavudine (d4T), and telbivudine (LdT) are approved for use in the treatment of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections. To promote positron emission tomography (PET) imaging studies on their pharmacokinetics, pharmacodynamics, and applications in cancer diagnosis, a convenient one-pot method for Pd(0)-Cu(I) co-mediated rapid C-C coupling of [(11)C]methyl iodide with stannyl precursor was successfully established and applied to synthesize the PET tracers [(11)C]zidovudine, [(11)C]stavudine, and [(11)C]telbivudine. After HPLC purification and radiopharmaceutical formulation, the desired PET tracers were obtained with high radioactivity (6.4-7.0 GBq) and specific radioactivity (74-147 GBq/µmol) and with high chemical (>99%) and radiochemical (>99.5%) purities. This one-pot Pd(0)-Cu(I) co-mediated rapid C-[(11)C]methylation also worked well for syntheses of [methyl-(11)C]thymidine and [methyl-(11)C]4'-thiothymidine, resulting twice the radioactivity of those prepared by a previous two-pot method. The mechanism of one-pot Pd(0)-Cu(I) co-mediated rapid C-[(11)C]methylation was also discussed.


Assuntos
Compostos Radiofarmacêuticos/síntese química , Zidovudina/síntese química , Radioisótopos de Carbono/química , Catálise , Técnicas de Química Sintética/métodos , Cobre/química , Metilação , Paládio/química , Zidovudina/análogos & derivados
11.
J Med Chem ; 56(21): 8765-80, 2013 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-24102161

RESUMO

3'-Azidothymidine (AZT) was the first approved antiviral for the treatment of human immunodeficiency virus (HIV). Reported efforts in clicking the 3'-azido group of AZT have not yielded 1,2,3-triazoles active against HIV or any other viruses. We report herein the first AZT-derived 1,2,3-triazoles with submicromolar potencies against HIV-1. The observed antiviral activities from the cytopathic effect (CPE) based assay were confirmed through a single replication cycle assay. Structure-activity-relationship (SAR) studies revealed two structural features key to antiviral activity: a bulky aromatic ring and the 1,5-substitution pattern on the triazole. Biochemical analysis of the corresponding triphosphates showed lower ATP-mediated nucleotide excision efficiency compared to AZT, which along with molecular modeling suggests a mechanism of preferred translocation of triazoles into the P-site of HIV reverse transcriptase (RT). This mechanism is corroborated with the observed reduction of fold resistance of the triazole analogue to an AZT-resistant HIV variant (9-fold compared to 56-fold with AZT).


Assuntos
Fármacos Anti-HIV/farmacologia , HIV/efeitos dos fármacos , Zidovudina/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Relação Estrutura-Atividade , Zidovudina/síntese química , Zidovudina/química
13.
Bioorg Khim ; 39(2): 184-93, 2013.
Artigo em Russo | MEDLINE | ID: mdl-23964518

RESUMO

One of the approaches to enhance bioavailability of nucleoside reverse transcriptase HIV inhibitors consists in design of their prodrugs based on 1,3-diacylglycerols, which may simulate nature lipids metabolic pathways promoting the improvement of drug delivery to the target cells. Glycerolipidic AZT conjugates with different functional phosphoric centers were synthesized by H-phosphonate technique in the present work. Study of prepared prodrugs sensibility to the chemical and enzymatic hydrolysis (in buffer solution and under the influence of pancreatic lipase) and also study of their anti-HIV activity on the T-lymphoid human MT-4 cells in regarding to virus HIV-1(899A) strain were carried out.


Assuntos
Fármacos Anti-HIV/síntese química , HIV-1/efeitos dos fármacos , Zidovudina/síntese química , Zidovudina/farmacologia , Fármacos Anti-HIV/química , Técnicas de Cultura de Células , Sistemas de Liberação de Medicamentos , Infecções por HIV/tratamento farmacológico , Humanos , Fósforo/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Zidovudina/análogos & derivados
15.
Bioorg Med Chem ; 21(7): 1964-71, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23415084

RESUMO

Baylis-Hillman-derived 3-(benzylaminomethyl)coumarins have been treated, sequentially, with chloroacetyl chloride and propargylamine to afford alkynylated coumarins as substrates for Click Chemistry reactions with azidothymidine (AZT) in the presence of a Cu(I) catalyst. The dual-action HIV-1 protease (PR) and reverse transcriptase (RT) inhibition potential of the resulting N-benzylated cycloaddition products, and a series of non-benzylated analogues, has been explored using saturation transfer difference (STD) NMR, computer modelling and enzyme inhibition techniques.


Assuntos
Cumarínicos/química , Cumarínicos/farmacologia , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/enzimologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Cumarínicos/síntese química , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Protease de HIV/metabolismo , Inibidores da Protease de HIV/síntese química , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , Humanos , Modelos Moleculares , Inibidores da Transcriptase Reversa/síntese química , Zidovudina/síntese química , Zidovudina/química , Zidovudina/farmacologia
16.
ACS Comb Sci ; 14(2): 108-14, 2012 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-22263689

RESUMO

The oligopeptide transporter PEPT1 is considered as a valuable target for prodrug design, but its 3D structure and substrate specificity of PEPT1 are not fully understood. In this study, we designed a focused dipeptide conjugated azidothymidine (AZT) library and described a convenient and efficient solid phase synthesis scheme based on click chemistry. Over 60 candidate structures containing various dipeptide sequences were obtained with high purity, and screened in a PEPT1 overexpressing cell model for their abilities to compete with the known ligand cephalexin. Some of the compounds selected to have medium or high affinity were tested for their in vivo transport in a single-pass intestinal perfusion experiment. Results showed that the designed library contained some new structure features that have high affinities toward PEPT1 and could be further explored for their application in prodrug design and development.


Assuntos
Antimetabólitos/química , Dipeptídeos/química , Dipeptídeos/metabolismo , Simportadores/metabolismo , Zidovudina/química , Antimetabólitos/síntese química , Antimetabólitos/metabolismo , Dipeptídeos/síntese química , Células HeLa , Humanos , Transportador 1 de Peptídeos , Técnicas de Síntese em Fase Sólida , Zidovudina/síntese química , Zidovudina/metabolismo
17.
Yao Xue Xue Bao ; 46(8): 1015-8, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22007530

RESUMO

In this research, phosphate and thiophosphate prodrugs 3a, 3b of anti-HIV agent AZT were synthesized, and their anti-HIV activities and cytotoxicities were investigated in vitro. Results showed that the prodrugs 3a and 3b with an IC50 value of 11.0 and 4.0 micromol x L(-1), respectively, were less toxic than AZT (1.0 micromol x L(-1)). Although the EC50 values of both 3a (0.04 micromol x (L(-1) and 3b (0.16 micromol x L(-1)) were lower than that of AZT (0.01 micromol x L(-1)), the therapeutic index (IC50/EC50) of prodrug 3a (275) was much higher than that of both AZT (100) and prodrug 3b (25). This indicated that the prodrug 3a merited further investigation as an anti-HIV agent.


Assuntos
Fármacos Anti-HIV/síntese química , Pró-Fármacos/síntese química , Zidovudina/análogos & derivados , Zidovudina/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Linfócitos T CD4-Positivos/citologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Humanos , Concentração Inibidora 50 , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Zidovudina/química , Zidovudina/farmacologia
18.
Bioorg Med Chem ; 19(21): 6375-82, 2011 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-21945463

RESUMO

A series of novel N-alkyl 5'-chloromethylphosphonates of 3'-azido-3'-deoxythymidine (6-15) was synthesized by means of phosphonylation of 3'-azido-3'-deoxythymidine (4) with P-chloromethylphosphonic ditriazolide (3) followed by a reaction with the appropriate amine. The synthesized phosphonamidates 6-15 were evaluated for their cytotoxic activity in two human cancer cell lines: oral (KB) and breast (MCF-7) using the sulforhodamine B (SRB) assay. The highest activity in KB human cancer cells was displayed by phosphonamidate 8 (IC(50)=5.8 µg/mL), however, this compound was less potent than the parent AZT (IC(50)=3.1 µg/mL). Phosphonamidate 10 showed only moderate activity (IC(50)=12.1 µg/mL) whereas the other phosphonamidates proved inactive. Similarly, the highest activity in MCF-7 human cancer cells was displayed by phosphonamidate 8 (IC(50)=3.7 µg/mL) but it proved somewhat less active than AZT (IC(50)=2.6 µg/mL). Some activity was also displayed by phosphonamidate 10 (IC(50)=12.8 µg/mL) but the other phosphonamidates were found inactive. Hydrolysis studies indicate that the synthesized phosphonamidates are likely to act as prodrugs of the parent nucleoside (AZT). Transport measurements showed that the most active phosphonamidates (8 and 10) were able to permeate across the intestinal epithelium in vitro. The apparent permeability coefficients determined in Caco-2 cell monolayers indicated that these compounds could be moderately absorbed in humans.


Assuntos
Antineoplásicos/síntese química , Neoplasias da Mama/tratamento farmacológico , Neoplasias Bucais/tratamento farmacológico , Organofosfonatos/síntese química , Pró-Fármacos/síntese química , Zidovudina/análogos & derivados , Antineoplásicos/química , Antineoplásicos/farmacologia , Transporte Biológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Organofosfonatos/química , Organofosfonatos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Ultravioleta , Relação Estrutura-Atividade , Zidovudina/síntese química , Zidovudina/química , Zidovudina/farmacologia
19.
Chemistry ; 17(5): 1649-59, 2011 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-21268168

RESUMO

A diastereoselective synthesis of cycloSal-phosphotriesters (cycloSal=cycloSaligenyl) based on chiral auxiliaries has been developed that allows the synthesis of single diastereomers of the cycloSal-pronucleotides. In previously described synthesis routes, the cycloSal-compounds were always obtained as 1:1 diastereomeric mixtures that could be separated in only rare cases. However, it was shown that the diastereomers have different antiviral activity, toxicity, and hydrolysis stabilities. Here, first a chiral thiazoline derivative was used to prepare nonsubstituted and 5-methyl-cycloSal-phosphotriesters in 48 and ≥95% de (de=diastereomeric excess). However, this approach failed to give the important group of 3-substituted cycloSal-nucleotides. Therefore, two other chiral groups were discovered that allowed the synthesis of (R(P))- and (S(P))-3-methyl-cycloSal-phosphotriesters as well. The antiviral activity was found to be five- to 20-fold different between the two individual diastereomers, which proved the importance of this approach.


Assuntos
Fármacos Anti-HIV/síntese química , Didesoxinucleotídeos/síntese química , Nucleotídeos/síntese química , Organofosfatos/síntese química , Estavudina/síntese química , Zidovudina/análogos & derivados , Fármacos Anti-HIV/farmacocinética , Didesoxinucleotídeos/química , Didesoxinucleotídeos/farmacocinética , Humanos , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , Nucleotídeos/química , Nucleotídeos/farmacocinética , Organofosfatos/química , Organofosfatos/farmacocinética , Estavudina/química , Estavudina/farmacocinética , Estereoisomerismo , Relação Estrutura-Atividade , Zidovudina/síntese química , Zidovudina/química , Zidovudina/farmacocinética
20.
J Org Chem ; 76(1): 105-26, 2011 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-21121618

RESUMO

Rhodium catalyzed O-H insertion reactions employing α-diazophosphonate 20 with appropriately protected thymidine, uridine, cytosine, adenosine and guanosine derivatives leads to novel 5'-phosphononucleoside derivatives. Deprotection led to a novel series of phosphono derivatives bearing a carboxylic acid moiety adjacent to the phosphonate group with potential antiviral and/or anticancer activity. The phosphononucleosides bearing an α-carboxylic acid group are envisaged as potential diphosphate mimics. Conversion to mono- and diphosphorylated phosphononucleosides has been effected for evaluation as nucleoside triphosphate mimics. Most of the novel phosphononucleosides proved to be inactive against a variety of DNA and RNA viruses. Only the phosphono AZT derivatives 56-59 showed weak activity against HIV-1 and HIV-2.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , HIV-1/química , Nucleotídeos/síntese química , Nucleotídeos/farmacologia , Zidovudina/síntese química , Antivirais/química , Catálise , HIV-1/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Nucleotídeos/química , Organofosfonatos/química , Fosforilação , Ródio/química , Zidovudina/química
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