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1.
Artigo em Inglês | MEDLINE | ID: mdl-15892257

RESUMO

3'-Azido-3',5-dideoxythymidine 5'-phosphonate and 3',5'-dideoxy-5'-difluoromethylenethymidine 5'-phosphonate were prepared by multistep syntheses. The nucleoside 5'-phosphonates were converted to their triphosphates and triphosphate mimics (P3Ms) containing beta,gamma-difluoromethylene, beta,gamma-dichloromethylene, or beta,gamma-imodo by condensation with pyrophosphate or pyrophosphate mimics, respectively. Inhibition of HIV-1 reverse transcriptase by the nucleoside P3Ms is briefly discussed.


Assuntos
Transcriptase Reversa do HIV/antagonistas & inibidores , Mimetismo Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Timidina/análogos & derivados , Nucleotídeos de Timina/síntese química , Zidovudina/análogos & derivados , Didesoxinucleotídeos , Estrutura Molecular , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade , Timidina/síntese química , Timidina/química , Timidina/farmacologia , Nucleotídeos de Timina/química , Nucleotídeos de Timina/farmacologia , Zidovudina/síntese química , Zidovudina/química , Zidovudina/farmacologia
2.
J Med Chem ; 48(7): 2695-700, 2005 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-15801860

RESUMO

The triphosphates of antiviral 2',3'-dideoxynucleosides (ddNs) are the active chemical species that inhibit viral DNA synthesis. The inhibition involves incorporation of ddNMP into DNA and subsequent chain termination. A conceivable strategy for antiviral drugs is to employ nucleoside 5'-triphosphate mimics that can entirely bypass cellular phosphorylation. AZT 5'-alpha-R(P)-borano-beta,gamma-(difluoromethylene)triphosphate (5'-alphaB-betagammaCF(2)TP) has been identified as a potent inhibitor of HIV-1 reverse transcriptase (HIV-1 RT). This work was aimed at confirming that 5'-alphaB-betagammaCF(2)TP is a useful generic triphosphate moiety and can render antiviral ddNs with potent inhibitory effects on HIV-1 RT. Thus, 10 ddNs were converted to their 5'-alphaB-betagammaCF(2)TPs via a sequence (one-pot) of reactions: formation of an activated phosphite, formation of a cyclic triphosphate, boronation, and hydrolysis. Other synthetic routes were also explored. All ddN 5'-alphaB-betagammaCF(2)TPs tested exhibited essentially the same level of inhibition of HIV-1 RT as the corresponding ddNTPs. A conclusion can be made that 5'-alphaB-betagammaCF(2)TP is a generic and promising triphosphate mimic (P3M) concerning HIV-1 RT inhibition and serum stability. It is anticipated that use of 5'-alphaB-betagammaCF(2)TP as P3M moiety will lead to the discovery of a new class of anti-HIV agents.


Assuntos
Fármacos Anti-HIV/síntese química , Compostos de Boro/síntese química , Desoxirribonucleotídeos/síntese química , Transcriptase Reversa do HIV/metabolismo , Inibidores da Transcriptase Reversa/síntese química , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/metabolismo , Compostos de Boro/química , Compostos de Boro/metabolismo , Bovinos , Desoxirribonucleotídeos/química , Desoxirribonucleotídeos/metabolismo , Técnicas In Vitro , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/metabolismo , Estereoisomerismo
3.
J Med Chem ; 48(4): 1199-210, 2005 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-15715486

RESUMO

Several triphosphates of modified nucleosides (1-6) were identified as inhibitors (IC(50) = 0.08-3.8 microM) of hepatitis C virus RNA-dependent RNA polymerase (RdRp). Although the initial SAR developed by determining the ability of the triphosphates to inhibit the in vitro activity of the HCV RdRp identified several potent inhibitors, none of the corresponding nucleosides exhibited significant inhibitory potency in a cell-based replicon assay. To improve upon the activity, bis(tBu-S-acyl-2-thioethyl) nucleoside 5'-monophosphate esters (7-12) were synthesized, and these derivatives exhibited improved potency compared to the corresponding nucleosides in the cell-based assay. Analysis of the intracellular metabolism demonstrated that the S-acyl-2-thioethyl (SATE) prodrug is metabolized to the 5'-triphosphate 40- to 155-fold more efficiently compared to the corresponding nucleoside. The prodrug approach involving bis(tBuSATE)cytidine 5'-monophosphate ester significantly reduced the deamination of cytidine derivatives by cellular deaminases. Additionally, chromosomal aberration studies with the SATE prodrug in cells showed no statistically relevant increase in aberrations compared to the concurrent controls.


Assuntos
Citidina Monofosfato/análogos & derivados , Citidina Monofosfato/síntese química , Citidina/análogos & derivados , Citidina/química , Hepacivirus/efeitos dos fármacos , Organofosfatos/síntese química , Pró-Fármacos/síntese química , Animais , Células CHO , Linhagem Celular Tumoral , Aberrações Cromossômicas/induzido quimicamente , Cricetinae , Cricetulus , Citidina Monofosfato/química , Citidina Monofosfato/farmacologia , Hepacivirus/genética , Humanos , Organofosfatos/química , Organofosfatos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , RNA Viral/antagonistas & inibidores , Trítio , Proteínas não Estruturais Virais/química , Replicação Viral/efeitos dos fármacos
4.
Nucleosides Nucleotides Nucleic Acids ; 24(10-12): 1651-64, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16438041

RESUMO

Nucleoside reverse transcriptase inhibitors (NRTIs) are prodrugs which require three intracellular phosphorylation steps to yield their corresponding, biologically active, nucleoside triphosphate. In order to circumvent this often inefficient phosphorylation cascade, a plausible approach is to provide the active species directly in the form of a stabilized nucleoside triphosphate mimic. We have previously shown that such a mimic, namely 5'-alpha-Rp-borano-beta,gamma-(difluoromethylene)triphosphate (5'-alphaBCF2TP) is a generic triphosphate mimic that is biologically stable and can render antiviral ddNs with potent inhibitory activity against HIV-1 RT. Herein we report the synthesis and activity against HIV-1 RT of several ddN 5'-alpha-modified-beta,gamma(difluoromethylene)triphosphate mimics with either a non-bridging calphaP-thio (5'-alphaSCF2TP) or alpha-P-seleno (5'-alpha SeCF2TP) modification. One compound, namely, AZT-5'-alpha-P-seleno-beta,gamma-(difluoromethylene)triphosphate (diastereomer I), was identified as a potent inhibitor of HIV-1 RT (Ki = 64 nM) and represents the first report of HIV-1 RT inhibition data for a nucleotide bearing an alpha-P-seleno modification. These triphosphate mimics may be useful in the investigation of enzyme mechanism and may have interesting properties with respect to drug resistance and polymerase selectivity.


Assuntos
Fármacos Anti-HIV/síntese química , Didesoxinucleosídeos/síntese química , Transcriptase Reversa do HIV/antagonistas & inibidores , Compostos Organosselênicos/síntese química , Inibidores da Transcriptase Reversa/síntese química , Sulfetos/síntese química , Fármacos Anti-HIV/química , Didesoxinucleosídeos/química , Transcriptase Reversa do HIV/química , Compostos Organosselênicos/química , Inibidores da Transcriptase Reversa/química , Sulfetos/química
5.
J Med Chem ; 47(27): 6902-13, 2004 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-15615539

RESUMO

In search of active nucleoside 5'-triphosphate mimics, we have synthesized a series of AZT triphosphate mimics (AZT P3Ms) and evaluated their inhibitory effects on HIV-1 reverse transcriptase as well as their stability in fetal calf serum and in CEM cell extracts. Reaction of AZT with 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one, followed by treatment of the phosphite intermediate 2 with pyrophosphate analogues, yielded the cyclic triphosphate intermediates 4b-4f, which were subjected to boronation and subsequent hydrolysis to give AZT 5'-alpha-borano-beta,gamma-bridge-modified triphosphates 6b-6f in moderate to good yields. Reaction of the cyclic intermediate 4d with iodine, followed by treatment with a series of nucleophiles, afforded the AZT 5'-beta,gamma-difluoromethylene-gamma-substituted triphosphates (7b-7i). Several different types of AZT P3Ms containing alpha-P-thio (or dithio) and beta,gamma-difluoromethylene (13,14), alpha,beta-difluoromethylene and gamma-P-methyl(or phenyl) (15,16), and alpha-borano-beta,gamma-difluoromethylene and gamma-O-methyl/phenyl (11,12) were also synthesized. The effectiveness of the compounds as inhibitors of HIV-1 reverse transcriptase was determined using a fluorometric assay and a poly(A) homopolymer as a template. A number of AZT P3Ms exhibited very potent inhibition of HIV-1 reverse transcriptase. Modifications at the beta,gamma-bridge of triphosphate rendered the AZT P3Ms 6b-6f with varied activities (K(i) from 9.5 to >>500 nM) while modification at the alpha,beta-bridge of triphosphate led to weak AZT P3M inhibitors. The results imply that the AZT P3Ms were substrate inhibitors, as is AZT triphosphate. The most active compound, AZT 5'-alpha-R(p)()-borano-beta,gamma-(difluoromethylene)triphosphate (AZT 5'-alphaB-betagammaCF(2)TP) (6d-I), is as potent as AZT triphosphate with a K(i)() value of 9.5 nM and at least 20-fold more stable than AZT triphosphate in the serum and cell extracts. Therefore, for the first time, a highly active and stable nucleoside triphosphate mimic has been identified, which is potentially useful as a new type of antiviral drug. The promising triphosphate mimic, 5'-alpha-borano-beta,gamma-(difluoromethylene)triphosphate, is expected to be valuable to the discovery of nucleotide mimic antiviral drugs.


Assuntos
Transcriptase Reversa do HIV/antagonistas & inibidores , Inibidores da Transcriptase Reversa/síntese química , Zidovudina/análogos & derivados , Estabilidade de Medicamentos , Humanos , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade
6.
J Med Chem ; 47(21): 5284-97, 2004 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-15456273

RESUMO

Hepatitis C virus infection constitutes a significant health problem in need of more effective therapies. We have recently identified 2'-C-methyladenosine and 2'-C-methylguanosine as potent nucleoside inhibitors of HCV RNA replication in vitro. However, both of these compounds suffered from significant limitations. 2'-C-Methyladenosine was found to be susceptible to enzymatic conversions by adenosine deaminase and purine nucleoside phosphorylase, and it displayed limited oral bioavailability in the rat. 2'-C-Methylguanosine, on the other hand, was neither efficiently taken up in cells nor phosphorylated well. As part of an attempt to address these limitations, we now report upon the synthesis and evaluation of a series of heterobase-modified 2'-C-methyl ribonucleosides. The structure-activity relationship within this series of nucleosides reveals 4-amino-7-(2-C-methyl-beta-d-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine and 4-amino-5-fluoro-7-(2-C-methyl-beta-d-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine as potent and noncytotoxic inhibitors of HCV RNA replication. Both 4-amino-7-(2-C-methyl-beta-d-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine and 4-amino-5-fluoro-7-(2-C-methyl-beta-d-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine display improved enzymatic stability profiles as compared to that of 2'-C-methyladenosine. Consistent with these observations, the most potent compound, 4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine ribonucleoside, is orally bioavailable in the rat. Together, the potency of the 2'-C-methyl-4-amino-pyrrolo[2,3-d]pyrimidine ribonucleosides and their improved pharmacokinetic properties relative to that of 2'-C-methyladenosine suggests that this class of compounds may have clinical utility.


Assuntos
Antivirais/síntese química , Hepacivirus/genética , RNA Viral/antagonistas & inibidores , Ribonucleosídeos/síntese química , Adenosina Desaminase/química , Administração Oral , Animais , Antivirais/química , Antivirais/farmacocinética , Disponibilidade Biológica , Linhagem Celular , Estabilidade de Medicamentos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Fosforilação , Purina-Núcleosídeo Fosforilase/química , RNA Viral/biossíntese , Ratos , Ribonucleosídeos/química , Ribonucleosídeos/farmacocinética , Relação Estrutura-Atividade
7.
J Med Chem ; 47(9): 2283-95, 2004 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-15084127

RESUMO

As part of a continued effort to identify inhibitors of hepatitis C viral (HCV) replication, we report here the synthesis and evaluation of a series of nucleoside analogues and their corresponding triphosphates. Nucleosides were evaluated for their ability to inhibit HCV RNA replication in a cell-based, subgenomic replicon system, while nucleoside triphosphates were evaluated for their ability to inhibit in vitro RNA synthesis mediated by the HCV RNA-dependent RNA polymerase, NS5B. 2'-C-Methyladenosine and 2'-C-methylguanosine were identified as potent inhibitors of HCV RNA replication, and the corresponding triphosphates were found to be potent inhibitors of HCV NS5B-mediated RNA synthesis. The data generated in the cell-based assay demonstrated a fairly stringent structure-activity relationship around the active nucleosides. Increase in steric bulk beyond methyl on C2, change in the stereo- or regiochemistry of the methyl substituent, or change of identity of the heterobase beyond that of the endogenous adenine or guanine was found to lead to loss of inhibitory activity. The results highlight the importance of the ribo configuration 2'- and 3'-hydroxy pharmacophores for inhibition of HCV RNA replication in the cell-based assay and demonstrate that inclusion of the 2'-C-methylribonucleoside pharmacophore leads to increased resistance to adenosine deaminase and purine nucleoside phosphorylase mediated metabolism.


Assuntos
Hepacivirus/química , Nucleosídeos de Purina/síntese química , Ribonucleosídeos/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Adenosina Desaminase/química , Ligação de Hidrogênio , Metilação , Conformação Molecular , Nucleosídeos de Purina/química , Purina-Núcleosídeo Fosforilase/química , Purinas/química , Ribonucleosídeos/química , Ribose/química , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/química
8.
Artigo em Inglês | MEDLINE | ID: mdl-15043157

RESUMO

IMPDH inhibitors have potential antimicrobial, anticancer and immunomodulatory effects. Nucleoside inhibitors of IMPDH exert their inhibitory effects via nucleoside 5'-MPs. Conversion of nucleoside analogs to NMPs by cellular nucleoside kinases is not assured, and usually is inefficient. In order to bypass cellular phosphorylation, a series of azole nucleoside 5'-MP mimics (P1Ms) based on ribavirin, EICAR and bredinin were synthesized and screened against human and C. albicans IMP dehydrogenises. P1Ms 8, 16, 25, 28 and 29 demonstrated substantial IMPDH inhibition with Ki values in low micromolar range.


Assuntos
Inibidores Enzimáticos/síntese química , IMP Desidrogenase/antagonistas & inibidores , Nucleotídeos/síntese química , Inibidores Enzimáticos/química , Nucleotídeos/química
9.
Org Lett ; 5(12): 2017-20, 2003 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-12790517

RESUMO

[structure: see text] Oligonucleotides with a novel, 2'-O-[2-[2-(N,N-dimethylamino)ethoxy]ethyl] (2'-O-DMAEOE) modification have been synthesized. This modification, a cationic analogue of the 2'-O-(2-methoxyethyl) (2'-O-MOE) modification, exhibits high binding affinity to target RNA (but not to DNA) and exceptional resistance to nuclease degradation. Analysis of the crystal structure of a self-complementary oligonucleotide containing a single 2'-O-DMAEOE modification explains the importance of charge factors and gauche effects on the observed antisense properties. 2'-O-DMAEOE modified oligonucleotides are ideal candidates for antisense drugs.


Assuntos
Etano/química , Éteres/química , Oligonucleotídeos Antissenso/química , Animais , Sequência de Bases , Estabilidade de Medicamentos , Etano/análogos & derivados , Modelos Moleculares , Conformação de Ácido Nucleico , Ácidos Nucleicos Heteroduplexes/química , Hibridização de Ácido Nucleico , Oligonucleotídeos Antissenso/metabolismo , Compostos Organofosforados/química , Compostos Organofosforados/metabolismo , Diester Fosfórico Hidrolases/metabolismo , RNA Complementar/metabolismo , Venenos de Serpentes/enzimologia , Espectrometria de Massas por Ionização por Electrospray , Eletricidade Estática , Estereoisomerismo , Relação Estrutura-Atividade
10.
Chem Rev ; 100(9): 3311-3340, 2000 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-11777426
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