RESUMO
Synthesis of acyclic nucleosides bearing a furanyl scaffold is described. The approach involved the construction of the base moiety onto a dihydrofuranyl intermediate. While the A and C analogues did exhibit some substrate activity toward deoxycytidine kinase, the compounds were devoid of any significant anti-HIV activity.
Assuntos
Antivirais/síntese química , Furanos/química , HIV , Nucleosídeos/química , Nucleosídeos/síntese química , Humanos , Linfócitos T/metabolismo , Linfócitos T/virologiaRESUMO
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 , RNA Polimerase Dependente de RNA/antagonistas & inibidores , 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 , RNA Polimerase Dependente de RNA/química , Ribonucleosídeos/química , Ribose/química , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/químicaRESUMO
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-AtividadeRESUMO
Novel 3'-substituted isonucleoside analogs were designed on the basis of the similarities of their electrostatic potential with the active anti-HIV compound, (S,S)-isodideoxy-adenosine. The key synthetic step involved coupling between the dideoxygenated sugar derivatives, 10 and 14, and adenine under Mitsunobu conditions. Anti-HIV data are mentioned.
Assuntos
Didesoxiadenosina/análogos & derivados , Didesoxiadenosina/síntese química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Didesoxiadenosina/farmacologia , HIV-1/efeitos dos fármacos , Humanos , Modelos Químicos , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of optically pure 1,3-dioxolane nucleoside mimics was synthesized by a synthetic route that allowed incorporation of a 5R-methyl substituent from commercially available starting materials. The pyrrolo[2,3-d]pyrimidine heterocycle was chosen as a substitute for the purine derivative. Coupling of the pyrrolo[2,3-d]pyrimidine and the dioxolane was performed under solid-liquid phase transfer conditions. The ability to inhibit HCV RNA replication was assessed in a cell based subgenomic replicon assay. None of the described compounds displayed significant anti-HCV activity.
Assuntos
Antivirais/farmacologia , Dioxolanos/síntese química , Dioxolanos/farmacologia , Hepacivirus/fisiologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Dioxolanos/química , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Indicadores e Reagentes , Conformação Molecular , Estrutura Molecular , RNA Viral/efeitos dos fármacos , RNA Viral/genética , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
1,3-Dioxolane and 1,3-oxathiolane nucleoside analogs play an important role in anti-viral and anti-neoplastic chemotherapy. We report here the synthesis of 2-hydroxymethyl-5-methyl-1,3-dioxolanylpurine nucleosides from 4-acetoxy-2-(benzyloxymethyl)-5-methyldioxolane. Dioxolanes of alpha-D-, beta-D-, alpha-L-, and beta-L-configuration were prepared, that included 5-methyl derivatives of both 5R and 5S configuration. Molecular mechanics calculations indicate that the 5S and 5R diastereoisomeric 1,3-dioxolanes possess distinct conformational bias, suggesting that methyl substitution may alter the conformational preference of 1,3-dioxolanes. The ability of the 1,3-dioxolanes to inhibit HCV RNA replication was evaluated in a cell-based, subgenomic replicon assay. In addition, activity against vaccinia and HIV was evaluated in cell-based assays. The 2-hydroxymethyl-5-methyl-1,3-dioxolanes were found to be inactive.