RESUMEN
A simple modular tandem approach to multiply substituted cyclopentane derivatives is reported, which succeeds by joining organometallic addition, conjugate addition, radical cyclization, and oxygenation steps. The key steps enabling this tandem process are the thus far rarely used isomerization of allylic alkoxides to enolates and single-electron transfer to merge the organometallic step with the radical and oxygenation chemistry. This controlled lineup of multiple electronically contrasting reactive intermediates provides versatile access to highly functionalized cyclopentane derivatives from very simple and readily available commodity precursors. The antiviral activity of the synthesized compounds was screened and a number of compounds showed potent activity against hepatitisâ C and dengue viruses.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Ciclopentanos/química , Ciclopentanos/farmacología , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Antivirales/síntesis química , Catálisis , Ciclopentanos/síntesis química , Dengue/tratamiento farmacológico , Virus del Dengue/efectos de los fármacos , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Humanos , Isomerismo , Modelos Moleculares , Compuestos Organometálicos/síntesis química , Elementos de Transición/químicaRESUMEN
Two series of new 4-aminopyrimido[4,5-b]indole ribonucleosides bearing phenyl or hetaryl group at position 5 or 6 have been prepared by Suzuki or Stille cross-coupling reactions employing X-Phos ligand with (het)arylboronic acids or stannanes. A series of 4-substituted nucleosides has been also prepared by Pd-catalyzed cross-couplings or nucleophilic substitution. Some of these compounds displayed moderate antiviral activities against HCV and dengue viruses.
Asunto(s)
Adenosina/análogos & derivados , Antivirales/síntesis química , Indoles/química , Ribonucleósidos/química , Antivirales/farmacología , Antivirales/toxicidad , Catálisis , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Virus del Dengue/efectos de los fármacos , Células HL-60 , Células HeLa , Células Hep G2 , Hepacivirus/efectos de los fármacos , Humanos , Paladio/química , Ribonucleósidos/farmacología , Ribonucleósidos/toxicidadRESUMEN
A series of novel sugar-modified derivatives of cytostatic 7-hetaryl-7-deazaadenosines (2'-C-methylribonucleosides, 2'-deoxy-2'-fluoroarabinonucleosides, arabinonucleosides and 2'-deoxyribonucleosides) was prepared and screened for biological activity. The synthesis consisted of preparation of the corresponding sugar-modified 7-iodo-7-deazaadenine nucleosides and their aqueous-phase Suzuki-Miyaura cross-coupling reactions with (het)arylboronic acids or Stille couplings with hetarylstannanes in DMF. The synthesis of 7-iodo-7-deazaadenine nucleosides was based on a glycosidation of 6-chloro-7-iodo-7-deazapurine with a suitable sugar synthon or on an interconversion of 2'-OH stereocenter (for arabinonucleosides). Several examples of 2'-C-Me-ribonucleosides showed moderate anti-HCV activities in a replicon assay accompanied by cytotoxicity. Several 7-hetaryl-7-deazaadenine fluoroarabino- and arabinonucleosides exerted moderate micromolar cytostatic effects. The most active was 7-ethynyl-7-deazaadenine fluoroarabinonucleoside which showed submicromolar antiproliferative activity. However, all the sugar-modified derivatives were less active than the parent ribonucleosides.
Asunto(s)
Antineoplásicos/farmacología , Antivirales/farmacología , Arabinonucleósidos/farmacología , Carbohidratos/química , Desoxirribonucleósidos/farmacología , Hepacivirus/efectos de los fármacos , Antineoplásicos/síntesis química , Antineoplásicos/química , Antivirales/síntesis química , Antivirales/química , Arabinonucleósidos/síntesis química , Arabinonucleósidos/química , Desoxirribonucleósidos/síntesis química , Desoxirribonucleósidos/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HL-60 , Células HeLa , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
Treatment of patients infected with hepatitis C virus (HCV) with direct acting antivirals can lead to the emergence of drug-resistant variants that may pose a long-term threat to viral eradication. HCV replicons have been used to select resistance mutations; however, genotype 2a JFH-1-based viruses provide the opportunity to perform resistance selection in a bona fide infection system. In this study, we used a tissue culture-adapted J6/JFH-1 virus to select resistance to the NS3 protease inhibitors BILN-2061 and VX-950. Lunet-CD81 cells were infected with J6/JFH-1 virus and maintained in the presence of inhibitors until high-titer viral supernatant was produced. Viral supernatants were passaged over naive cells at escalating drug concentrations, and the resulting viruses were then characterized. Three NS3 resistance mutations were identified in BILN-2061-resistant viruses: A156G, D168A, and D168V. Interestingly, D168A, D168V, and A156T/V, but not A156G, were selected in parallel using a genotype 2a replicon. For VX-950, the T54A and A156S NS3 resistance mutations were identified in the virus selections, whereas only A156T/V emerged in genotype 2a replicon selections. Of note, VX-950 resistance mutations selected using the 2a virus (T54A and A156S) were also observed during VX-950 clinical studies in genotype 2 patients. We also performed viral fitness evaluations and determined that the mutations selected in the viral system did not confer marked reductions in virus production kinetics or peak titers. Overall, the HCV infection system is an efficient tool for drug resistance selections and has advantages for the rapid identification and characterization of clinically relevant resistance mutations.
Asunto(s)
Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Inhibidores de Proteasas/farmacología , Línea Celular , Farmacorresistencia Viral/genética , Humanos , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
GS-9190 (Tegobuvir) is a novel imidazopyridine inhibitor of hepatitis C virus (HCV) RNA replication in vitro and has demonstrated potent antiviral activity in patients chronically infected with genotype 1 (GT1) HCV. GS-9190 exhibits reduced activity against GT2a (JFH1) subgenomic replicons and GT2a (J6/JFH1) infectious virus, suggesting that the compound's mechanism of action involves a genotype-specific viral component. To further investigate the GS-9190 mechanism of action, we utilized the susceptibility differences between GT1b and GT2a by constructing a series of replicon chimeras where combinations of 1b and 2a nonstructural proteins were encoded within the same replicon. The antiviral activities of GS-9190 against the chimeric replicons were reduced to levels comparable to that of the wild-type GT2a replicon in chimeras expressing GT2a NS5B. GT1b replicons in which the ß-hairpin region (amino acids 435 to 455) was replaced by the corresponding sequence of GT2a were markedly less susceptible to GS-9190, indicating the importance of the thumb subdomain of the polymerase in this effect. Resistance selection in GT1b replicon cells identified several mutations in NS5B (C316Y, Y448H, Y452H, and C445F) that contributed to the drug resistance phenotype. Reintroduction of these mutations into wild-type replicons conferred resistance to GS-9190, with the number of NS5B mutations correlating with the degree of resistance. Analysis of GS-9190 cross-resistance against previously reported NS5B drug-selected mutations showed that the resistance pattern of GS-9190 is different from other nonnucleoside inhibitors. Collectively, these data demonstrate that GS-9190 represents a novel class of nonnucleoside polymerase inhibitors that interact with NS5B likely through involvement of the ß-hairpin in the thumb subdomain.
Asunto(s)
Antivirales/farmacología , Inhibidores Enzimáticos/farmacología , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Purinas/farmacología , Piridazinas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/genética , Antivirales/química , Línea Celular , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Mutación , Plásmidos/genética , Purinas/química , Piridazinas/químicaRESUMEN
There is an urgent need for the development of novel antimicrobial agents that offer effective treatment against MRSA. Using a new class of dipeptide antibiotic TAN-1057A/B as lead, we designed, synthesized and evaluated analogs of TAN-1057A/B. Several novel dihydropyrimidinone antibiotics demonstrating comparable antibiotic efficacy while possessing favorable selectivity were identified.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
A series of sugar-modified derivatives of cytostatic 7-heteroaryl-7-deazaadenosines (2'-deoxy-2'-fluororibo- and 2'-deoxy-2',2'-difluororibonucleosides) bearing an aryl or heteroaryl group at positionâ 7 was prepared and screened for biological activity. The difluororibonucleosides were prepared by non- stereoselective glycosidation of 6-chloro-7-deazapurine with benzoyl-protected 2-deoxy-2,2-difluoro-D-erythro-pentofuranosyl-1-mesylate, followed by amination and aqueous Suzuki cross-couplings with (het)arylboronic acids. The fluororibo derivatives were prepared by aqueous palladium-catalyzed cross-coupling reactions of the corresponding 7-iodo-7-deazaadenine 2'-deoxy-2'-fluororibonucleoside 20 with (het)arylboronic acids. The key intermediate 20 was prepared by a six-step sequence from the corresponding arabinonucleoside by selective protection of 3'- and 5'-hydroxy groups with acid-labile groups, followed by stereoselective SN 2 fluorination and deprotection. Some of the title nucleosides and 7-iodo-7-deazaadenine intermediates showed micromolar cytostatic or anti-HCV activity. The most active were 7-iodo and 7-ethynyl derivatives. The corresponding 2'-deoxy-2',2'-difluororibonucleoside 5'-O-triphosphates were found to be good substrates for bacterial DNA polymerases, but are inhibitors of human polymeraseâ α.
Asunto(s)
Adenina/química , Antineoplásicos/farmacología , Antivirales/farmacología , Citostáticos/farmacología , Hepacivirus/efectos de los fármacos , Ribonucleósidos/farmacología , Adenina/análogos & derivados , Antineoplásicos/síntesis química , Antineoplásicos/química , Antivirales/síntesis química , Antivirales/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Citostáticos/síntesis química , Citostáticos/química , ADN Polimerasa Dirigida por ADN/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HL-60 , Células HeLa , Células Hep G2 , Hepacivirus/genética , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Inhibidores de la Síntesis del Ácido Nucleico , Ribonucleósidos/síntesis química , Ribonucleósidos/química , Relación Estructura-ActividadRESUMEN
A novel and efficient method for the one-pot synthesis of diamide (bis-amidate) prodrugs of acyclic nucleoside phosphonates, starting from free phosphonic acids or phosphonate diesters is reported. The approach from phosphonate diesters via their bis(trimethylsilyl) esters is highly convenient, eliminates isolation and tedious purification of the phosphonic acids, and affords the corresponding bis-amidates in excellent yields (83-98%) and purity. The methodology has been applied to the synthesis of the potent anticancer agent GS-9219, and symmetrical bis-amidates of other biologically active phosphonic acids. Anti-HIV, antiproliferative, and immunomodulatory activities of the compounds are discussed including the bis-amidate prodrugs 14 and 17 that exhibited anti-HIV activity at submicromolar concentrations with minimal cytotoxicity.
Asunto(s)
Diamida/síntesis química , Diamida/farmacología , Nucleósidos/química , Organofosfonatos/química , Profármacos/síntesis química , Profármacos/farmacología , Adyuvantes Inmunológicos/síntesis química , Adyuvantes Inmunológicos/química , Adyuvantes Inmunológicos/farmacología , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Línea Celular , Proliferación Celular/efectos de los fármacos , Diamida/química , Evaluación Preclínica de Medicamentos , Humanos , Espectroscopía de Resonancia Magnética , Ratones , Ratones Endogámicos C57BL , Profármacos/química , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
A novel series of HCV replication inhibitors based on a pyrido[3,2-d]pyrimidine core were optimized for pharmacokinetics (PK) in rats. Several associations between physicochemical properties and PK were identified and exploited to guide the design of compounds. In addition, a simple new metric that may aid in the prediction of bioavailability for compounds with higher polar surface area is described (3*HBD-cLogP).
RESUMEN
Bacterial protein synthesis is the target for several classes of established antibiotics. This report describes the characterization of a novel translation inhibitor produced by the soil bacterium Flexibacter. The dipeptide antibiotic TAN1057 A/B was synthesized and designated GS7128. As reported previously, TAN1057 inhibits protein synthesis in both Escherichia coli and Staphylococcus aureus, leaving transcription unaffected. Cell-free translation systems from E. coli were used to further dissect the mechanism of translational inhibition. Binding of mRNA to ribosomes was unaffected by the drug, whereas the initiation reaction was reduced. Elongation of translation was completely inhibited by GS7128. Detailed analysis showed that the peptidyl transferase reaction was strongly inhibited, whereas tRNA binding to both A- and P-site was unaffected. Selection and analysis of drug-resistant mutants of S. aureus suggests that drug uptake may be mediated by a dipeptide transport mechanism.