RESUMEN
A series of 7-deazaadenine ribonucleosides bearing alkyl, alkenyl, alkynyl, aryl, or hetaryl groups at position 7 as well as their 5'-O-triphosphates and two types of monophosphate prodrugs (phosphoramidates and S-acylthioethanol esters) were prepared and tested for antiviral activity against selected RNA viruses (Dengue, Zika, tick-borne encephalitis, West Nile, and SARS-CoV-2). The modified triphosphates inhibited the viral RNA-dependent RNA polymerases at micromolar concentrations through the incorporation of the modified nucleotide and stopping a further extension of the RNA chain. 7-Deazaadenosine nucleosides bearing ethynyl or small hetaryl groups at position 7 showed (sub)micromolar antiviral activities but significant cytotoxicity, whereas the nucleosides bearing bulkier heterocycles were still active but less toxic. Unexpectedly, the monophosphate prodrugs were similarly or less active than the corresponding nucleosides in the in vitro antiviral assays, although the bis(S-acylthioethanol) prodrug 14h was transported to the Huh7 cells and efficiently released the nucleoside monophosphate.
Asunto(s)
Antivirales/farmacología , Profármacos/farmacología , Purinas/farmacología , Virus ARN/efectos de los fármacos , Ribonucleósidos/farmacología , COVID-19/virología , Línea Celular Tumoral , Virus del Dengue/efectos de los fármacos , Virus de la Encefalitis Transmitidos por Garrapatas/efectos de los fármacos , Humanos , Fosfatos/farmacología , Nucleósidos de Purina , ARN Polimerasa Dependiente del ARN/metabolismo , SARS-CoV-2/efectos de los fármacos , Virus del Nilo Occidental/efectos de los fármacos , Virus Zika/efectos de los fármacos , Tratamiento Farmacológico de COVID-19RESUMEN
Two isomeric sets of 4-substituted pyridopyrrolopyrimidine nucleobases were prepared through nucleophilic substitutions or cross-coupling reactions of 4-chloropyridopyrrolopyrimidines. The corresponding 4-amino-pyridopyrrolopyrimidines were glycosylated with 5-O-tritylribose using the modified Mitsunobu protocol. Several examples of the title heterocycles showed blue or green fluorescence. Testing of the pyridopyrrolopyrimidine nucleobases for the cytotoxic effect revealed micromolar activity of 4-benzofuryl derivatives in both series, preferentially in multidrug-resistant cancers.
RESUMEN
All four isomeric series of novel 4-substituted pyrido-fused 7-deazapurine ribonucleosides possessing the pyridine nitrogen atom at different positions were designed and synthesized. The total synthesis of each isomeric fused heterocycle through multistep heterocyclization was followed by glycosylation and derivatization at positionâ 4 by cross-coupling reactions or nucleophilic substitutions. All compounds were tested for cytostatic and antiviral activity. The most active were pyrido[4',3':4,5]pyrimidine nucleosides bearing MeO, NH2 , MeS, or CH3 groups at positionâ 4, which showed submicromolar cytotoxic effects and good selectivity for cancer cells. The mechanism involved activation by phosphorylation and incorporation to DNA where the presence of the modified ribonucleosides causes double-strand breaks and apoptosis.