RESUMEN
We report the design, synthesis and evaluation of a family of ca 50 phosphoramidate ProTides of the potent anti-HCV compound 4'-azidocytidine (R1479), with variation on the ester, amino acid and aryl moiety of the ProTide. Sub-muM inhibitors of HCV emerge. The compounds are all non-cytotoxic in the replicon assay. We herein report detailed SARs for each of the regions of the ProTide.
Asunto(s)
Antivirales/síntesis química , Química Farmacéutica/métodos , Citidina/análogos & derivados , Hepacivirus/metabolismo , Hepatitis C/tratamiento farmacológico , Tecnología Farmacéutica/métodos , Aminoácidos/química , Antivirales/farmacología , Citidina/síntesis química , Citidina/farmacología , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Modelos Químicos , Profármacos , Replicón/efectos de los fármacos , Replicación ViralRESUMEN
A variety of new prodrugs of 2'-methyl cytidine based on acyloxy ethylamino phosphoramidates have been synthesized and tested in vitro and in vivo for their biological activity. Compared with the parent drug a 10- to 20-fold increase in formation of nucleotide triphosphate in rat and human hepatocytes could be achieved.
Asunto(s)
Amidas/síntesis química , Citidina/análogos & derivados , Citidina/síntesis química , Ácidos Fosfóricos/síntesis química , Profármacos/síntesis química , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Proteínas no Estructurales Virales/antagonistas & inhibidores , Amidas/farmacología , Animales , Células Cultivadas , Citidina/farmacología , Perros , Evaluación Preclínica de Medicamentos/métodos , Hepacivirus/efectos de los fármacos , Hepacivirus/enzimología , Hepatocitos/efectos de los fármacos , Hepatocitos/enzimología , Hepatocitos/virología , Humanos , Ácidos Fosfóricos/farmacología , Profármacos/farmacología , ARN Polimerasa Dependiente del ARN/metabolismo , Conejos , Ratas , Proteínas no Estructurales Virales/metabolismoRESUMEN
The impact of the presence of nonnatural bases on the properties of oligodeoxynucleotides has been studied. First, oligodeoxynucleotides carrying 2'-deoxyzebularine were prepared, and the stability of duplexes carrying this analogue was determined by DNA melting experiments. Melting temperatures and thermodynamic data indicated the preference of 2'-deoxyzebularine for 2'-deoxyguanosine, which behaves as a 2'-deoxycytidine analogue, forming a less stable base pair due to the absence of the amino group at position 4. Moreover, the duplex-hairpin equilibrium of a self-complementary oligodeoxynucleotide carrying several natural and nonnatural bases including 2'-deoxyzebularine as a central mispair, was studied. Depending on the base present in the middle of the sequence, it is possible to affect the stability of the bimolecular duplex modulating the duplex-hairpin equilibrium. Magnesium ions were shown to stabilize preferentially the bimolecular duplex form. The results indicate the importance of the modifications and the role of cations in shifting the structural equilibrium.
Asunto(s)
Citidina/análogos & derivados , ADN/química , Oligodesoxirribonucleótidos/química , Emparejamiento Base , Secuencia de Bases , Citidina/síntesis química , Citidina/química , ADN/genética , Conformación de Ácido Nucleico , Desnaturalización de Ácido Nucleico , Hibridación de Ácido Nucleico , Oligodesoxirribonucleótidos/genética , Temperatura , TermodinámicaRESUMEN
The syntheses of four selenonucleosides, namely 4'-beta-selenoadenosine, -cytidine, -thymidine, and -uridine are described. Commercially available D-ribonolactone was converted to the key intermediate 1,4-anhydro-4-seleno-D-ribitol in seven steps in overall excellent yield. Oxidation of the seleno-d-ribitol with MCPBA gave a single diastereomeric selenoxide in excellent yield, which upon Pummerer reaction in the presence of silylated purine or pyrimidine bases gave stereoselectively the corresponding 4'-beta-selenonucleosides. The stereochemistry at the anomeric center was determined by means of 1D-NOE experiments.
Asunto(s)
Adenosina/análogos & derivados , Nucleósidos/síntesis química , Compuestos de Organoselenio/síntesis química , Selenio/química , Adenosina/síntesis química , Citidina/análogos & derivados , Citidina/síntesis química , Glicosilación , Estereoisomerismo , Timidina/análogos & derivados , Timidina/síntesis química , Uridina/análogos & derivados , Uridina/síntesis químicaRESUMEN
The 1'alpha-phenylselenouridine derivative 13 was successfully synthesized by enolization of the 3',5'-O-TIPDS-2'-ketouridine 8, and was subjected to a radical reaction with a vinylsilyl tether--an efficient procedure for preparing 1'alpha-branched-chain sugar pyrimidine nucleosides. Successive treatment of 8 with LiHMDS and PhSeCl in THF at < -70 degrees C gave the desired 1'-phenylseleno products in 85% yield as an anomeric mixture of the 1'alpha-product 11 and the 1'beta-product 12 (11/12= 2.5:1). Highly stereoselective reduction at the 2'-carbonyl of the 1'alpha-product 11 occurred from the beta-face by using NaBH4/CeCl3 in MeOH, and subsequent introduction of a dimethylvinylsilyl tether at the 2'-hydroxyl gave the radical reaction substrate 14. The photochemical radical atom-transfer reaction of 14 by using a high-pressure mercury lamp proceeded effectively in benzene to give the exo-cyclized PhSe-transferred product 18, in which (PhSe)2 proved to be essential as an additive for radical atom-transfer cyclization reactions. Subsequent phenylseleno-group elimination of 18 gave the sugar-protected 1'alpha-vinyluridine. With this procedure, 1'alpha-vinyluridine (22) and -cytidine (25), designed to be potential antitumor agents, were successfully synthesized. This study is the first example of functionalization at the anomeric 1'-position of a nucleoside by starting from a natural nucleoside to produce a ribo-type 1'-modified nucleoside.