The current therapy for hepatitis C virus (HCV) infection has limited efficacy, in particular against the genotype 1 virus, and a range of side effects. In this context of high unmet medical need, more efficacious drugs targeting HCV nonstructural proteins are of interest. Here we describe 2'-deoxy-2'-spirocyclopropylcytidine (5) as a new inhibitor of the HCV NS5B RNA-dependent RNA polymerase, displaying an EC(50) of 7.3 μM measured in the Huh7-Rep cell line and no associated cytotoxicity (CC(50) > 98.4 μM). Computational results indicated high similarity between 5 and related HCV inhibiting nucleosides. A convenient synthesis was devised, facilitating synthesis of multigram quantities of 5. As the exposure measured after oral administration of 5 was found to be limited, the 3'-mono- and 3',5'-diisobutyryl ester prodrugs 20 and 23, respectively, were evaluated. The oral dosing of 23 led to substantially increased exposure to 5 in both rats and dogs.
An efficient convergent approach has been developed for the construction of novel, nonnatural polysubstituted carbohydrate-based macrolides. A key step in the synthesis is the formation of the macrocyclic ring via a ring-closing metathesis reaction. The obtained macrolide analogues have been screened for biological activity against gram-positive and gram-negative bacteria, yeasts, and molds.
The limited efficacy, in particular against the genotype 1 virus, as well as the variety of side effects associated with the current therapy for hepatitis C virus (HCV) infection necessitates more efficacious drugs. We found that phosphoramidate prodrugs of 2'-deoxy-2'-spirooxetane ribonucleosides form a novel class of HCV NS5B RNA-dependent RNA polymerase inhibitors, displaying EC50 values ranging from 0.2 to >98 μM, measured in the Huh7-replicon cell line, with no apparent cytotoxicity (CC50 > 98.4 μM). Confirming recent findings, the 2'-spirooxetane moiety was identified as a novel structural motif in the field of anti-HCV nucleosides. A convenient synthesis was developed that enabled the synthesis of a broad set of nucleotide prodrugs with varying substitution patterns. Extensive formation of the triphosphate metabolite was observed in both rat and human hepatocyte cultures. In addition, after oral dosing of several phosphoramidate derivatives of compound 21 to rats, substantial hepatic levels of the active triphosphate metabolite were found.
[reaction: see text] An efficient convergent approach has been developed for the construction of novel, non-natural, carbohydrate-based macrolides. The key step in the synthesis is the formation of the macrocyclic ring via a ring-closing metathesis reaction. The obtained macrolide analogues have been screened for biological activity against gram-positive and gram-negative bacteria, including resistant strains, yeasts, and molds.
Abstract:(E)-1-hydroxy-2-methyl-but-2-enyl 4-diphosphate (HMBPP) is an intermediate in the nonmevalonate pathway for the biosynthesis of isoprenoids and also serves as a very strong activator of human T cells expressing V9/V2 receptors. This paper describes the synthesis of analogues of HMBPP, in which the diphosphate group is replaced by potential isosteric moieties, i.e. carbamate, N-acyl-N'-oxy sulfamate or aminosulfonyl carbamate functionalities. The potential of the synthesized analogues to stimulate V9/V2 T cell response or to inhibit GcpE and LytB, the last enzymes in the non-mevalonate pathway was assessed.
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