Synthesis of New Indanyl Nucleoside Analogues and their Biological Evaluation on Hepatitis C Virus (HCV) Replicon.

Matías Gómez,Verónica Mathet,Albertina Moglioni,M Martini,María Cuestas,Emiliano Gentile,Graciela Moltrasio

doi:10.3390/molecules24050990

Abstract

Here, we report a convenient synthetic procedure for the preparation of four novel indanyl carbanucleoside derivatives in the racemic form. The action of these compounds against hepatitis C virus was evaluated in vitro using the replicon cell line, Huh7.5 SG. Contrary to our expectations, all these compounds did not inhibit, but rather promoted HCV genotype 1b (HCVg1b) replication. Similar effects have been reported for morphine in the replicon cell lines, Huh7 and Huh8. Several biological experiments and computational studies were performed to elucidate the effect of these compounds on HCVg1b replication. Based on all the experiments performed, we propose that the increase in HCVg1b replication could be mediated, at least in part, by a similar mechanism to that of morphine on the enhancement of this replication. The presence of opioid receptors in Huh7.5 SG cells was indirectly determined for the first time in this work.

Highlights

Interest in the design and synthesis of modified nucleosides has increased steadily over the past few decades [1,2,3,4,5]
Results showed that the exposure of Huh7.5 SG cells to 25.00 μM
We report here a convenient synthetic procedure for the preparation of novel three purinyl- and 8-azapurinyl-carbanucleoside derivatives, obtained as a racemic mixture from cis-2-amino-1-indanol, as well as one triazolyl analogue obtained from racemic cis-2-azido-1-indanol

Summary

Introduction

Interest in the design and synthesis of modified nucleosides has increased steadily over the past few decades [1,2,3,4,5]. The introduction of structural diversity into the nucleoside scaffold for use as potential chemotherapeutic agents has long been considered an important approach to drug design. In this sense, the substitution of the furan ring with a cyclopentane ring, and the subsequent replacement of both at positions 2’ and 3’ by an aromatic or heteroaromatic cycle (Figure 1: I and II, respectively), lead to differences in the physicochemical properties of the synthesized carbanucleosides, which may influence the biological activity due to higher lipophilicity, conformational rigidity, and steric hindrance than their natural nucleosides [6]. Figure cycle in in their their structure.

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Conclusion