1'-Homonucleosides and their structural analogues: A review

Eur J Med Chem. 2016 Aug 8;118:121-42. doi: 10.1016/j.ejmech.2016.04.034. Epub 2016 Apr 14.

Abstract

Nucleoside analogues belong to an important class of antiviral and anticancer drugs. Insertion of a methylene fragment between the anomeric carbon and pyrimidine or purine bases transforms nucleosides into 1'-homonucleosides. When compared with nucleosides this modification lengthens the separation between HO-C5' of pentofuranoside fragments and nitrogen (N1 or N9) atoms of nucleobases, lowers the steric and electronic interactions between nucleobases and sugar rings, introduces greater flexibility around a CH2-Base bond and thus allows for more rotational freedom, and since the anomeric effect no longer operates any sugar or pseudosugar moiety exists in its unique conformation and experiences specific conformational mobility and hydrolysis of the C1'-CH2Base bond by cellular enzymes is no longer feasible. This review covers 1'-homonucleosides with a tetrahydrofuran ring and its nitrogen and sulfur analogues as well as those containing a cyclopentane moiety as a sugar replacer. Achievements in syntheses of sugar or pseudosugar scaffolds are of primary interest since pathways to install nucleobases are well recognized. Whenever possible, the biological activity, mostly antiviral and antitumor but sometimes as inhibitors of specific enzymes, will be presented and discussed to help identify structural features responsible for the particular mode of action and thus possible therapeutic significance.

Keywords: Antiviral activity; Cytotoxicity; Homonucleosides; Nucleosides.

Publication types

  • Review

MeSH terms

  • Humans
  • Nucleosides / chemistry*
  • Pyrrolidines / chemistry

Substances

  • Nucleosides
  • Pyrrolidines
  • pyrrolidine