This review presents synthesis and chemistry of nucleoside analogs, possessing an additional fused, heterocyclic ring of the “etheno” type, such as 1,N6-ethenoadenosine, 1,N4-ethenocytidine, 1,N2-ethenoguanosine, and other related derivatives. Formation of ethenonucleosides, in the presence of α-halocarbonyl reagents and their mechanism, stability and degradation, reactions of substitution and transglycosylation, as well as their application in the nucleoside synthesis, have been described. Some of the discussed compounds may be applied as chemotherapeutic agents in antiviral and anticancer treatment, acting as pro-nucleosides of already known, biologically active nucleoside analogs..

This review covers studies which exploit triazole-modified nucleic acids in the range of chemistry and biology to medicine. The 1,2,3-triazole unit, which is obtained via click chemistry approach, shows valuable and unique properties. For example, it does not occur in nature, constitutes an additional pharmacophore with attractive properties being resistant to hydrolysis and other reactions at physiological pH, exhibits biological activity (i.e., antibacterial, antitumor, and antiviral), and can be considered as a rigid mimetic of amide linkage. Herein, it is presented a whole area of useful artificial compounds, from the clickable monomers and dimers to modified oligonucleotides, in the field of nucleic acids sciences. Such modifications of internucleotide linkages are designed to increase the hybridization binding affinity toward native DNA or RNA, to enhance resistance to nucleases, and to improve ability to penetrate cell membranes. The insertion of an artificial backbone is used for understanding effects of chemically modified oligonucleotides, and their potential usefulness in therapeutic applications. We describe the state-of-the-art knowledge on their implications for synthetic genes and other large modified DNA and RNA constructs including non-coding RNAs.

Acyclo analogues of wyosine 2 and 3-methylguanosine 3, viz. 9-[(2-hydroxyethoxy)methyl]-3methyl-1, N-2-(prop-1 -ene-1,2-diyl)guanine 5a and 9-[(2-hydroxyethoxy)methyl]-3-methylguanine (3-methylacyclovir, 6a) were synthesized from acyclovir 4. The route to compound 5a involved methylation of the tricyclic acetate 7b with diazomethane-zinc iodide reagent and subsequent deacetylation; tricycle 5a was transformed into compound 6a with N-bromosuccinimide followed by ammonium hydroxide. Direct coupling of 3-methylguanine with the appropriate chain component resulted exclusively in formation of compound 9a, the N-7 regioisomer of 6a. The glycosidic hydrolysis rates of compounds 2 and 3 differed from those of the much less sterically compressed analogues 5a and 6a by less than one order of magnitude. This contrasts with the 10⁵-fold increase in hydrolysis rate of compounds 2 and 3, compared with that of guanosine 1, and suggests that electronic factors must play an important role in the accelerated hydrolysis of 9-substituted 3-methylguanine derivatives. The antiviral activity of acyclovir was virtually abolished following N-3 methylation (6a). The other compounds (2, 3 and 5a) also failed to show any antiviral activity.