Abstract

Long-lasting interest in the synthesis of nucleos(t)ide analogues is dictated by hope to obtain compounds possessing antibacterial, antiviral and antitumor activities [1, 2]. Introduction of a methylene linker between an anomeric carbon and the nucleobase nitrogen atom produces a new class of compounds called 1’-homonucleos(t)ides as potentially active analogues. Although a sugar ring in nucleosides can be replaced by several cyclic or even acyclic moieties we focus attention on compounds containing the tetrahydrofuran ring. Since methods of attachment of nucleobases are limited to their alkylation with appropriate compounds and the de novo synthesis we discussed various synthetic approaches to substituted tetrahydrofuranes in racemic or optically pure forms. Various pentose and hexose derivatives were employed as starting materials and their transformations into the final sugar frameworks were detailed, thus revealing the importance of these class of compounds. To prepare deoxysugars Barton-McCombie reaction sequence was applied. A significant number of final 1’-homonucleos(t)ides were screened for antiviral and cytotoxic activity to identify a few very potent compounds. Thus, phosphonates trans- and cis-138a were as active against HCMV as ganciclovir. In addition trans- -138a inhibited the proliferation of several murine and human cancer cell lines with IC50s in the μM range. 1’-Homonucleosides 64b and 66b exhibited selective antiviral activity against HSV-1 TK– and HSV-2 TK– (MIC = 8–12 μg/mL). Compound 129 was found active against HCV (EC = 6.31 μM) and reduced growth of CCRF-CEM cells with IC50= 5.73 μM. Despite limited activity observed so far for the known 1’-homonucleos( t)ides and their analogues, they deserve further interest both from the synthetic point of view and biological potential inherent in molecules having nucleobase scaffolds.

Authors and Affiliations