Nucleosides and oligonucleotides with diynyl side chains: Base pairing and functionalization of 2′-deoxyuridine derivatives by the copper(I)-catalyzed alkyne-azide 'click' cycloaddition

Abstract

Oligonucleotides containing the 5-substituted 2′-deoxyuridines 1b or 1d bearing side chains with terminal C≡C bonds are described, and their duplex stability is compared with oligonucleotides containing the 5-alkynyl compounds 1a or 1c with only one nonterminal C≡C bond in the side chain. For this, 5-iodo-2′-deoxyuridine (3) and diynes or alkynes were employed as starting materials in the Sonogashira cross-coupling reaction (Scheme 1). Phosphoramidites 2b-d were prepared (Scheme 3) and used as building blocks in solid-phase synthesis. Tm Measurements demonstrated that DNA duplexes containing the octa-1,7-diynyl side chain or a diprop-2-ynyl ether residue, i.e., containing 1b or 1d, are more stable than those containing only one triple bond, i.e., 1a or 1c (Table 3). The diyne-modified nucleosides were employed in further functionalization reactions by using the protocol of the Cu 1-catalyzed Huisgen-Meldal-Sharpless [2 + 3] cycloaddition ('click chemistry') (Scheme 2). An aliphatic azide, i. e., 3′-azido-3′- deoxythymidine (AZT; 4), as well as the aromatic azido compound 5 were linked to the terminal alkyne group resulting in 1H-1,2,3-triazole-modified derivatives 6 and 7, respectively (Scheme2), of which 6 forms a stable duplex DNA (Table 3). The Husigen-Meldal-Sharpless cycloaddition was also performed with oligonucleotides (Schemes 4 and 5). © 2007 Verlag Helvetica Chimica Acta AG.