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Nucleosides and Oligonucleotides with Diynyl Side Chains: Base Pairing and Functionalization of 2′‐Deoxyuridine Derivatives by the Copper(I)‐Catalyzed AlkyneAzide ‘Click’ Cycloaddition

2007; Wiley; Volume: 90; Issue: 3 Linguagem: Inglês

10.1002/hlca.200790055

1522-2675

Frank Seela, Venkata Ramana Sirivolu,

Advanced biosensing and bioanalysis techniques

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. T m 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 I ‐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 1 H ‐1,2,3‐triazole‐modified derivatives 6 and 7 , respectively ( Scheme 2 ), of which 6 forms a stable duplex DNA ( Table 3 ). The Husigen–Meldal–Sharpless cycloaddition was also performed with oligonucleotides ( Schemes 4 and 5 ).