Use of Carbonyl Group Addition−Elimination Reactions for Synthesis of Nucleic Acid Conjugates

Abstract

This review outlines the synthesis of covalent conjugates of oligonucleotides and their analogues that are obtained by reactions of carbonyl compounds with various nucleophiles such as primary amines, N-alkoxyamines, hydrazines, and hydrazides. The products linked by imino, oxime, hydrazone, or thiazolidine groups are shown to be useful intermediates for a wide range of chemical biology applications. Methods for their preparation, isolation, purification, and analysis are highlighted, and the comparative stabilities of the respective linkages are evaluated. The relative merits of incorporation of a carbonyl group, particularly an aldehyde group, into either the oligonucleotide or the ligand parts are considered. Examples of harnessing of aldehyde-nucleophile coupling for the labeling of nucleic acids are given, as well as their conjugation to various biomolecules (e.g. peptides and small molecule ligands), site-specific cross-linking of oligonucleotides to nucleic acid-binding proteins, assembly of multibranched supramolecular structures, and immobilization on functionalized surfaces. Future perspectives of bioconjugation and complex molecular engineering via carbonyl group addition-elimination reactions in nucleic acids chemistry are discussed.

Glycotargeting to improve cellular delivery efficiency of nucleic acids

“…With the development of methods to introduce aldehyde groups into nucleic acids, as reviewed elsewhere [113], and the availability of commercial phosphoramidite bearing aldehyde functions (30 from SoluLink Biosciences and 31 from Link Technologies and Trilink Biotechnologies) [114,115], it should also be possible to form carbohydrateoligonucleotide conjugates by reacting amino sugars with oligonucleotides bearing aldehyde modifications.…”

Linking the 3′ Ends of Oligonucleotide Duplexes with Cystine Disulfide Bridges

“…[1] Peptide-oligonucleotide conjugates have been prepared using different synthetic approaches that may give rise to different types of covalent linkage. [2,3] Over the past years, our group has developed methodology for the synthesis of a particular type of peptide-oligonucleotide conjugate, often referred to as the nucleopeptide, in which a phosphodiester group links one end of the oligonucleotide moiety and the side chain of a hydroxylated amino acid. [4] We obtained two cysteine-containing nucleopeptides and their corresponding disulfide dimers, [5] which formed 3Ј-3Ј interstrand cross-linked duplexes that were noticeably more stable than the corresponding parent duplexes.…”

Directed synthesis of semicarbazones, thiosemicarbazones, and guanylhydrazones of 1-vinylpyrrole-2-carbaldehydes

“…HCl [5,9]. However stirring an alcohol solution of a mixture of aldehyde 1b and thiosemicarbazide (20-25 o C, 24 h) did not lead to the formation of thiosemicarbazone 3b.…”