DNA functionalization by dynamic chemistry.

Zeynep Kanlidere,Oleg Jochim,Marta Cal,Ulf Diederichsen

doi:10.3762/bjoc.12.203

Abstract

Dynamic combinatorial chemistry (DCC) is an attractive method to efficiently generate libraries of molecules from simpler building blocks by reversible reactions under thermodynamic control. Here we focus on the chemical modification of DNA oligonucleotides with acyclic diol linkers and demonstrate their potential for the deoxyribonucleic acid functionalization and generation of libraries of reversibly interconverting building blocks. The syntheses of phosphoramidite building blocks derived from D-threoninol are presented in two variants with protected amino or thiol groups. The threoninol building blocks were successfully incorporated via automated solid-phase synthesis into 13mer oligonucleotides. The amino group containing phosphoramidite was used together with complementary single-strand DNA templates that influenced the Watson–Crick base-pairing equilibrium in the mixture with a set of aldehyde modified nucleobases. A significant fraction of all possible base-pair mismatches was obtained, whereas, the highest selectivity (over 80%) was found for the guanine aldehyde templated by the complementary cytosine containing DNA. The elevated occurrence of mismatches can be explained by increased backbone plasticity derived from the linear threoninol building block as a cyclic deoxyribose analogue.

Highlights

The well-defined duplex structure, self-assembling by base-pair recognition, and the accessibility by solid-phase synthesis make DNA oligonucleotides an ideal supramolecular scaffold in a wide field of applications [1,2]
The obtained compound 9 containing two hydroxy groups and the cyanoethyl protected thiol group was converted into the phosphoramidite being compatible with conditions of solid-phase oligonucleotide synthesis
The base-labile cyanoethyl group [51,52] is known to be resistant under synthesis conditions for the preparation of the phosphoramidite building block and for solid-phase oligonucleotide synthesis [49,53]

Summary

Introduction

The well-defined duplex structure, self-assembling by base-pair recognition, and the accessibility by solid-phase synthesis make DNA oligonucleotides an ideal supramolecular scaffold in a wide field of applications [1,2]. Threoninol can be introduced in oligonucleotides via the corresponding phosphoramidite generating a ribose-free abasic site on the backbone that provides the amine group for later functionalization [22-28]. A thiol functionality can be introduced by substitution of the amine group of threoninol and incorporated into the oligonucleotide backbone.

Results

Conclusion