Abstract
Many strategies have been developed to modulate the biological or biotechnical properties of oligonucleotides by introducing new chemical functionalities or by enhancing their affinity and specificity while restricting their conformational space. Among them, we review our approach consisting of modifications of the 5’-C-position of the nucleoside sugar. This allows the introduction of an additional chemical handle at any position on the nucleotide chain without disturbing the Watson–Crick base-pairing. We show that 5’-C bromo or propargyl convertible nucleotides (CvN) are accessible in pure diastereoisomeric form, either for nucleophilic displacement or for CuAAC conjugation. Alternatively, the 5’-carbon can be connected in a stereo-controlled manner to the phosphate moiety of the nucleotide chain to generate conformationally constrained nucleotides (CNA). These allow the precise control of the sugar/phosphate backbone torsional angles. The consequent modulation of the nucleic acid shape induces outstanding stabilization properties of duplex or hairpin structures in accordance with the preorganization concept. Some biological applications of these distorted oligonucleotides are also described. Effectively, the convertible and the constrained approaches have been merged to create constrained and convertible nucleotides (C2NA) providing unique tools to functionalize and stabilize nucleic acids.
Highlights
Since nucleic acids were first envisaged as a serious therapeutic option and as powerful tools for biotechnical applications, their limited biostability and chemical repertoire has been constantly enhanced by chemists
We focus here on the recent development of oligonucleotide (ON) conjugation while describing our contribution to the field which is aimed at the development of chemical modification at the 5’-C-position of the sugar moiety of the nucleotide leading to 5’-C-introduction of a chemical handle, or a label of interest, by means of a convertible or functionalized approach, respectively
It can clearly be seen that the topological landscape covered by the constrained nucleotides (CNA) dinucleotide 3u.2n.itBsehisavwioirdoef aαn,βd-Dre-pCrNeAsenwtisthainvOerlyigoinntuecrleeosttiidnegs toolbox for the fine-tuning of local and dispaArsatae pDrNooAf ostfrucocntucreepst., we showed that when reducing the conformational states of DNA single strands to those that match the geometry of the strand in duplex form, by l3o.c2k. iBneghaαviaorndof αβ,βto-Drs-iCoNnaAl wanitghliensOwliigtohninucαle,oβt-idDe-sCNA (g−, t), duplex stabilities were increaseAdsbayp+r5oo°Cf /omf coodnacnedpt+, 3w°eCs/hmoowdetdowthaartdws thheenirrDedNuAcinangdthReNcAoncfourmntaetripoanratls,srtaetsepseoc-f tDivNelAy s(iFnigluersetr8a)n, dasntdo thhoesesetlheactimviatytchwtahse pgereosmerevtreydotfotwhearsdtrsanmdisinmdautcphledx fboarmse,pbyailroinckg[i1n3g3–α1a3n5]d
Summary
Since nucleic acids were first envisaged as a serious therapeutic option and as powerful tools for biotechnical applications, their limited biostability and chemical repertoire has been constantly enhanced by chemists. We focus here on the recent development of oligonucleotide (ON) conjugation while describing our contribution to the field which is aimed at the development of chemical modification at the 5’-C-position of the sugar moiety of the nucleotide leading to 5’-C-introduction of a chemical handle, or a label of interest, by means of a convertible or functionalized approach, respectively This chemistry has allowed us, in an alternative manner, to describe the use and impact of structural constraints on oligonucleotides by covalently restricting the conformation of torsional angles, based on the introduction of a 1,3,2,-dioxaphosphorinane ring within the sugar-phosphate backbone. Starting from a free thiol function on the ON, the partners could be linked through a disulfide bridge after a disulfide bond exchange, usually with a pyridyldithiol-activated species [36] This approach was recently reviewed [37], mostly to study transient non-canonical DNA secondary structures. Thiol-ene chemistry was exemplified by the Hocek group, reaching good coupling yield without the need of UV irradiation [39,40]
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