Metal‐Mediated Base Pairing of Rigid and Flexible Benzaldoxime Metallacycles

Abstract

Oligonucleotides incorporating a central C‐nucleoside with either a rigid or flexible benzaldoxime base moiety have been synthesized, and the hybridization properties of their metallacyclic derivatives have been studied by UV melting experiments. In all cases, the metallated duplexes were less stable than their unmetallated counterparts, and the metallacyclic nucleobases did not show a clear preference for any of the canonical nucleobases as a base‐pairing partner. With palladated oligonucleotides, increased flexibility translated to less severe destabilization, whereas the opposite was true for the mercurated oligonucleotides; this reflects the greater difficulties in accommodating a rigid Pd II ‐mediated base pair than a rigid Hg II ‐mediated base pair within the base stack of a double helix.

N-Methoxy-1,3-oxazinane nucleic acids (MOANAs) – a configurationally flexible backbone modification allows post-synthetic incorporation of base moieties

“…Of the commonly used conjugation reactions, oximation yields the smallest linkage and we have had some success using it for the incorporation of metallacyclic benzaldehydes into aminooxy-functionalized oligonucleotides. 30,31 However, even in that case the sugar and base moieties were separated by an additional oxymethylene linker. With a PNA backbone, "base filling" through peptide coupling and reductive amination has met with considerable success 32 but, to the best of our knowledge, the feasibility of a similar strategy with a sugar phosphate backbone remains to be demonstrated.…”

Still Elusive – Pd(II)‐Mediated Base Pairing by an Acetophenone Oxime Palladacycle within 15N‐Labelled Double‐Helical Oligonucleotides

“…With thymine as the base pairing partner, Pd(II) would in all likelihood coordinate to N3, whereas with adenine both N1‐ and N7‐coordination are possible [42] . At least duplexes ON1bo‐Pd ⋅ ON2a and ON1bo‐Pd ⋅ ON2t would appear to be more stable than the previously studied [29] counterparts bearing either a more flexible or, especially, a more rigid analogue of the palladacyclic oxime residue. Unfortunately, difficulties in determining the higher melting temperature in the latter two cases preclude a more quantitative comparison.…”

“…Melting temperature measurements, for example, are complicated by the relatively slow ligand exchange at Pd(II), which manifests itself as multiphasicity and hysteresis between the denaturation and renaturation curves. [28][29][30] We have previously tried to address this problem by complementing melting temperature measurements with a FRET-based strand displacement assay, with moderate success. [30] However, strand displacement and melting temperature experiments both fundamentally quantify the same property, namely hybridization affinity of an oligonucleotide as a whole.…”

“…On the other hand, the metal ion employed in the very first artificial metal‐mediated base pair, [27] namely Pd(II), has proven challenging and elusive to the conventional experiments. Melting temperature measurements, for example, are complicated by the relatively slow ligand exchange at Pd(II), which manifests itself as multiphasicity and hysteresis between the denaturation and renaturation curves [28–30] . We have previously tried to address this problem by complementing melting temperature measurements with a FRET‐based strand displacement assay, with moderate success [30] .…”

2-Trifluoromethyl-6-mercurianiline Nucleotide, a Sensitive 19F NMR Probe for Hg(II)-mediated Base Pairing

“…The premature dissociation may be prevented by stable organometallic complexes. They do not require similar external metal ion content and may thus be more applicable in biological systems. − …”