Organomercury Nucleic Acids: Past, Present and Future.

Synthetic efforts towards nucleosides, nucleotides, oligonucleotides and nucleic acids covalently mercurated at one or more of their base moieties are summarized, followed by a discussion of the proposed, realized and abandoned applications of this unique class of compounds. Special emphasis is given to fields in which active research is ongoing, notably the use of HgII -mediated base pairing to improve the hybridization properties of oligonucleotide probes. Finally, this minireview attempts to anticipate potential future applications of organomercury nucleic acids.

1,8-Dimercuri-6-Phenyl-1H-Carbazole as a Monofacial Dinuclear Organometallic Nucleobase.

A C-nucleoside with 6-phenyl-1H-carbazole as the base moiety has been synthesized and incorporated in the middle of an oligonucleotide. Mercuration of this modified residue at positions 1 and 8 gave the first example of an oligonucleotide featuring a monofacial dinuclear organometallic nucleobase. The dimercurated oligonucleotide formed stable duplexes with unmodified oligonucleotides placing either cytosine, guanine, or thymine opposite to the organometallic nucleobase. A highly stabilizing (ΔTm =7.3 °C) HgII -mediated base pair was formed with thymine. According to DFT calculations performed at the PBE0DH level of theory, this base pair is most likely dinuclear, with the two HgII ions coordinated to O2 and O4 of the thymine base.

2,6-Dimercuriphenol as a Bifacial Dinuclear Organometallic Nucleobase.

A C-nucleoside having 2,6-dimercuriphenol as the base moiety has been synthesized and incorporated into an oligonucleotide. NMR and UV melting experiments revealed the ability of this bifacial organometallic nucleobase surrogate to form stable dinuclear HgII -mediated base triples with adenine, cytosine, and thymine (or uracil) in solution as well as within a triple-helical oligonucleotide. A single HgII -mediated base triple between 2,6-dimercuriphenol and two thymines increased both Hoogsteen and Watson-Crick melting temperatures of a 15-mer pyrimidine⋅purine*pyrimidine triple helix by more than 10 °C relative to an unmodified triple helix of the same length. This novel binding mode could be exploited in targeting certain pathogenic nucleic acids as well as in DNA nanotechnology.

Triplex Formation by Oligonucleotides Containing Organomercurated Base Moieties.

Homothymine oligonucleotides with a single 5-mercuricytosine or 5-mercuriuracil residue at their termini have been synthesized and their capacity to form triplexes has been examined with an extensive array of double-helical targets. UV and circular dichroism (CD) melting experiments revealed the formation and thermal denaturation of pyrimidine⋅purine*pyrimidine-type triple helices with all oligonucleotide combinations studied. Nearly all triplexes were destabilized upon mercuration of the 3'-terminal residue of the triplex-forming oligonucleotide, in all likelihood due to competing intramolecular HgII -mediated base pairing. Two exceptions from this general pattern were, however, observed: 5-mercuricytosine was stabilizing when placed opposite to a T⋅A or A⋅T base pair. The stabilization was further amplified in the presence of 2-mercaptoethanol (but not hexanethiol, thiophenol or cysteine), suggesting a stabilizing interaction other than HgII -mediated base pairing.

5-Mercuricytosine: An Organometallic Janus Nucleobase.

The base-pairing properties of 5-mercuricytosine have been explored at the monomer level by NMR titrations and at the oligonucleotide level by melting temperature measurements. The NMR studies revealed a relatively high affinity for guanine, hypoxanthine, and uridine, that is, bases that are deprotonated upon coordination of Hg(II) . Within an oligonucleotide duplex, 5-mercuricytosine formed Hg(II) -mediated base pairs with thymine and guanine. In the former case, the duplex formed was as stable as the respective duplex comprising solely Watson-Crick base pairs. Based on detailed thermodynamic analysis of the melting curves, the stabilization by the Hg(II) -mediated base pairs may be attributed to a comparatively low entropic penalty of hybridization.