Recognition of DNA/RNA bulges by antimicrobial and antitumor metallohelices

Abstract

Bulged structures have been identified in nucleic acids and have been shown to be linked to biomolecular processes involved in numerous diseases. Thus, chemical agents with affinity for bulged nucleic acids are of general biological significance. Herein, the mechanism of specific recognition and stabilization of bulged DNA and RNA by helical bimetallic species was established through detailed molecular biophysics and biochemistry assays. These agents, known as 'flexicates', are potential mimetics of α-helical peptides in cancer treatment, exhibiting antimicrobial and antitumor effects. The flexicates have positive impacts on the thermal stability of DNA duplexes containing bulges, which means that the flexicates interact with the duplexes containing bulges, and that these interactions stabilize the secondary structures of these duplexes. Notably, the stabilising effect of the flexicates increases with the size of the bulge, the maximal stabilization is observed for the duplexes containing a bulge composed of at least three bases. The flexicates bind most preferentially to the bulges composed of pyrimidines flanked on both sides also by pyrimidines. It is suggested that it is so because these bulges exhibit greatest conformational variability in comparison with other combinations of bases in the bulge loop and bases flanking the bulge. Finally, the results indicate that there is only one dominant binding site for the flexicates on the DNA and RNA bulges and that the flexicates bind directly to the bulge or in its close proximity. It is also shown that the flexicates effectively bind to RNA duplexes containing the bulged region of HIV-1 TAR RNA.

Anticancer metallohelices: nanomolar potency and high selectivity

“…We have previously concluded that the induction of DNA damage is not involved in the mode of action of earlier flexicates, despite particular examples binding in a cell free environment. 20 , 32 , 33 We investigated the effect that the new flexicates had on the denaturation temperature ( T m ) of ct-DNA to screen for any indications of DNA binding.…”

Self‐Assembly of Functional Discrete Three‐Dimensional Architectures in Water

“…[107] Detailed research has also implicated M 2 L 3 complexes in selective G quadruplex binding, [108] and at DNAb ulges. [109,110] An umber of studies have highlighted that due to the polycationic charge of many metal-organic complexes,they are efficiently able to condense polyanionic DNAa nd inhibit natural enzymatic processes. [103,111] Them ode of action of these small metal-organic constructs is however not limited to DNAi nteractions,a nd biophysical measurements have shown that some flexicates do not interact significantly with DNA.…”

Selbstorganisation von funktionellen diskreten dreidimensionalen Architekturen in Wasser

“…Mittlerweile hat die Modifizierung von 23 Helikate mit verbesserter Erkennung von Dreiwege‐Kreuzungen hervorgebracht . Ausführliche Forschungen befassten sich auch mit M 2 L 3 ‐Komplexen zur selektiven Bindung an G‐Quadruplexe und DNA‐Ausbuchtungen . In einer Reihe von Studien wurde betont, dass viele Metall‐organische Komplexe wegen ihres polykationischen Käfigs effizient in der Lage sind, polyanionische DNA zu verdichten und natürliche enzymatische Vorgänge zu hemmen …”