Bis-indole derivatives with antitumor activity turn out to be specific ligands of human telomeric G-quadruplex.

Jussara Amato,Rita Morigi,Bruno Pagano,Annamaria Biroccio,Mirella Rambaldi,Nunzia Iaccarino,Alberto Leoni,Ettore Novellino,Antonio Randazzo,Pasquale Zizza,Alessandra Locatelli

doi:10.3389/fchem.2014.00054

Jussara Amato, Rita Morigi + Show 9 more

Open Access

https://doi.org/10.3389/fchem.2014.00054

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Abstract

Bis-indolinone derivatives having either 2,6-disubstituted pyridine core (1a and 1b) or 1,10-disubstituted phenanthroline core (2a and 2b), already known to have antitumor activity, have been tested as potential G-quadruplex binders. Compounds 2a and 2b are able to selectively stabilize G-quadruplex over duplex DNA, and also to discriminate among different G-quadruplex structures, having a particular affinity for the parallel form of the human telomeric G-quadruplex. Both compounds are also able to induce telomeric DNA damage that may explain the activity of these compounds.

Highlights

G-quadruplexes (G4) are four-stranded nucleic acid structures that spontaneously form within G-rich sequences of DNA and RNA in the presence of cations (Bochman et al, 2012)
In order to investigate the G-quadruplex binding properties of compounds 1a,b and 2a,b (Figure 1), a number of G-quadruplex forming sequences were selected for this investigation
As far as telomeric DNA is concerned, it is well known that, in the presence of K+, it can fold into a variety of G-quadruplex topologies depending on experimental conditions and length of the sequences (Dai et al, 2008)

Summary

Introduction

G-quadruplexes (G4) are four-stranded nucleic acid structures that spontaneously form within G-rich sequences of DNA and RNA in the presence of cations (Bochman et al, 2012). A telomere maintenance mechanism is provided by the six-membered protein complex called shelterin and by telomerase The latter adds copies of the repeated motif to the end of the single-stranded overhang. It has been demonstrated that molecules that stabilize telomeric G-quadruplexes increase the inhibition of the telomerase (Sun et al, 1997) and lead to telomeric protein uncapping, which, in turn, leads to the onset of DNA damage responses and cellular apoptosis. This has opened a new drug intervention field in anticancer therapy. Compounds having a central pyridine (like, for example, pyridostatin and 360A) (Granotier et al, 2005; Rodriguez et al, 2008) or 1,10-phenanthroline (like, for example, PhenDC3, and PhenDC6) moieties (Dhamodharan et al, 2012) belong to this latter group

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