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

Amato J, Iaccarino N, Pagano B, Morigi R, Locatelli A, Leoni A, Rambaldi M, Zizza P, Biroccio A, Novellino E, Randazzo A - Front Chem (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, University of Naples "Federico II" Naples, Italy.

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.

No MeSH data available.


Related in: MedlinePlus

G-quadruplex folding topologies. Pictorial representations of the parallel, hybrid 1 and 2 folding topologies of human telomeric G-quadruplexes.
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Figure 2: G-quadruplex folding topologies. Pictorial representations of the parallel, hybrid 1 and 2 folding topologies of human telomeric G-quadruplexes.

Mentions: 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). Since this can have important implications in drug discovery, we selected telomeric DNA truncations and experimental conditions such as to have three different folding topologies, which possess most of the structural features of numerous folding topologies of telomeric DNA. Thus, we considered two different truncations of human telomeric DNA sequence, namely tel23 and tel26 (Material and Methods). Vorlickova and co-workers have demonstrated that a high DNA concentration promotes the G4 parallel folding of human telomeric sequence (Renciuk et al., 2009) and that, although intermolecular species may be formed at high concentrations, the majority of oligonucleotides form intramolecular G4 structures. Thus, we prepared a couple of sample of tel23 that were structured at “low concentration” (10 μM) and “high concentration” (10 mM) conditions, respectively. Particularly, at “low concentration” conditions, tel23 is expected to form the so-called hybrid 1 G4 structure (Figure 2) (hereafter referred to as tel23-h), whereas, at “high concentration” conditions, the tel23 is expected to fold into a G4 parallel structure (hereafter referred to as tel23-p). On the other hand, the sequence tel26 at 10 μM is expected to fold into the hybrid 2 G4 structure (Figure 2). In order to verify that these sequences actually adopt the expected folding, CD experiments were performed. Indeed, CD is a well-established technique for determining the presence and the overall topologies of G4 structures (Masiero et al., 2010; Karsisiotis et al., 2011; Randazzo et al., 2013), although it should be noted that the interpretation of CD spectra requires spectra of well characterized G4 structures for comparison. The tel26 sequence showed a CD spectrum having two positive bands at 290 and 268 nm, and a weak negative band at around 240 nm (Figure S1, Supplementary Material). These data are consistent with a hybrid 2 G4 folding topology. Very similar CD spectrum was obtained for tel23-h, indicating also in this case an antiparallel G4 folding topology (namely hybrid 1) (Figure S1, Supplementary Material). Tel23-p actually adopts a parallel conformation, having positive band around 265 nm and a negative band around 240 nm in the CD spectrum (Figure S1, Supplementary Material).


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

Amato J, Iaccarino N, Pagano B, Morigi R, Locatelli A, Leoni A, Rambaldi M, Zizza P, Biroccio A, Novellino E, Randazzo A - Front Chem (2014)

G-quadruplex folding topologies. Pictorial representations of the parallel, hybrid 1 and 2 folding topologies of human telomeric G-quadruplexes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4109613&req=5

Figure 2: G-quadruplex folding topologies. Pictorial representations of the parallel, hybrid 1 and 2 folding topologies of human telomeric G-quadruplexes.
Mentions: 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). Since this can have important implications in drug discovery, we selected telomeric DNA truncations and experimental conditions such as to have three different folding topologies, which possess most of the structural features of numerous folding topologies of telomeric DNA. Thus, we considered two different truncations of human telomeric DNA sequence, namely tel23 and tel26 (Material and Methods). Vorlickova and co-workers have demonstrated that a high DNA concentration promotes the G4 parallel folding of human telomeric sequence (Renciuk et al., 2009) and that, although intermolecular species may be formed at high concentrations, the majority of oligonucleotides form intramolecular G4 structures. Thus, we prepared a couple of sample of tel23 that were structured at “low concentration” (10 μM) and “high concentration” (10 mM) conditions, respectively. Particularly, at “low concentration” conditions, tel23 is expected to form the so-called hybrid 1 G4 structure (Figure 2) (hereafter referred to as tel23-h), whereas, at “high concentration” conditions, the tel23 is expected to fold into a G4 parallel structure (hereafter referred to as tel23-p). On the other hand, the sequence tel26 at 10 μM is expected to fold into the hybrid 2 G4 structure (Figure 2). In order to verify that these sequences actually adopt the expected folding, CD experiments were performed. Indeed, CD is a well-established technique for determining the presence and the overall topologies of G4 structures (Masiero et al., 2010; Karsisiotis et al., 2011; Randazzo et al., 2013), although it should be noted that the interpretation of CD spectra requires spectra of well characterized G4 structures for comparison. The tel26 sequence showed a CD spectrum having two positive bands at 290 and 268 nm, and a weak negative band at around 240 nm (Figure S1, Supplementary Material). These data are consistent with a hybrid 2 G4 folding topology. Very similar CD spectrum was obtained for tel23-h, indicating also in this case an antiparallel G4 folding topology (namely hybrid 1) (Figure S1, Supplementary Material). Tel23-p actually adopts a parallel conformation, having positive band around 265 nm and a negative band around 240 nm in the CD spectrum (Figure S1, Supplementary Material).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, University of Naples "Federico II" Naples, Italy.

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.

No MeSH data available.


Related in: MedlinePlus