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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

CD melting experiments. Normalized CD melting curves of tel23-p in the absence (solid) and in presence of 4 molar equiv of ligands 1a (dash), 1b (dot), 2a (dash dot), and 2b (dash dot dot). Tm values are listed in Table 1.
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Figure 3: CD melting experiments. Normalized CD melting curves of tel23-p in the absence (solid) and in presence of 4 molar equiv of ligands 1a (dash), 1b (dot), 2a (dash dot), and 2b (dash dot dot). Tm values are listed in Table 1.

Mentions: Then, the DNA-stabilizing properties of the compounds were evaluated by measuring the ligand-induced change in the melting temperature (ΔTm) of the various G4-forming sequences as well as of the duplex-forming sequence in CD melting experiments (Giancola and Pagano, 2013). All the thermal denaturations were monitored at the wavelengths of maximum CD intensity. In particular, the melting profiles of the parallel G4 structures were recorded at 264 nm (tel23-p) and 262 nm (ckit1, ckit2), while the thermal denaturations of the hybrid-type G4s were monitored at 289 nm (tel23-h) and 290 nm (tel26) (Figure S2, Supplementary Material). Instead, CD melting curves of ds12 duplex were recorded at 280 nm. Ligands 1a and 1b did not increase significantly the stability of any G4 DNAs as well as of duplex (Table 1). On the other hand, ligands 2a and 2b enhanced the stability of the parallel telomeric G4 tel23-p by 5.5 and 15.5°C, respectively (Figure 3 and Table 1). Very interestingly, the same ligands showed to induce only a slight increase (up to 3.0°C) of thermal stability of all the other investigated G4s and none for the duplex. These results highlight the fact that ligands 2a and 2b not only selectively stabilize G4 over duplex DNA, but also discriminate among different G-quadruplex structures.


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)

CD melting experiments. Normalized CD melting curves of tel23-p in the absence (solid) and in presence of 4 molar equiv of ligands 1a (dash), 1b (dot), 2a (dash dot), and 2b (dash dot dot). Tm values are listed in Table 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: CD melting experiments. Normalized CD melting curves of tel23-p in the absence (solid) and in presence of 4 molar equiv of ligands 1a (dash), 1b (dot), 2a (dash dot), and 2b (dash dot dot). Tm values are listed in Table 1.
Mentions: Then, the DNA-stabilizing properties of the compounds were evaluated by measuring the ligand-induced change in the melting temperature (ΔTm) of the various G4-forming sequences as well as of the duplex-forming sequence in CD melting experiments (Giancola and Pagano, 2013). All the thermal denaturations were monitored at the wavelengths of maximum CD intensity. In particular, the melting profiles of the parallel G4 structures were recorded at 264 nm (tel23-p) and 262 nm (ckit1, ckit2), while the thermal denaturations of the hybrid-type G4s were monitored at 289 nm (tel23-h) and 290 nm (tel26) (Figure S2, Supplementary Material). Instead, CD melting curves of ds12 duplex were recorded at 280 nm. Ligands 1a and 1b did not increase significantly the stability of any G4 DNAs as well as of duplex (Table 1). On the other hand, ligands 2a and 2b enhanced the stability of the parallel telomeric G4 tel23-p by 5.5 and 15.5°C, respectively (Figure 3 and Table 1). Very interestingly, the same ligands showed to induce only a slight increase (up to 3.0°C) of thermal stability of all the other investigated G4s and none for the duplex. These results highlight the fact that ligands 2a and 2b not only selectively stabilize G4 over duplex DNA, but also discriminate among different G-quadruplex structures.

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