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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

Nondenaturing PAGE. Nondenaturing PAGE of human telomeric DNA tel23-p (50 μM) with increasing equivalents of ligands (2 and 4 eq.) at 5°C. Lanes 1 and 2: bromophenol blue; lane 3: tel23-p alone; lane 4: [tel23-p+1a] 1:2 mixture; lane 5: [tel23-p+1a] 1:4 mixture; lane 6: [tel23-p+1b] 1:2 mixture; lane 7: [tel23-p+1b] 1:4 mixture; lane 8: [tel23-p+2a] 1:2 mixture; lane 9: [tel23-p+2a] 1:4 mixture; lane 10: [tel23-p+2b] 1:2 mixture; lane 11: [tel23-p+2b] 1:4 mixture; lane 12: bromophenol blue.
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Figure 4: Nondenaturing PAGE. Nondenaturing PAGE of human telomeric DNA tel23-p (50 μM) with increasing equivalents of ligands (2 and 4 eq.) at 5°C. Lanes 1 and 2: bromophenol blue; lane 3: tel23-p alone; lane 4: [tel23-p+1a] 1:2 mixture; lane 5: [tel23-p+1a] 1:4 mixture; lane 6: [tel23-p+1b] 1:2 mixture; lane 7: [tel23-p+1b] 1:4 mixture; lane 8: [tel23-p+2a] 1:2 mixture; lane 9: [tel23-p+2a] 1:4 mixture; lane 10: [tel23-p+2b] 1:2 mixture; lane 11: [tel23-p+2b] 1:4 mixture; lane 12: bromophenol blue.

Mentions: Nondenaturing gel electrophoresis experiments were performed on tel23-p, that is the G-quadruplex more stabilized by the ligands. In particular, the experiments were performed before and after the addition of the ligands, to confirm the presence of the intramolecular G4 structure as major conformation in solution. As shown in Figure 4, tel23-p moves essentially as single band in the gel, thus suggesting the absence of high-order structures. Moreover, the addiction of ligands did not have any pronounced effect on the G4 mobility. This clearly indicates that (i) all investigated ligands do not induce DNA dimerization/oligomerization, (ii) in agreement with CD results these ligands do not promote any G4 conformational change.


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)

Nondenaturing PAGE. Nondenaturing PAGE of human telomeric DNA tel23-p (50 μM) with increasing equivalents of ligands (2 and 4 eq.) at 5°C. Lanes 1 and 2: bromophenol blue; lane 3: tel23-p alone; lane 4: [tel23-p+1a] 1:2 mixture; lane 5: [tel23-p+1a] 1:4 mixture; lane 6: [tel23-p+1b] 1:2 mixture; lane 7: [tel23-p+1b] 1:4 mixture; lane 8: [tel23-p+2a] 1:2 mixture; lane 9: [tel23-p+2a] 1:4 mixture; lane 10: [tel23-p+2b] 1:2 mixture; lane 11: [tel23-p+2b] 1:4 mixture; lane 12: bromophenol blue.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Nondenaturing PAGE. Nondenaturing PAGE of human telomeric DNA tel23-p (50 μM) with increasing equivalents of ligands (2 and 4 eq.) at 5°C. Lanes 1 and 2: bromophenol blue; lane 3: tel23-p alone; lane 4: [tel23-p+1a] 1:2 mixture; lane 5: [tel23-p+1a] 1:4 mixture; lane 6: [tel23-p+1b] 1:2 mixture; lane 7: [tel23-p+1b] 1:4 mixture; lane 8: [tel23-p+2a] 1:2 mixture; lane 9: [tel23-p+2a] 1:4 mixture; lane 10: [tel23-p+2b] 1:2 mixture; lane 11: [tel23-p+2b] 1:4 mixture; lane 12: bromophenol blue.
Mentions: Nondenaturing gel electrophoresis experiments were performed on tel23-p, that is the G-quadruplex more stabilized by the ligands. In particular, the experiments were performed before and after the addition of the ligands, to confirm the presence of the intramolecular G4 structure as major conformation in solution. As shown in Figure 4, tel23-p moves essentially as single band in the gel, thus suggesting the absence of high-order structures. Moreover, the addiction of ligands did not have any pronounced effect on the G4 mobility. This clearly indicates that (i) all investigated ligands do not induce DNA dimerization/oligomerization, (ii) in agreement with CD results these ligands do not promote any G4 conformational change.

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