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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

Binding pose of 2b on tel23-p. Side (A) and top-view (B) of the binding pose of 2b on tel23-p obtained by docking calculations. Hydrogen bond between the indolinone moiety and the O4' atom of a deoxyribose ring is depicted with a dashed black line.
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Figure 7: Binding pose of 2b on tel23-p. Side (A) and top-view (B) of the binding pose of 2b on tel23-p obtained by docking calculations. Hydrogen bond between the indolinone moiety and the O4' atom of a deoxyribose ring is depicted with a dashed black line.

Mentions: In order to understand the mode of binding and the fit of the best ligands (2a,b) within the tel23-p G-quadruplex structure (the most stabilized G4) we performed molecular docking calculations. Among computational methods, molecular docking is one of the most important techniques, and it has been widely used to predict or to give insight into the interaction between small ligands and biological macromolecules (such as proteins and nucleic acids). As more and more G4 structures have been determined (Neidle, 2009), a number of novel ligands have been discovered using this technique (Cosconati et al., 2009; Alcaro et al., 2012; Pagano et al., 2012). We docked the ligands to an X-ray crystal structure of the parallel 23-mer human telomeric G4 (PDB ID 3CDM) using AutoDock (Morris et al., 2009). For each ligand, the most favorable complex was selected from the docked structures on the basis of the calculated binding energies. As expected, in both cases, the predicted most favorable binding mode was one where the phenanthroline core is parallel to the plane of the terminal G-tetrad, making extensive π –π stacking interactions. Noteworthy, in the case of 2b, we observed that the NH group of one of the indolinone systems is hydrogen bonded to the O4' atom of a deoxyribose ring (Figure 7). On the other hand, 2a does not seem capable of forming this additional interaction, probably because of the different spatial arrangement of the indolinone systems, which seem to be involved in an intramolecular lone pair-π stacking interaction, conferring rigidity to the molecule (Figure S3, Supplementary Material). This could justify the higher ability of 2b to increase the thermal stability of the telomeric G4.


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)

Binding pose of 2b on tel23-p. Side (A) and top-view (B) of the binding pose of 2b on tel23-p obtained by docking calculations. Hydrogen bond between the indolinone moiety and the O4' atom of a deoxyribose ring is depicted with a dashed black line.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Binding pose of 2b on tel23-p. Side (A) and top-view (B) of the binding pose of 2b on tel23-p obtained by docking calculations. Hydrogen bond between the indolinone moiety and the O4' atom of a deoxyribose ring is depicted with a dashed black line.
Mentions: In order to understand the mode of binding and the fit of the best ligands (2a,b) within the tel23-p G-quadruplex structure (the most stabilized G4) we performed molecular docking calculations. Among computational methods, molecular docking is one of the most important techniques, and it has been widely used to predict or to give insight into the interaction between small ligands and biological macromolecules (such as proteins and nucleic acids). As more and more G4 structures have been determined (Neidle, 2009), a number of novel ligands have been discovered using this technique (Cosconati et al., 2009; Alcaro et al., 2012; Pagano et al., 2012). We docked the ligands to an X-ray crystal structure of the parallel 23-mer human telomeric G4 (PDB ID 3CDM) using AutoDock (Morris et al., 2009). For each ligand, the most favorable complex was selected from the docked structures on the basis of the calculated binding energies. As expected, in both cases, the predicted most favorable binding mode was one where the phenanthroline core is parallel to the plane of the terminal G-tetrad, making extensive π –π stacking interactions. Noteworthy, in the case of 2b, we observed that the NH group of one of the indolinone systems is hydrogen bonded to the O4' atom of a deoxyribose ring (Figure 7). On the other hand, 2a does not seem capable of forming this additional interaction, probably because of the different spatial arrangement of the indolinone systems, which seem to be involved in an intramolecular lone pair-π stacking interaction, conferring rigidity to the molecule (Figure S3, Supplementary Material). This could justify the higher ability of 2b to increase the thermal stability of the telomeric G4.

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