Fig 1.
Some reported DNA intercalators and their basic pharmacophoric features.
Schematic representation of classical and threading DNA intercalation (based on Ref. [17]).
Fig 2.
The rationale of molecular design of new DNA-intercalators.
Scheme 1.
General procedures for the synthesis of the key compounds 7a, b, 9, and 10.
Scheme 2.
General procedure for the synthesis of the target compounds 11a,b,15a,b.
Scheme 3.
General procedure for the synthesis of the target compounds 16–20.
Table 1.
The antiproliferative activities of the tested compounds toward HepG2, and HCT‐116 cell lines, Topo II activity, and DNA‐intercalating affinity.
Fig 3.
Effect of compound 16 and m-AMSA on relaxation of supercoiled pBS-SK (+) DNA by human recombinant Topo II.
Supercoiled DNA was incubated with human recombinant Topo II in the absence (Topo-II) or presence of compound 16 at 5 and 10 μM concentrations.
Fig 4.
A) Flow cytometric analysis of cell cycle phases post the compound 16 treatment. B) Flow cytometric analysis of apoptosis in HCT-116 cells exposed to compound 16.
Table 2.
Effect of compound 16 on cell cycle progression in HCT-116 cells after 48h treatment.
Table 3.
Effect of compound 16 on stages of the cell death process in HCT-116 cells after 48 h treatment.
Fig 5.
The immunoblotting of BAX and Bcl-2 (Normalized to β-actin).
Table 4.
Effect of compound 16 on the levels of BAX, and Bcl-2 proteins expression in HCT-116 cells treated for48 h.
Fig 6.
Binding of amsacrine with DNA-Topo II complex.
Table 5.
The docking binding free energies (ΔG) of the synthesized compounds with DNA-topoisomerase II complex.
Fig 7.
Binding of compound 11a with DNA-Topo II complex.
Fig 8.
Binding of compound 12b with DNA-Topo II complex.
Fig 9.
Binding of compound 16 with DNA-Topo II complex.
Fig 10.
Binding of compound 17 with DNA-Topo II complex.
Fig 11.
Binding of compound 19 with DNA-Topo II complex.
Fig 12.
The different MD analyses results done on the protein including A) RMSD, B) H-bonds, C) RoG, D) SASA, and E) RMSF.
Fig 13.
The center of mass distances between the protein-DNA complex and the ligand (Blue line), and the protein and DNA (red line).
Fig 14.
3D interactions between the ligand and the protein_DNA complex in the first (C1) and second (C2) clusters.
Ligand is in orange sticks representation. Amino acid and nitrogenous bases are in blue sticks representations. H-bond: Solid blue line, Hydrophobic interactions: dashed grey lines. Names of amino acids and nitrogenous bases are in red letters.
Table 6.
The number of clusters, number of interactions, and their types between the ligand and protein_DNA complex.
Fig 15.
The contributions from the different energy components of MM-GBSA.
Fig 16.
The contributions of amino acids around 10 Å of the ligand to the binding free energy.