Background::
Drug resistance has been a problem in cancer chemotherapy, which often causes shortterm
effectiveness. Further, the literature indicates that telomere G-quadruplex could be a promising anti-cancer
target.
Objective::
We synthesized and characterized two new pyrimidine derivatives as ligands for G-quadruplex DNA
Methods::
The interaction of novel non-cationic and cationic pyrimidine derivatives (3a, b) with G-quadruplex
DNA (1k8p and 3qsc) was explored by circular dichroism (CD) and ultraviolet-visible spectroscopy and polyacrylamide
gel electrophoresis (PAGE) methods. The antiproliferative activity of desired compounds was evaluated
by the MTT assay. Apoptosis induction was assessed by Propidium iodide (P.I.) staining and flow cytometry.
Computational molecular modeling (CMM) and molecular dynamics simulation (MD) were studied on the
complexes of 1k8p and 3qsc with the compounds. The van der Waals, electrostatic, polar solvation, solventaccessible
surface area (SASA), and binding energies were calculated and analyzed.
method:
The interaction of novel non-cationic and cationic pyrimidine derivatives (3a, b) with G-quadruplex DNA (1k8p and 3qsc) was explored by circular dichroism (CD) and ultraviolet-visible spectroscopy and polyacrylamide gel electrophoresis (PAGE) methods. The antiproliferative activity of desired compounds was evaluated by the MTT assay. Apoptosis induction was assessed by Propidium iodide (P.I.) staining and flow cytometry. Computational molecular modeling (CMM) and molecular dynamics simulation (MD) were studied on the complexes of 1k8p and 3qsc with the compounds. The van der Waals, electrostatic, polar solvation, solvent-accessible surface area (SASA), and binding energies were calculated and analyzed.
Results::
The experimental results confirmed that both compounds 3a and 3b interacted with 1k8p and 3qsc and
exerted cytotoxic and proapoptotic effects on cancer cells. The number of hydrogen bonds and the RMSD values
increased in the presence of the ligands, indicating stronger binding and suggesting increased structural dynamics.
The electrostatic contribution to binding energy was higher for the cationic pyrimidine 3b, indicating more negative
binding energies.
Conclusion::
Both experimental and MD results confirmed that 3b was more prone to form a complex with DNA
G-quadruplex (1k8p and 3qsc), inhibit cell growth, and induce apoptosis, compared to the non-cationic pyrimidine
3a.
