Synthesis and Molecular Dynamic Simulation of Novel Cationic and Non-cationic Pyrimidine Derivatives as Potential G-quadruplex-ligands


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Abstract

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.

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.

About the authors

Hoda Atapour-Mashhad

Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences

Email: info@benthamscience.net

Mohammad Soukhtanloo

Department of Clinical Biochemistry, Mashhad University of Medical Sciences

Email: info@benthamscience.net

Shiva Golmohammadzadeh

Nanotechnology Research Center, Pharmaceutical Technology Institute,, Mashhad University of Medical Sciences

Email: info@benthamscience.net

Jamshidkhan Chamani

Department of Biology, Faculty of Sciences, Mashhad Branch, Islamic Azad University

Email: info@benthamscience.net

Mojgan Nejabat

Department of Medicinal Chemistry, School of Pharmacy,, Mashhad University of Medical Sciences

Author for correspondence.
Email: info@benthamscience.net

Farzin Hadizadeh

Biotechnology Research Center, Pharmaceutical Technology Institute,, Mashhad University of Medical Sciences

Author for correspondence.
Email: info@benthamscience.net

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