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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

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

Author(s): Hoda Atapour-Mashhad, Mohammad Soukhtanloo, Shiva Golmohammadzadeh, Jamshidkhan Chamani, Mojgan Nejabat* and Farzin Hadizadeh*

Volume 24, Issue 15, 2024

Published on: 04 June, 2024

Page: [1126 - 1141] Pages: 16

DOI: 10.2174/0118715206291797240523112439

Price: $65

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.

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