Novel Anthraquinone-Based Heterocyclic Compounds as Potential Inhibitors of PKM2 and Topoisomerase: Synthesis, Cytotoxicity, Docking, and ADME Profiling

Mousa , Mohammed Hasan Mohammed, Mazin N.

	Novel Anthraquinone-Based Heterocyclic Compounds as Potential Inhibitors of PKM2 and Topoisomerase: Synthesis, Cytotoxicity, Docking, and ADME Profiling
Al-Kunooze Scientific Journal
Volume 11, Issue 4, October 2025, Pages 87-98 PDF (652.09 K)
Document Type: Original Article
Author
Mazin N. Mousa , Mohammed Hasan Mohammed
Abstract
This study aimed to develop novel anticancer agents by synthesizing and evaluating anthraquinone-based heterocyclic compounds as potential inhibitors of Pyruvate Kinase M2 (PKM2) and topoisomerase. Three target compounds incorporating 1,3,4-oxadiazole (Compound 3), 1,2,4-triazole (Compound 5), and 1,3,4-thiadiazole (Compound 6) moieties with an anthraquinone core were synthesized and characterized using spectroscopic methods (FT-IR, 1HNMR, 13C-NMR). In silico molecular docking revealed that Compound 6 exhibited the highest binding affinity for both topoisomerase II (ΔG: -8.313 kcal/mol) and PKM2 (ΔG: -9.342 kcal/mol). ADME predictions indicated all compounds possess high gastrointestinal absorption, are not BBB permeant, and adhere to Lipinski's rule of five. Cytotoxicity studies (MTT assay) against A549 lung and HepG2 liver cancer cell lines, along with normal HDF cells, demonstrated Compound 6 as the most potent, with IC₅₀ values of 104.37 µg/ml (A549) and 126.59 µg/ml (HepG2). Compound 6 also showed the highest selectivity for A549 cells (SI: 2.61981). These integrated findings identify Compound 6 as a promising lead candidate for further investigation in anticancer drug development
Keywords
Anthraquinone; Cytotoxicity; Docking; Pyruvate Kinase; Topoisomerase

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