Design, Synthesis, and In Vitro Preliminary Cytotoxicity Evaluation of New Anthraquinone-2-Carboxylic Acid Derivatives

Introduction DNA intercalators are among the most clinically effective anticancer drugs, targeting topoisomerase, a crucial enzyme that regulates DNA topology during essential cellular functions. Several topoisomerase inhibitors are widely used in clinical oncology. However, their application is often limited due to severe side effects and dose-dependent toxicity, necessitating continuous efforts to develop innovative and efficient therapeutic approaches. This study aimed to perform a virtual evaluation, synthesize, and examine the in vitro cytotoxic activity of six newly designed compounds. These compounds were derived from the hybridization of an anthraquinone scaffold with N-acyl hydrazone and N-acyl sulfonyl hydrazide derivatives, using amino acids, specifically proline and glycine, as linkers. Methods The plausible inhibitory effect of the designed compounds against the topoisomerase enzyme was evaluated in silico using Maestro software from Schrödinger. Molecular dynamics simulations were conducted to assess compound stability and interaction behavior. Pharmacokinetic properties (ADME) were evaluated to determine compliance with drug-likeness standards. The compounds were successfully synthesized and purified using conventional synthetic techniques. The synthesized intermediates and final products were characterized by melting points, TLC, FT-IR spectroscopy, 1 H NMR, and 13 C NMR studies. In vitro cytotoxic activity was assessed using the MTT assay against the human colonic cancer (HCT-116) cell line. Results Most designed compounds exhibited higher docking scores than the reference compound, doxorubicin. Compound 3a demonstrated good stability and favorable interaction behavior in molecular dynamics simulations. The MTT assay revealed significant concentration-dependent inhibition of HCT-116 cell growth, with IC 50 values of 15.85 µM and 22.46 µM for compounds 3a and 4c , respectively. Discussion The results revealed appreciable cell growth inhibition and topoisomerase targeting, indicating that anthraquinone hybrids may serve as lead structures with improved therapeutic profiles, paving the way for more effective and less toxic anticancer agents. Conclusions The newly designed anthraquinone hybrids exhibited strong topoisomerase inhibitory activity and potent cytotoxic effects, highlighting their promise for further development as anticancer agents.