Evaluation of doxorubicin and β-lapachone analogs as anticancer agents, a biological and computational study.
Itzel Mercado-SánchezJulio LópezRogelio Chávez-RochaIsmael Vargas-RodríguezAdán Bazán-JiménezMariana Segovia-MendozaHeriberto Prado-GarciaMiguel A VázquezRocío García-BecerraMarco A Garcia-RevillaPublished in: Chemical biology & drug design (2024)
We have conducted an experimental and computational evaluation of new doxorubicin (4a-c) and β-lapachone (5a-c) analogs. These novel anticancer analogs were previously synthesized, but had not been tested or characterized until now. We have evaluated their antiproliferative and DNA cleavage inhibition properties using breast (MCF-7 and MDA-MB-231) and prostate (PC3) cancer cell lines. Additionally, cell cycle analysis was performed using flow cytometry. Computational studies, including molecular docking, pharmacokinetic properties, and an analysis of DFT and QTAIM chemical descriptors, were performed to gain insights into the electronic structure and elucidate the molecular binding of the new β-lapachone and doxorubicin analogs with a DNA sequence and Topoisomerase II (Topo II)α. Our results show that 4a analog displays the highest antiproliferative activity in cancer cell lines by inducing cell death. We observed that stacking interactions and hydrogen bonding are essential to stabilize the molecule-DNA-Topo IIα complex. Moreover, 4a and 5a analogs inhibited Topo's DNA cleavage activity. Pharmacodynamic results indicated that studied molecules have favorable adsorption and permeability properties. The calculated chemical descriptors indicate that electron accumulation in quinone rings is relevant to the reactivity and biological activity. Based on our results, 4a is a strong candidate for becoming an anticancer drug.
Keyphrases
- molecular docking
- cell cycle
- circulating tumor
- molecular dynamics simulations
- flow cytometry
- cell death
- papillary thyroid
- single molecule
- cell free
- drug delivery
- cancer therapy
- squamous cell
- prostate cancer
- breast cancer cells
- cell proliferation
- dna binding
- nucleic acid
- endothelial cells
- childhood cancer
- binding protein
- young adults
- density functional theory
- amino acid
- electronic health record
- pi k akt