Density functional theory (DFT) analysis indicated that electrophilicity and electronic softness correlate with cytotoxic potency, highlighting the mechanistic relevance and therapeutic potential of 1,2,4-trioxanes as promising leads for further development as breast cancer therapeutics.
Abstract
Breast cancer remains the most common malignancy among women to date, with increasing incidence and resistance to conventional therapies driving the search for novel treatments. 1,2,4-Trioxanes, known for their antimalarial activity, have emerged as promising anticancer agents due to their ability to generate reactive oxygen species (ROS) through iron-mediated activation, selectively inducing apoptosis in cancer cells. In this study, a series of hydroxy-functionalized and hemi-succinate trioxane derivatives were synthesized and evaluated against the MCF-7 breast cancer cell line. Among them, compound 10b3 showed the highest potency with an IC50 of 0.642 µM, outperforming the reference drug doxorubicin (IC50 = 0.857 µM). To complement the experimental findings, Boltz-2–guided binding affinity prediction was employed to estimate protein–ligand interaction free energies, enabling rapid and accurate assessment of binding strength beyond conventional scoring approaches. To explore the probable iron-mediated activation mechanism molecular docking experiments were further conducted to investigate binding orientation, active-site interactions, and the spatial proximity of the endoperoxide bridge to the catalytic iron atom. The compounds preferentially occupied hydrophobic pockets within the active site, stabilized mainly by hydrophobic contacts along with occasional hydrogen-bonding interactions. Notably, compound 10b3 exhibited a favourable binding orientation and interaction profile consistent with its superior in vitro activity. Density functional theory (DFT) analysis indicated that electrophilicity and electronic softness correlate with cytotoxic potency. These findings highlight the mechanistic relevance and therapeutic potential of 1,2,4-trioxanes as promising leads for further development as breast cancer therapeutics.
NSCLC is still one of the leading causes of cancer mortality around the world, and there is a need for new therapeutic agents to overcome the limitations of existing targeted therapies, including the development of resistance to the drugs and significant side effects. In this study, several 1,2,3-triazole hybrids based on cabotegravir were assessed in an integrated computational methodology for their potential as anticancer agents by targeting a lung cancer-associated protein (PDB ID: 2ITY). Molecular docking was performed using PyRx 0.8 to assess binding affinities. The pharmaceutical properties of the compounds were evaluated for pharmacokinetic properties and the likelihood of toxicity, using SwissADME and pkCSM, respectively, and Gefitinib was used as the reference drug. Many of the compounds had statistically superior binding energies than Gefitinib (−7.5 kcal/mol); among the compounds studied, compounds 5e, 5h, and 6d showed the best binding energies [−10.2 kcal/mol].
Findings identify compound 7e as a promising VEGFR-2-targeted anticancer lead with strong enzymatic inhibition, potent cytotoxicity, and a well-supported mechanistic profile integrating experimental and computational evidence.
A. Metwaly, Walid E. Elgammal, I. Eissa et al.· RSC Advances· 0 citations
These findings highlight benzimidazole derivatives, particularly 16a and 17b and their nanoparticle formulations, as promising anticancer candidates, driven primarily by strong cellular potency and favorable safety, substantiating their potential as lead candidates for further optimization and therapeutic development.
Mai Montaser Abdullah, R. Hathout, Reham S. Elezaby et al.· RSC Medicinal Chemistry· 0 citations
Breast cancer remains the most commonly diagnosed cancer among women worldwide and continues to present significant therapeutic challenges, particularly in aggressive subtypes such as triple-negative breast cancer (TNBC), where effective targeted therapies are limited. Chalcones, a class of α,β-unsaturated carbonyl compounds, have emerged as promising anticancer scaffolds because of their structural simplicity, synthetic accessibility, and diverse biological activities. Among them, 4-chloro-4′-methoxychalcone has attracted considerable interest due to its unique electronic architecture, generated by the combination of an electron-withdrawing para-chloro group and an electron-donating para-methoxy group, which enhances molecular polarization and target-binding potential. This review summarizes current evidence regarding the pharmacological activity, molecular targets, and structure–activity relationships (SARs) of 4-chloro-4′-methoxychalcone and related chloro-methoxy chalcone analogues in breast cancer. Available studies indicate that these compounds exert anticancer effects through multiple mechanisms, including modulation of estrogen receptor-α (ERα), HER2/EGFR tyrosine kinases, Bcl-2/BAX-mediated apoptosis, cyclin B1/CDK1 cell-cycle regulation, β-tubulin polymerization, VEGF/VEGFR-2 signaling, NF-κB, histone deacetylases, and MAPK/PI3K/AKT pathways. SAR analyses consistently identify the para-chloro/para-methoxy substitution pattern as favorable for enhanced anticancer activity, while molecular docking studies support strong interactions with several oncogenic targets. Related analogues have demonstrated low micromolar cytotoxicity against breast cancer cell lines, including MCF-7 and MDA-MB-231. Despite these promising findings, major translational gaps remain, including limited in vivo validation, insufficient ADMET characterization, and the absence of clinical studies. Overall, 4-chloro-4′-methoxychalcone represents a promising multi-target lead scaffold for future breast cancer drug development.
R. Elavarasi, Vishnu R, Praveen A et al.· World journal of pharmacy an...· 0 citations
Breast cancer remains a significant global health challenge, necessitating the development of novel therapeutic strategies beyond conventional chemotherapy, which often faces limitations due to drug resistance and adverse side effects. In this context, quinone‐based metal complexes have emerged as promising candidates, offering tunable bioactivity and diverse mechanisms of action against various breast cancer subtypes. This review mainly summarizes the advances reported from 2018 to 2026 and also includes selected milestone studies published before 2018 to provide the historical and mechanistic background for understanding the evolution of quinone‐based metal complexes for breast cancer therapy. Specifically, we examine the structural features of various quinone ligands and transition metals that influence their anticancer efficacy, focusing on their capacity to induce reactive oxygen species (ROS), modulate DNA integrity, disrupt mitochondrial function, and inhibit key enzymatic pathways. Finally, we delineate the current challenges in translating these complexes from preclinical research to clinical application, including issues related to stability, solubility, and off‐target effects, while also outlining future directions for rational design and personalized medicine approaches.
Sana Ejaz, Asma Rehman, A. H. Ibrahim et al.· ChemistrySelect· 0 citations
The development of new therapeutic agents for glioblastoma and hepatocellular carcinoma (HCC) remains a priority due to poor prognosis, limited treatment options, and high recurrence rates. Herein, we report a one‐pot synthesis of aromatic aminopropyl lactams (ArAPLs) via hydrolysis of bicyclic amidines (DBN, DBU), followed by reductive amination with aromatic aldehydes. These compounds were designed to target histamine H3 receptors (H3R), which are often overexpressed in these malignancies. Docking studies suggested that compounds 3a and 4a may act as H3R antagonists, showing favorable binding through hydrophobic and hydrogen‐bonding interactions. Biological evaluation identified 3a and 4a as the most promising compounds, exhibiting micromolar antiproliferative activity in glioblastoma and HCC cell models. Compound 3a showed the best balance between potency and selectivity, including activity in 3D spheroid models and modulation of cell cycle‐related markers. In coculture systems, spheroids displayed reduced size and density, although a slight increase in viability was observed, particularly with 4a. Variations in peripheral cell layers suggest a role for macrophage behavior. Overall, these findings support the cytotoxic potential of ArAPLs, although further studies are required to confirm their role as H3R antagonists.
M. Martins, Ruben Valente, Ruben Amaro et al.· ChemMedChem· 0 citations