Jul 2026· World journal of pharmacy and biotechnology· 0 citations
TL;DR
Overall, 4-chloro-4′-methoxychalcone represents a promising multi-target lead scaffold for future breast cancer drug development.
Abstract
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.
This review highlights the structure-activity relationship (SAR) of different quinazolinone derivatives along with their binding interactions which indicate that the electronic and lipophilic characteristics of substituents on different positions of the quinazolinone core significantly affect their activity in breast cancer.
Simran Kaur, Shivani Kasana, B. Kurmi et al.· RSC Medicinal Chemistry· 0 citations
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.
Microtubule-targeting agents remain among the most effective chemotherapeutics for the treatment of cancer. Inspired by the natural tubulin polymerization inhibitor combretastatin A-4 (CA-4), a series of novel thiazolidine-2,4-dione derivatives was designed, synthesized, and evaluated as potential tubulin-targeting anticancer agents. The cytotoxic activities of the compounds were assessed against the MDA-MB-231, while human umbilical vein endothelial cells (HUVEC) were employed to evaluate selectivity. Compounds 2 and 3 emerged as the most active members of the series (IC50 = 3.60 and 3.71 μM, respectively), accompanied by remarkably high selectivity indices of 49.7 and 51.3. To elucidate their mechanism of action, compounds 2 and 3 were further evaluated in an in vitro tubulin polymerization assay. Compound 3 displayed the strongest inhibitory activity (IC50 = 1.07 μM), surpassing the reference inhibitor CA-4 (IC50 = 2.73 μM). Flow cytometric analysis showed that compound 3 induced G2/M cell-cycle arrest, increasing the G2/M population from 21.8% to 30.8%, and markedly promoted apoptosis, with total apoptotic cells increasing from 0.13% to 43.9% in MDA-MB-231 cells. Molecular docking and MM-GBSA calculations revealed favorable binding within the colchicine-binding site of tubulin, with compounds 2 and 3 exhibiting substantially stronger predicted binding affinities (ΔG = -89.53 and -92.86 kcal/mol, respectively) than CA-4 (ΔG = -70.08 kcal/mol). Molecular dynamics simulations confirmed the stability of the ligand-protein complexes throughout the simulation period, supporting the proposed binding mode. Furthermore, in silico ADME analysis suggested favorable drug-likeness, high predicted oral absorption, and improved pharmacokinetic characteristics compared with paclitaxel. The present study identifies compounds 2 and 3 as promising lead candidate that combines potent and selective antiproliferative activity, strong tubulin polymerization inhibition, and favorable binding characteristics.
F. S. Tokalı, Şeyma Ateşoğlu, Pelin Tokalı et al.· European journal of medicina...· 0 citations
Breast cancer is the most frequently diagnosed malignancy in women, and safer, more effective therapies are urgently needed. Inspired by the prenylated coumarin scaffolds of Ferulin C and Miliusol, we rationally designed and synthesized a series of novel 4-hydroxycoumarin derivatives (A, B, and PB series) to develop potent anti-breast cancer agents. Among them, lead compound PB1-3 (7-methoxy, geranyl-substituted) exhibited the most potent antiproliferative activity against MCF-7 (IC₅₀ = 3.13 μM) and 4 T1 (IC₅₀ = 4.28 μM) cells, with high selectivity over normal cells. Structure-activity relationship (SAR) analysis underscored that the combination of a methoxy group and an extended geranyl side chain is crucial for activity. Integrated computational studies (molecular docking, 100 ns MD simulations, and MM-PBSA) confirmed that PB1-3 establishes stable hydrogen-bond and hydrophobic interactions with CDK4/6. Mechanistically, PB1-3 functions as a dual-acting CDK4/6 pathway modulator: it not only directly binds to CDK4/6 but, notably, downregulates their total protein expression, thereby reducing Rb phosphorylation and inducing G0/G1 phase arrest. Concurrently, PB1-3 triggers a potent ROS burst, collapses mitochondrial membrane potential (MMP), upregulates the Bax/Bcl-2 ratio, and activates cleaved caspase-3, driving the intrinsic apoptotic cascade. In a 4 T1 orthotopic syngeneic model, PB1-3 (20 mg/kg, i.p.) significantly suppressed tumor growth comparable to cisplatin, while exhibiting excellent biosafety (LD₅₀ > 2000 mg/kg, no hepatotoxicity/nephrotoxicity) and acceptable oral pharmacokinetics (T₁/₂ = 3.0 h). Collectively, PB1-3 represents a promising prenylated coumarin lead that orchestrates both CDK4/6-Rb cell cycle checkpoint blockade and ROS-dependent mitochondrial apoptosis, offering a valuable scaffold for developing targeted breast cancer therapies, especially for TNBC.
Xinyao Pan, Shiyu Wang, Kaifeng Lai et al.· Bioorganic chemistry (Print)· 0 citations
Present work describes the development and evaluation of novel piperazine–pyrrolidone acyl hydrazide hybrids as potential anticancer agents for breast cancer treatment. The cytotoxic activities of these compounds were determined against human breast cancer cell lines (MCF-7) by alamar blue assay. A compound 1-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)-5-oxopyrrolidine-3-carbohydrazide (7b) showed the highest cytotoxicity with IC50 value of 1.46 µM. The lead candidate exhibited superior activity compared to the standard drug tamoxifen (1.75 µM) and was approximately two-fold less potent than doxorubicin (0.73 µM). A structure–activity relationship (SAR) analysis was carried out to understand the effect of structural modifications on anticancer activity. The findings suggest that the lead molecule induces apoptosis in cancer cells by inhibiting the interaction between BCL-XL and BAD, a mechanism supported by in silico studies.
D. Nagaraju, Mamatha S. Kempasiddegowda, M. Kumaraswamy et al.· Asian Journal of Chemistry· 0 citations
This study reports an efficient synthesis of 6-(4-methoxyphenyl)-3-aryl-[1,2,4]triazolo[4,3-b]pyridazine derivatives via oxidative cyclization of the corresponding hydrazones using iodobenzene diacetate as a mild and metal-free oxidizing agent. The structures of the synthesized compounds were confirmed by 1H NMR, 13C NMR, FTIR, and mass spectrometry. Their in vitro anticancer activity was evaluated against the MCF-7 breast cancer cell line, where four compounds (7a, 7c, 7d, and 7f) exhibited notable cytotoxic effects. Molecular docking studies suggested favorable binding interactions of these compounds with several cancer-related targets, including human 17β-hydroxysteroid dehydrogenase, topoisomerase IIα, p73 tetramerization domain, Bcl2-xL, EGFR tyrosine kinase, and survivin. Docking of the complete compound series (7a-7j) further supported the observed activity trends. These findings indicate that triazolopyridazine derivatives represent promising scaffolds for further investigation as anticancer agents. IBD was used as an environment friendly reagent for the synthesis of 1,2,4-triazolo[4,3-b]pyridazines by oxidative cyclization of hydrazone derivatives. 1,2,4-Triazoles showed excellent anticancer activity against breast cancer Michigan Cancer Foundation-7 (MCF-7) cells. The molecular docking studies were carried out with several enzymes associated with breast cancer to find the effective binding of the synthesized compounds.
S. Malik, R. Soni, M. Sihag et al.· Discover Chemistry· 0 citations
