Aug 2026· RSC Medicinal Chemistry· 0 citations· 98 references
Medicine
TL;DR
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.
Abstract
Breast cancer is the most frequently occurring cancer worldwide and has become the second primary cause of cancer-associated fatalities among females. It mainly arises from the abnormal proliferation of epithelial cells in the breast tissue and differs in prognosis, biological behaviour and treatment. The study of quinazolinone derivatives has gained attention as promising anti-breast cancer agents by suppressing tumor cell growth and progression. The presence of a carbonyl group and a nitrogen atom in the quinazolinone scaffold contributes to hydrogen bonding with amino acid residues of target proteins indicating strong and specific target binding affinities of these compounds. 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. The incorporation of electron-donating and electron-withdrawing groups on the phenyl ring at the third position of the quinazolinone ring can affect cellular permeability and interaction with biological targets. The introduction of different substituents to the quinazolinone moiety can improve selectivity and potency across breast cancer cell lines. Recent studies have suggested that quinazolinone derivatives act as promising therapeutic candidates for breast cancer therapy. Further optimization through SAR studies and detailed mechanistic investigations could facilitate the design of highly effective and selective anti-breast cancer agents with low toxicity.
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.
A one‐pot synthesis of aromatic aminopropyl lactams (ArAPLs) via hydrolysis of bicyclic amidines (DBN, DBU), followed by reductive amination with aromatic aldehydes supports the cytotoxic potential of ArAPLs.
M. Martins, Ruben Valente, Ruben Amaro et al.· ChemMedChem· 0 citations
A novel set of imidazo[2,1-b]thiazolediones 4a,b and 5a-d, with anticipated EGFR and IDO1 inhibition activities, was designed and prepared. These novel derivatives were evaluated in the NCI 60 cell line panel in which the superior compounds 5b and 5d were chosen for further evaluation of their five dose cytotoxicity toward the most sensitive cancer cells namely non-small cell lung cancer EKVX and HOP-92, breast HS 578 T, and normal WI-38 cells. The presence of a substituted benzylidene moiety at position-2 of the imidazothiazole scaffold in compounds 5a-d positively influences anticancer activity, with the phenylallylidene moiety at position-6 exhibiting superior cytotoxic effects compared to the 2-thienylidene moiety. Among the examined hybrids, 5d showed significant antiproliferative effect against HS 578 T tumor cell. To explore the underlying cell-death mechanisms, secondary biological evaluations were conducted, including cell-free EGFR and IDO1 enzymatic inhibition, apoptosis assay, and cell cycle analysis. In cell-free biochemical assays, the most active derivatives demonstrated a promising potential dual inhibitory profile against EGFR and IDO1, with compound 5d exhibiting sub-micromolar activity against both target enzymes, providing a plausible biochemical rationale for its potent cell killing. Furthermore, compound 5d induced cell cycle arrest at the G2/M phase and triggered apoptosis in HS 578 T cells, as supported by the up-regulation of Caspase-3 and Bax accompanied by the down-regulation of Bcl-2. In-silico ADMET profiling and molecular docking simulations further supported the favorable drug-like properties and binding modes of the key compounds within the target active sites. Overall, these findings highlight compound 5d as a promising lead candidate for further optimization and cellular mechanistic validation in anti-cancer drug discovery.
M. Sarg, Fatma G. Abdulrahman, Yasmin S. Sheta et al.· Bioorganic & Medicinal Chemi...· 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
Breast cancer is the most frequently diagnosed malignancy in women globally, representing a major global health burden, with a significant subset of cases exhibiting resistance to standard therapeutic regimens. Recently, m6A RNA demethylases such as FTO have been identified as important oncogenes in breast cancer, which modify the epitranscriptome of tumor cells to favor expression of growth-promoting genes while suppressing expression of anti-apoptotic genes. In this study, we performed virtual screening of 1,000 dietary compounds targeting the FTO protein in order to discover potential therapies for breast cancer. 7-Deshydroxypyrogallin-4-carboxylic acid (DCA) was identified as the top-ranked candidate. Molecular dynamics (MD) simulations of DCA-FTO complex displayed the formation of stable hydrogen bonds for 200 ns of MD simulations. The ADMET-prediction of DCA showed high gastrointestinal tract absorption and is not expected to be Ames-toxic. The effect of DCA on the growth of MCF-7 human breast cancer cells was assessed by Sulforhodamine B (SRB) cytotoxicity assays and found to be dose- and time-dependent. The IC₅₀ values for the growth inhibition of MCF-7 breast cancer cells were found to be 90.7 µg/mL (365.4 µM) after 24 h of treatment and 40.8 µg/mL (164.4 µM) after 48 h. As a secondary exploratory analysis, lupinine was computationally evaluated against NQO1; however, its suboptimal binding stability and safety concerns preclude experimental advancement at this stage. These findings provide a preliminary mechanistic and experimental framework for DCA as a dietary FTO inhibitor in breast cancer, necessitating further validation through orthogonal target engagement assays, m6A quantification, and in vivo tumor models.
Shuaib Pasha, S. Harishkumar, Revanth Handralu Chandraiah et al.· Naunyn-Schmiedeberg's Archiv...· 0 citations