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.
Abstract
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.
The limited efficacy and resistance associated with current anticancer therapies necessitate the development of novel agent, particularly for aggressive malignancies. In this study, a series of fluorine-substituted isoindolinone-amino acid conjugates was designed and evaluated for antiproliferative activity using a phenotypic screening approach. A library of 24 compounds was screened against lung, breast and skin cancer cell lines, among which 11 derivatives demonstrated promising antiproliferative activity with IC50 values ranging from 7.36 to 41.99 µM. SAR analysis revealed that incorporation of trifluoromethoxy (-OCF3) substitution with Trp, Tyr, and Phe conjugation significantly enhances activity relative to trifluoromethyl (-CF3) and mono-fluoro analogues. The lead compounds 9c, 9d, 9e, and 10c markedly inhibited cancer cell proliferation, clonogenic survival, and migration, while inducing apoptosis and a pronounced S-phase cell-cycle arrest. Network pharmacology identified CDK2 and GSK3B as key hub genes associated with cell-cycle regulation. Mechanistic studies demonstrated downregulation of CDK2 and PCNA, activation of p53-p21 signaling pathway, and increased γ-H2AX expression, indicating replicating-associated damage. Molecular docking predicted favorable interactions with the CDK2 catalytic pocket, which was further validated by an in vitro CDK2/CyclinA2 kinase inhibition and reduced CDK2 protein expression determined by western blot analysis, collectively implicating CDK2 as a key molecular target. Furthermore, compounds 9c, 9d, 9e and 10c exhibited significant tumor growth inhibition (TGI) values of 53.50%, 79.47%, 64.50% and 69.14% respectively, in the 4T1 murine breast cancer model without evident systemic toxicity. Collectively, these findings identify fluorinated isoindolinone-amino acid conjugates as promising anticancer leads targeting CDK2-associated cell-cycle signaling against triple-negative breast cancer.
Soma Mandal, Rajat Choudhary, A.A.I. Parvaj Laskar et al.· Biomedicine & pharmacotherap...· 0 citations
Abstract A series of novel sulfonamide derivatives of 6-(aminothiazole) flavones have been designed, synthesized and evaluated in MTT cell proliferation assay against three human cell lines, HeLa (Cervical carcinoma), Hep3B (Hepatocytic carcinoma) and MCF-7 (Breast carcinoma). All the compounds were analyzed by spectroscopic methods. Compound 10c IC50 of 21.93 µM is the good inhibitor of MCF-7 cell line. In sulfonamide series 10h with IC50 values 20.32 µM and 17.23 µM against HeLa and HeP3B cell lines is showing activity comparable with methotrexate. Docking results also have supported above observations by indicating that compounds are held in the active pocket by combination of various hydrogen and hydrophobic interactions. Graphical abstractChemical synthesis diagram of 2-Aminothiazole and Flavone hybridization, with IC50 values and molecular docking of compound 10b with proteins.The figure presents a detailed chemical synthesis diagram split into sections. At the top left, the structure of 2-Aminothiazole (pink) and Flavone (blue) are displayed, connected by an arrow indicating their hybridization. Below is a modified Flavone derivative marked with a sulfonamide group (in red). The central section features compound 10h's structure along with its HeLa IC50 = 20.32 µM and Hep3B IC50 = 17.23 µM values. Two molecular docking images illustrate compound 10b interacting with proteins 7L1X and 3QX3, labeled with amino acids and molecular interactions.
N. M. Thorat, Ashvini U. Chaudhari, A. P. Ingale et al.· Phosphorus Sulfur and Silico...· 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.
Cancer remains a leading cause of mortality worldwide, necessitating the continuous discovery and development of novel therapeutic agents with improved efficacy and reduced toxicity. Heterocyclic compounds are privileged scaffolds in medicinal chemistry, and among them, the triazole ring system (1,2,3-triazoles and 1,2,4-triazoles) has emerged as a highly versatile and promising pharmacophore for anti-cancer drug discovery. This review is an attempt to bridge the gap between synthetic structural biology and translational oncology by systematically connecting the structure- activity relationships of novel triazole hybrids targeting Aromatase, VEGFR-2, IDO1, and Carbonic Anhydrase. We present a comprehensive overview of the recent advancements in the design, structure-activity relationships, and biological evaluation of triazole derivatives as potent anticancer agents. Triazoles are known to play an important role in modulating key oncogenic pathways (such as apoptosis induction, cell cycle arrest, angiogenesis inhibition, and metastasis suppression) by binding to various pharmacological targets. Here, we critically present the spatial configuration, such as the "tail approach" needed for carbonic anhydrase inhibition and the very specific heme-iron distances of the IDO1 pathway that govern the therapeutic promise. Clinical progress, toxicity, bioavailability, and resistance challenges have also been addressed. This review underscores the significance of triazole derivatives as multifunctional anticancer agents and provides insights into future directions for their development as targeted and potent chemotherapeutic agents. Although triazole derivatives are widely recognized as versatile, drug-like moieties, a critical research gap persists in understanding minor structural or electronic modifications near the triazole ring system to make the molecule target-specific and prevent liabilities due to non-selectivity.
Yashika Jangra, S. Dev, P. Jain· Mini-Reviews in Medical Chem...· 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
Histone deacetylase (HDAC) inhibitors are important epigenetic anticancer agents that regulate gene expression, induce cell cycle arrest, and promote apoptosis. In this study, a novel series of 2-oxoindoline-capped hydroxamic acids was designed, synthesized and evaluated for their capacity to inhibit histone deacetylases and suppress cancer cell proliferation. The screening panel incorporated multiple cancer models spanning different organ systems, including colorectal adenocarcinoma (SW620, HCT116), triple-negative breast cancer (MDA-MB-231), non-small cell lung carcinoma (A549), and prostate cancer (PC-3). Comparative assessment against non-transformed fibroblasts (MRC-5) enabled evaluation of selectivity and tolerability profiles. Several derivatives exhibited potent HDAC inhibition at submicromolar concentrations, with compounds 7c, 10b, and 10c showing stronger activity than the reference inhibitor SAHA. Among them, compound 10c demonstrated broad antiproliferative effects while maintaining relatively low toxicity toward normal cells. Mechanistic investigations revealed that 10c induced S-phase cell cycle arrest and promoted apoptosis in SW620 colorectal cancer cells. Molecular docking studies against multiple HDAC isoforms supported the experimental findings by revealing favorable zinc coordination and key interactions within the catalytic pocket. To further elucidate the binding behavior and dynamic features of the most active derivatives, molecular dynamics simulations were performed for HDAC complexes with 7c, 10b, and 10c. The simulations revealed stable protein–ligand interactions without perturbation of the overall protein structure, while highlighting distinct binding dynamics among the compounds, with 10c exhibiting the highest binding persistence, followed by 7c and 10b. In addition, in silico ADME and toxicity predictions were carried out for compound 10c as a representative highly active derivative, indicating acceptable drug-like properties and a favorable safety profile. Overall, 2-oxoindoline-based hydroxamic acids, particularly those bearing extended alkyl linkers, represent promising scaffolds for further development of HDAC-targeted anticancer agents.
Huong Thi Lan Tran, Hwa Kyung Kim, Thai Anh Nguyen et al.· RSC Advances· 0 citations
