Overall, the cytotoxic effects of 7k on MV4-11 cells are attributed to the coordinated induction of ROS-mediated oxidative stress, G0/G1 cell cycle arrest, and caspase-dependent apoptosis, highlighting its promising antiproliferative potential.
Abstract
A novel series of 1H-1,2,3-triazole-linked dihydropyrimidinone (DHPM)–isatin hybrids was designed, synthesized and evaluated for antiproliferative activity against MV4-11 (acute myeloid leukemia), LN229 (glioblastoma) and SHSY-5Y (neuroblastoma). Among the synthesized derivatives, compound 7k, bearing a propyl-linked dibromoisatin-DHPM core, emerged as the most potent analogue, exhibiting an IC50 of 0.8 ± 0.1 µM in MV4-11 cells, significantly surpassing cisplatin (IC50 = 4.5 ± 0.2 µM), while showing low toxicity toward HaCaT cells, indicating good selectivity (SI = 37.12) as compared to cisplatin (SI = 7.62). Mechanistic studies demonstrated that 7k induced G0/G1 phase arrest in MV4-11 cells and elevated intracellular ROS levels, promoting mitochondrial dysfunction. The ROS induction strongly correlated with caspase activation and enhanced apoptotic cell death. Overall, the cytotoxic effects of 7k on MV4-11 cells are attributed to the coordinated induction of ROS-mediated oxidative stress, G0/G1 cell cycle arrest, and caspase-dependent apoptosis, highlighting its promising antiproliferative potential.
Findings identify compound 9 as a promising multi-target quinoxaline-based agent with dual antiproliferative and anti-inflammatory activities, mediated through induction of mitochondrial apoptosis and modulation of oxidative stress and cytokine signaling pathways.
S. Alshawwa, Ghazi A. Bamagous, Hatem A. Sembawa et al.· RSC Advances· 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
The high mortality rate of prostate cancer remains a major threat to men's health worldwide, highlighting an urgent need for novel therapeutic agents with improved efficacy and safety profiles. In this study, we employed a rational structural modification strategy to synthesize 14 novel 1,2,3-triazole-hybridized derivatives of piperlongumine (PL), a natural alkaloid with proven anticancer activity. The antiproliferative activity of these derivatives was evaluated in vitro against multiple cancer cell lines (PC-3, A549, T47D, and SMMC-7721), with normal HEK293 cells used to assess their selectivity. All synthesized derivatives (1 M-14 M) exhibited significant antitumor efficacy, with lead compound 11 M showing pronounced inhibition of PC-3 cell proliferation and migration. Mechanistic studies revealed that 11 M induced G2/M phase arrest and triggered mitochondrial-dependent apoptosis, while concurrently activating the ROS-MAPK signaling pathway and autophagic flux. Notably, 11 M attenuated DNMT3A-mediated global DNA hypomethylation. In vivo validation in PC-3 xenograft mice confirmed that 11 M exerted robust tumor growth suppression with low systemic toxicity, accompanied by DNMT3A downregulation and MAPK pathway activation, substantiating its multi-target therapeutic mechanism.
G glycine conjugation of a coumarin-quinazoline hybrid has not been reported previously, and the results identify it as a substituent- and cell-line-dependent strategy for improving anticancer potency and selectivity.
N. Çalışkan, M. Emirik, F. Yılmaz et al.· Bioorganic chemistry (Print)· 0 citations
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with chemoresistance posing major treatment challenges. Here, we investigated the anticancer potential of pyrazolo[4,3-
e
]tetrazolo[1,5-
b
][1,2,4]triazine sulfonamides (MM129 and MM137) in combination with the ATM inhibitor KU-60,019 in HCT-116 and HT-29 CRC models. Combinatorial treatment significantly decreased cell viability, suppressed proliferation (BrdU and Ki-67), and increased neutral comet and γH2AX-associated DNA damage parameters compared to single-agent treatments. Cell death analyses showed mainly apoptosis-associated changes, while partial protection by NEC-1 suggests that additional non-apoptotic mechanisms may contribute under selected conditions. Our results indicate that MM compounds exhibit measurable anticancer activity in 3D spheroid models and that their combination with ATM inhibition modulates both viability and spheroid morphology, as reflected by changes in ATP levels, core size, and diffusion parameters. Further optimization and mechanistic studies are required to determine the extent and basis of any combinatorial benefit in this context.
M. Kciuk, Katarzyna Wanke, M. Mojzych et al.· Scientific Reports· 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