Aug 2026· Bioorganic chemistry (Print)· Vol 181, pp.
110369
· 0 citations· 47 references
Medicine
TL;DR
Flow cytometry analyses revealed that these agents induced apoptosis and G0/G1 cell cycle arrest, indicating that their cytotoxic effects are mediated through these mechanisms, highlighting the potential of thiazolyl hydrazones as targeted therapeutic agents, warranting further investigations for NSCLC treatment.
Abstract
To identify targeted cytotoxic agents for the treatment of non-small cell lung cancer (NSCLC), novel thiazolyl hydrazones (2a-t) were synthesized and evaluated for their cytotoxicity toward A549 human lung adenocarcinoma and L929 mouse embryonic fibroblast cells. Among these compounds, compound 2b exhibited the highest cytotoxic activity against A549 cells (IC50= 6.10 µM), followed by compounds 2g, 2k, 2r, 2f, 2o, 2e, 2s, and 2h, all of which were more potent than erlotinib (IC50 = 77.35 μM). In vitro mechanistic assays were conducted to assess their effects on apoptosis, cell cycle, epidermal growth factor receptor (EGFR), Akt, and signal transducer and activator of transcription 3 (STAT3). Flow cytometry analyses revealed that these agents induced apoptosis and G0/G1 cell cycle arrest, indicating that their cytotoxic effects are mediated through these mechanisms. Compound 2f was identified as the most promising compound, exhibiting selective cytotoxicity mediated by the concurrent inhibition of EGFR, Akt, and STAT3, with greater inhibitory potency toward EGFR and STAT3 relative to the EGFR TKI erlotinib and the STAT3 inhibitor C188-9. Compound 2e emerged as a potent dual EGFR/STAT3 inhibitor, exerting EGFR inhibitory activity comparable to that of erlotinib while exhibiting superior STAT3 inhibitory activity relative to C188-9. Compound 2b showed the highest cytotoxic potency against A549 cells, primarily through EGFR inhibition, with 8.3-fold greater activity than erlotinib. Compound 2r was identified as the most potent STAT3 inhibitor, exerting 10.8-fold higher activity than C188-9. These findings highlight the potential of thiazolyl hydrazones as targeted therapeutic agents, warranting further investigations for NSCLC treatment.
Compound 4v emerged as a leading candidate, showing EGFR kinase inhibitory activity comparable to Erlotinib, and computational analysis of 4v and EGFR molecular binding suggests that it serves as a superior binder to the inactive EGFR conformation.
Amr Elagamy, Mohamed S. Nafie, Ahmed Elnahrawy et al.· European journal of medicina...· 0 citations
The increasing global incidence of cancer and the recurrent development of resistance to standard treatments require a rapid development of innovative, multi-targeted chemotherapeutic medicines. This study focused on the strategic design and synthesis of a range of new cyanopyridine derivatives (1a,b-5a,b) targeting the critical oncogenic kinases. The antiproliferative efficacy of these derivatives was assessed against the breast cancer cell line (MCF-7) and the colorectal cancer cell line (HCT116), demonstrating moderate to significant inhibitory activity, with IC50 values ranging from 6.93 to 43.49 μM. Compound 2b emerged as the most selective and potent derivative in the series, showing greater activity against HCT116 cells (IC50 = 7.34 μM) compared to MCF-7 cells (IC50 = 17.55 μM). Experimental investigations demonstrated that compound 2b exerts its anticancer effects by inducing apoptosis and initiating G0-G1 cell cycle arrest. Moreover, compound 2b was identified as an effective inhibitor of key tumor-promoting signaling pathways, including EGFR (IC50 = 0.300 μM), AKT (IC50 = 0.706 μM), ERK (IC50 = 0.143 μM), and p38-MAPKα (IC50 = 0.308 μM). The structural design was validated by molecular docking simulations and molecular dynamics simulations, which revealed favorable binding affinities to the target kinases' active sites. In silico ADME analysis of compound 2b showed favorable drug-like properties, including compliance with the Veber rules and a bioavailability score of 0.55. The combined results underscore the promise of the cyanopyridine scaffold as a framework for developing selective multi-target anticancer medicines.
Shimaa M. Alhamaky, Marwa S. A. Hassan, Eman M. Ahmed et al.· Bioorganic chemistry (Print)· 0 citations
Background: Glioblastoma (GBM) is the most aggressive subtype of malignant glioma. Current therapeutic options remain limited, highlighting the need for the development of novel compounds capable of improving the efficacy of standard treatments. This study aimed to evaluate the biological activity of a series of pyrazolone-based hydrazone compounds (TPPs) in vitro GBM cell lines. Methods: The eight TPPs were synthesized by a nucleophilic addition reaction of different substituted hydrazines with 1-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2-phenylethan-1-one and tested on two human GBM cell lines, T98 and U87. The cytotoxic effects were evaluated via MTT assay. The most active compound was further investigated at IC50 and IC25 concentrations to evaluate mechanisms of cellular damage, including reactive oxygen species (ROS) production and mitochondrial membrane potential (ΔΨm) changes. Additional assays included colony formation, cell cycle analysis, and evaluation of DNA damage and apoptosis markers. Results: TPP25 exhibited the highest activity with IC50 values of 11.01 μM (95% CI: 10.42 to 11.64) and 13.12 μM (95% CI: 10.23 to 16.87) on T98 and U87 lines, respectively. Treatment induced early ROS production and mitochondrial depolarization, along with a significant reduction in colony formation. Cell cycle analysis revealed accumulation in the sub-G0 phase, consistent with increased cell death, supported by propidium iodide uptake. Furthermore, the results suggest the involvement of an apoptotic-like mechanism as supported by Annexin V positivity, γ-H2AX upregulation and transient caspase-3 activation. Conclusions: TPP25 demonstrates significant in vitro cytotoxicity, likely driven by a pro-apoptotic mechanism. This profile positions it as a potential lead compound for further preclinical evaluation, supporting its future transition into in vivo GBM models.
G. Cameli, Alessia Piergentili, Eleonora Spinozzi et al.· Pharmaceuticals· 0 citations
PANoptosis, a combination of apoptosis, pyroptosis, and necroptosis, plays a key role in the occurrence and development of tumors. In this article, a series of benzimidazole-carbazole-based compounds were developed, which exhibited broad cytotoxicity against eight different cancer cell lines, with significant activity against HepG2 cells. Among them, 3m shows the strongest antiproliferative by preventing HepG2 cells in the G2/M stage. Moreover, 3m can effectively inhibit cell colony formation and migration. Mechanistically, 3m induce PANoptosis in HepG2 cells by upregulating of NLRP3, BAX/BCL2, and cleaved caspase3 expressions, along with the cleavage of gasdermin E (GSDME) into its N-terminal fragment (GSDME-N) and increasing phosphorylation level of MLKL. Additionally, 3m responds to pH/Viscosity. The present study describes a novel therapeutic 3m for the treatment of cancer, providing valuable insights into understanding the anticancer properties of these compounds.
Bei-Bei Wu, Ming-Rong Xie, Bang-Guo Chi et al.· Bioorganic chemistry (Print)· 0 citations
AIMS
To design, synthesize, and biologically evaluate novel bis-thiazole derivatives as potential PIM-1 kinase inhibitors for breast cancer therapy.
MATERIALS AND METHODS
A series of new bis-thiazole derivatives were synthesized and evaluated for their antiproliferative activity against MDA-MB-231 and MCF-7 breast cancer cell lines. The most active compound 15c was further investigated for PIM-1 kinase inhibition, selectivity toward normal WI38 cells, apoptosis induction, and molecular interactions with the PIM-1 active site.
RESULTS AND CONCLUSION
Among the synthesized compounds, derivative 15c exhibited the highest antiproliferative activity against MDA-MB-231 and MCF-7 cells, with IC50 values of 2.17 and 1.46 μM, respectively. It demonstrated potent PIM-1 inhibitory activity (IC50 = 0.74 μM), a favorable selectivity index, and low toxicity toward WI38 cells. Furthermore, 15c significantly increased p53 and Bax levels by 6.8- and 6.2-folds, respectively, while reducing Bcl-2 levels to 0.34-fold relative to the control, indicating apoptosis induction. Molecular docking studies revealed strong binding interactions with key amino acid residues within the PIM-1 active site. Hence, compound 15c represents a promising PIM-1 kinase inhibitor with potent antiproliferative and pro-apoptotic activities, supporting its potential as a candidate for breast cancer treatment.
Alaa M. Abu Alnjaa, Jihan Qurban, E. Abbas et al.· Future Medicinal Chemistry· 0 citations
Abstract Cancer is one of the world’s most deadly diseases. According to the American Cancer Society, 2 million people in the US are diagnosed with cancer, and nearly half of the patients died in 2024. Many challenges need to be overcome when treating cancer, such as the destructive effect of long-term treatment and drug resistance. To overcome these problems, the synthesis of 4-oxo-4-(4-(2-oxo-2-(2-(substitutedcarbamothioyl)hydrazinyl)ethoxy)phenyl)butanoic acid derivatives (3a-3f) was designed, and activity studies were performed. Nuclear magnetic resonance (NMR) spectroscopy, Fourier-transform infrared spectroscopy (FTIR), and high-performance liquid chromatography (HPLC) were used for structural analysis. Cytotoxicity studies of the synthesized compounds were carried out on NIH3T3 (non-cancerous mouse embryonic fibroblast), MCF7 (breast cancer), and A549 (human lung carcinoma) cells. The IC50 value of 3e was determined to be 8.495 ± 0.367 µM in A549 cells, and 50.132 ± 0.901 µM in MCF7 cells. In addition, 3e was found to have selective cytotoxic activity against cancer cells, which didn’t cause significant damage to non-cancerous cells. This way, our molecule may be effective on cancer patients without showing any side effects. In silico studies showed that 3e and 3f interacted with the allosteric cavity of the caspase-3 enzyme. Both showed similar localization on the enzyme. Consequently, both compounds have been brought to literature as potential antiproliferative molecules with selective cytotoxicity. GRAPHICAL ABSTRACTMulti-panel figure illustrating molecular structures, flow cytometry data, and interactions between 3e and enzyme.The figure contains four panels. The top left displays a reaction scheme for the transformation of a starting molecule into compound 3e, with chemical structures labeled 3a-3f. The top right shows a flow cytometry plot with FITC-A and SSC-A axes highlighting population distributions P2 (97.02%) and P3 (2.97%). The bottom left features 3D representation of interactions between 3e and enzyme, and the bottom right presents a detailed diagram of interactions among surrounding amino acids and water.
Aybüke Züleyha Kaya, Derya Osmani̇ye, A. Evren et al.· Phosphorus Sulfur and Silico...· 0 citations
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