The findings suggest that SN-1 exerts selective anticancer activity against both drug-sensitive and chemoresistant breast cancer cells through the regulation of apoptosis, cell cycle progression, and metabolic pathways.
Abstract
INTRODUCTION/
Objective
Breast cancer is the most common malignancy among women worldwide, and the emergence of resistance to anthracycline-based chemotherapy remains a major clinical challenge. Benzimidazole scaffolds have attracted considerable interest in medicinal chemistry due to their broad pharmacological properties and anticancer potential. This study aimed to investigate the anticancer activity, selectivity, and molecular mechanisms of novel nitro-benzimidazole derivatives in luminal and Adriamycin-resistant breast cancer cell lines.
Methods
A series of benzimidazole derivatives was synthesized and evaluated using in silico pharmacokinetic analyses. Cytotoxicity was assessed by MTT assay in MCF-7, adriamycinresistant MCF-7 (MCF-7/Adr), and normal human fibroblast cells CCD-1072sk. The most active compound was further investigated by RT-qPCR-based gene expression and pathway enrichment analyses, flow cytometry-based evaluation of apoptosis and cell cycle distribution, fluorescence-based morphological analyses, and gene-metabolite interaction analysis.
Results
Among the tested compounds, SN-1 exhibited the strongest antiproliferative activity, with IC₂⁽ values of 4.86 ± 0.27 μM in MCF-7 cells and 8.62 ± 1.51 μM in MCF-7/Adr cells, along with a high selectivity index. SN-1 significantly induced apoptosis and caused cell cycle arrest at the G2/M phase in MCF-7 cells and at the G0/G1 phase in MCF-7/Adr cells. Gene enrichment and metabolite interaction analyses revealed modulation of apoptosis-, cell cycle-, and metabolism-related pathways, including associations with glycerol, ATP, and ADP.
Discussion
These findings suggest that SN-1 exerts selective anticancer activity against both drug-sensitive and chemoresistant breast cancer cells through the regulation of apoptosis, cell cycle progression, and metabolic pathways. The observed effects on resistant cells further indicate the therapeutic potential of SN-1 in overcoming chemotherapy resistance.
Conclusion
The nitro-benzimidazole derivative SN-1 exhibits strong and selective anticancer effects in both drug-sensitive and chemoresistant breast cancer cells by modulating apoptosis, cell cycle progression, and key metabolic pathways.
Among the synthesized compounds, PBc1 exhibited the greatest in vitro antiproliferative activity against both MDA-MB-231 and SK-OV-3 cell lines, suggesting that PBc1 is a promising compound for further biological and mechanistic investigation.
Prachita Gauns Dessai, Parixit J. Bhandurge, Celina Nazareth et al.· Journal of the Iranian Chemi...· 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.
The benzanilide scaffold is well known for its biological activities, such as antifungal, antibacterial, herbicide, and anti-tumor activity. Benzanilides with halogen substitution were computationally designed and screened against EGFR kinase, with erlotinib as a reference compound, using molecular docking. Two compounds were synthesized by the Schotten-Baumann reaction and confirmed based on FT-IR spectrophotometry, TLC, and sharp, narrow-range melting point analyses. The synthesized compounds were tested for antiproliferative activity and acute toxicity using the MTT assay with the (MCF-7) human breast cancer cell line. The effect of the compounds on non-cancerous cells in the human body was tested using blood lymphocytes. The mechanism of action evaluated by an in vitro cytotoxicity study revealed IC50 values of compound A = 75.54 ± 4.7 μM and compound B = 178.5 ± 9.0 μM (mean ± SEM, n = 3), showing promising growth-inhibitory cytotoxic actions with increasing concentrations against EGFR in breast cancer. Docking studies revealed that synthesized compounds interacted with a similar enzyme and ATP binding site of EGFR-TK in the reference drug erlotinib, along with additional strong interactions indicating efficacy and potency. To predict better tolerability and late failure, toxicity predictions were made for the synthesized compounds. Therefore, this research aimed to demonstrate the activity of several promising benzanilide molecules.
M. Parab, Pramodkumar P. Gupta, S. Shetty et al.· Biotechnology Notes· 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.
Chromone derivatives are acknowledged as a privileged scaffold, recognized for their diverse pharmacological activities, including anti-cancer properties, although comprehensive investigations in this domain have been limited. This research addresses the design, synthesis, and biological evaluation of a new series of C-2 anilinated chromone derivatives. Compounds 4v, 4x, and 4y exhibited significant in vitro cytotoxicity against hepatocellular carcinoma (HepG-2) and breast adenocarcinoma (MCF-7) cell lines. Importantly, all three compounds exceeded the cytotoxicity of Erlotinib against MCF-7 and HepG-2 cancer cells. Compound 4v emerged as a leading candidate, showing EGFR kinase inhibitory activity (IC50 = 60.7 nM) comparable to Erlotinib. It prompted cellular apoptosis and initiated cell cycle arrest at the G2/M phase. Mechanistic studies indicated that compound 4v upregulated essential pro-apoptotic factors, including P53, Bax, PUMA, and caspases-7, -8, and -9. In vivo experiments utilizing a xenograft SEC model demonstrated similar tumor growth inhibition and volume reduction between 4v and erlotinib. Computational analysis of 4v and EGFR molecular binding, considering both the active (PDB ID: 1M17) and inactive (PDB ID: 4HJO) forms, suggests that it serves as a superior binder to the inactive EGFR conformation. These results collectively underscore C-2 anilinated chromone derivatives, particularly 4v as a lead, as promising candidates for the advancement of effective anti-cancer therapeutics.
Amr Elagamy, Mohamed S. Nafie, Ahmed Elnahrawy et al.· European journal of medicina...· 0 citations
Background/Objectives: Colorectal cancer is one of the most common malignancies worldwide and is frequently associated with dysregulation of apoptosis, oxidative stress, and the p53 regulatory axis. The development of novel compounds capable of modulating these pathways remains an important challenge in anticancer drug discovery. This study aimed to evaluate the biological activity of newly synthesized triazole–diquinothiazine derivatives in colorectal cancer cells and to identify the most promising lead compound for further development. Methods: The synthesized derivatives were evaluated in HCT116 colorectal cancer cells harboring wild-type TP53 and in normal BEAS-2B cells. Cytotoxicity, apoptosis, cell cycle distribution, intracellular reactive oxygen species (ROS) generation, and the expression of genes associated with apoptosis, oxidative stress, and inflammatory response were analyzed. Results: The investigated compounds exhibited diverse biological effects, including modulation of apoptosis, cell cycle progression, and oxidative stress. Among the tested derivatives, compound B5 demonstrated the most favorable biological profile, characterized by a more pronounced biological response in HCT116 cells than in BEAS-2B cells, increased ROS generation, reduced MDM2 expression, and a marked induction of early apoptosis. Conclusions: The obtained results indicate that triazole–diquinothiazine derivatives represent promising lead structures for further optimization. In particular, compound B5 warrants additional mechanistic and preclinical studies to evaluate its potential as a candidate for colorectal cancer therapy.