Current Medicinal Chemistry - Volume 32, Issue 37, 2025

Boron-containing compounds (BCC) are attracting attention in drug design. Certain chemical features invite the exploration of efficacious interactions on known and potential drug targets for human use.

The objective of this study is to analyze the reported crystal structure studies to determine trends resulting from the inclusion of boron atoms in potential drugs.

Published data in the Protein Data Bank (PDB) with at least one BCC were analyzed; both ligands and targets were analyzed to describe the inferred or reported biological activity and the potential application as a drug in the treatment of human diseases.

Data from the PDB indicated targets for certain infectious diseases and cancers; however, potential treatments may extend to many other human pathologies as a consequence of the careful analysis of BCCs with proteins. All classes of enzymes and receptors have been crystallized with BCCs as ligands with most complexes demonstrating interactions in the regions known as relevant to protein function.

The number of crystallized BCC-proteins complexes is increasing, and the variability of proteins expands the possibilities of medical applications. Currently, most systems are related to cancer growth and treatment, but deeper analysis may expand BCC utility and efficacy to many other chronic and degenerative diseases.

This study aimed to develop Imatinib Mesylate (IMT)-loaded Poly Lactic-co-Glycolic Acid (PLGA)-D-α-tocopheryl polyethylene glycol succinate (TPGS)- Polyethylene glycol (PEG) hybrid nanoparticles (CSLHNPs) with optimized physicochemical properties for targeted delivery to glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most destructive type of brain tumor with several complications. Currently, most treatments for drug delivery for this disease face challenges due to the poor blood-brain barrier (BBB) and lack of site-specific delivery. Imatinib Mesylate (IMT) is one of the most effective drugs for GBM, but its primary issue is low bioavailability. Therefore, nanotechnology presents a promising solution for targeted IMT delivery to GBM. This article primarily explores the fabrication of IMT-loaded core-shell lipid-polymer hybrid nanoparticles (CSLHNPs) to achieve enhanced brain delivery with therapeutic efficacy.

The primary objective of this study is to develop optimized, stable IMT-loaded hybrid nanoparticles with an encapsulated polymer matrix and to evaluate these nanoparticles using sophisticated instruments such as SEM and TEM to achieve smooth, spherical nanoparticles in a monodispersed phase.

The enhanced stable formulation yielded a notable increase in entrapment efficiency, reaching 58.89 ± 0.5%. The physical stability analysis of nanoparticles was assessed over 30 days under conditions of 25 ± 2°C and 60 ± 5% relative humidity. Hemolytic assays affirmed the biocompatibility and safety profile of the nanoparticles. In vitro drug release kinetics revealed a sustained IMT release over 48 hours.

The formulated CSLHNPs achieved a narrow size distribution with a mean vesicle diameter of 155.03 ± 2.41 nm and a low polydispersity index (PDI) of 0.23 ± 0.4, indicating monodispersity. A high negative zeta potential of -23.89 ± 3.47 mV ensured excellent colloidal stability in physiological conditions. XRD analysis confirmed the successful encapsulation of IMT within the nanoparticle matrix, with the drug transitioning to an amorphous state for enhanced dissolution. During cell-cell viability assays on LN229, glioblastoma cells were treated with IMT-loaded nanoparticles and showed a significantly enhanced inhibitory effect compared to free IMT. These hybrid nanoparticles demonstrated potential in reducing oxidative stress-induced cellular damage by mitigating reactive oxygen species (ROS). Thus, the prepared IMT hybrid nanoparticles showed higher cellular uptake and superior cytotoxicity compared to the plain drug.

This study posits the IMT-PLGA-TPGS-DSPE PEG 2000-CSPLHNPs as a formidable and innovative drug delivery system for Glioblastoma Multiforme (GBM) treatment, warranting further exploration into their clinical application potential. Future work could involve conducting in vivo studies to evaluate the pharmacokinetics, biodistribution, and therapeutic efficacy of the IMT-PLGA-TPGS-DSPE PEG 2000-CSPLHNPs in animal models of Glioblastoma Multiforme (GBM). Additionally, further research may focus on optimizing the nanoparticle formulation for enhanced targeting capabilities, investigating long-term stability under varied storage conditions, exploring potential combination therapies to synergize with the nanoparticles, and assessing the scalability and manufacturability of the developed drug delivery system for potential clinical translation. Integration of advanced imaging techniques for real- time tracking and visualization of nanoparticle distribution within tumours could also be a promising direction for future investigations.

Glioblastoma (GBM) is an aggressive malignancy. The inherent resistance of GBM to radiotherapy poses great challenges for clinical treatment.

The primary objective of this study is to explore the molecular mechanisms of radiotherapy resistance in GBM and identify the key influencing factors that contribute to this phenomenon.

The single-cell RNA sequencing (scRNA-seq) data of GBM were downloaded from the Gene Expression Omnibus (GEO) database. Cells were clustered using the Seurat R package, and the clusters were annotated using the CellMarker database. Pseudotime analysis was conducted using Monocle2. Marker scores were calculated based on the RNA-seq data of GBM from the UCSC database, and the enrichment of Hallmark gene sets was measured with the AUCell package. Furthermore, the most frequently mutated genes were identified using the simple nucleotide variation data from The Cancer Genome Atlas (TCGA) applying the maftools package.

This study identified two oligodendrocyte subsets (ODC3 and ODC4) as radiotherapy-resistant groups in GBM. Enrichment and Pseudotime analysis revealed that the inflammatory response and immune activation pathways were enriched in ODC3, while the cell division and interferon response pathways were enriched in ODC4. The enrichment scores of hallmark gene sets further confirmed that ODC3 and ODC4 subpopulations developed radiotherapy resistance via distinct molecular mechanisms. Analysis of gene mutation frequencies showed that TP53 exhibited the most significant change in mutation frequency, indicating that it was an important risk factor involved in radiotherapy resistance in GBM.

We identified two ODC subpopulations that exhibited resistance to radiotherapy, providing a new perspective and potential targets for personalized treatment strategies for GBM.

Resistance to lenvatinib poses a serious threat to the therapy of patients with Hepatocellular Carcinoma (HCC). The mechanism by which HCC develops resistance to lenvatinib is currently unknown.

The aim of this study was to identify key genes and pathways involved in lenvatinib resistance in HCC using bioinformatic analysis and experimental validation.

Differentially expressed genes (DEGs) were identified from the GSE186191 gene expression profile, comparing HCC cell lines with lenvatinib-resistant HCC cell lines. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were then carried out using DAVID. A protein-protein interaction network was constructed to visualize DEGs and identify hub genes. The expression and prognostic significance of these hub genes were further examined. Additionally, genomic enrichment analysis (GSEA) was utilized to investigate the potential functions of key genes. Following this, the presence of AHSG was validated in both the original Huh7 cells and the lenvatinib-resistant Huh7 (Huh7LR) cells resistant to lenvatinib through the utilization of quantitative real-time PCR (qRT-PCR).

A total of 232 DEGs were identified between HCC cell lines and those that are resistant to lenvatinib. These DEGs were significantly associated with arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, dilated cardiomyopathy, and mucin-type O-glycan biosynthesis. Three hub genes, including AHSG, C6, and ORM1, were identified. The low expression of AHSG showed a poorer prognosis in HCC. GSEA demonstrated a significant correlation between low AHSG expression and pathways involving fatty acid metabolism, ribosome function, glycine, serine, and threonine metabolism, peroxisome activity, and bile acid biosynthesis. The expression of AHSG was notably reduced in Huh7LR cells (p = 0.006) compared to Huh7 cells.

Diminished AHSG expression is strongly associated with lenvatinib resistance in HCC, suggesting that it may have implications for developing effective strategies to overcome this resistance.

This study aims to investigate the effect of Gallic Acid (GA) on the alleviation of chemotherapy-induced bone marrow suppression, with a comparison to Diyu sheng bai tablets (DYSB) and RhG-CSF.

A mouse model of bone marrow suppression was established in BALB/c mice using intraperitoneal injections of cyclophosphamide (CTX). All procedures were performed after obtaining ethical clearance from the institutional animal ethics committee. Mice were treated with low (100 mg/kg/d), medium (200 mg/kg/d), and high (400 mg/kg/d) doses of Gallic Acid (GA) to mitigate CTX-induced bone marrow suppression. In parallel, mice in the positive control group were also treated with DYSB and RhG-CSF at their respective standard doses (DYSB: 100 mg/kg/day, RhG-CSF: 125 mg/kg/day). The efficacy of GA in alleviating chemotherapy-induced bone marrow suppression was evaluated through blood cell counts, immune organ (thymus and spleen) indices, bone marrow nucleated cell (BMNC) counts, cell cycle analysis, apoptosis, histopathology of bone marrow and spleen, and analysis of splenic hematopoietic factors.

CTX induced a decrease in peripheral blood cells and BMNC counts, reduced spleen and thymus indices, and diminished abnormal pathology of bone marrow and spleen, as well as decreasing disturbances in hematopoietic factors. GA was able to alleviate these abnormalities in the bone marrow. It modulated cell proliferation and apoptosis, adjusted the proportion of cells in the G0/G1 phase, and reduced apoptosis in femoral bone marrow.

Gallic Acid (GA) alleviates chemotherapy-induced bone marrow suppression by improving immune organ function, promoting bone marrow cell recovery, and inhibiting apoptosis. These findings support GA as a potential adjunct therapy for chemotherapy, with promising clinical applications.

The aim of this study is the evaluation of an Azomethine derivative, BCS2, for its antioxidant and anti-tumor activities against mammary carcinoma through the Nrf2-Keap1-HO-1 pathway.

The global prevalence of breast cancer is rising at an alarming rate. The facilitation of abnormal cell proliferation in mammary carcinoma occurs due to the disruption of signaling pathways that balance pro- and antioxidant status, thereby producing oxidative stress that disrupts genomic stability. Therefore, introducing a potent antioxidant molecule with antitumor activity is of paramount importance for treating breast cancer.

Synthesis, characterization, and in vitro, in vivo, and in silico evaluation of an Azomethine derivative, BCS2, for its antioxidant and anti-tumor activities against chemical carcinogen-induced mammary carcinogenesis in Sprague-Dawley rats.

An azomethine derivative, 1-(4-nitrophenyl)-N-phenylmethanimine (BCS2), was synthesized and characterized based on its spectral data. The cytotoxic potential was observed on breast cancer cells, MCF-7, MDA-MB-231, and MDA-MB-468. The in vivo chemotherapeutic potential of BCS2 was established on 7,12-dimethylbenz(a)anthracene (DMBA) induced breast cancer in Sprague-Dawley (SD) rats. The effect of BCS2 on kelch-like ECH-associated protein-1 (Keap1), Nrf2, heme oxygenase-1 (HO-1), mitogen-activated protein kinase (MAPK), and nuclear factor kappa-light-chain-enhancer of activated-B (NF-κB) was evaluated through ELISA and qPCR techniques. Furthermore, the binding potential and stability of BCS2 with Keap-1, HO-1, and MAPK were predicted using in silico molecular docking and dynamics studies. Additionally, drug-likeness properties of BCS2 were evaluated using in silico ADMET tools.

BCS2 showed remarkable cytotoxic activity on MCF-7 cells followed by MDA-MB-231 and MDA-MB-468 cells having an IC50 of 2.368 µM, 4.843 µM and 6.472 µM respectively, without affecting normal breast cells, MCF-10A. In the DMBA-induced animal model, BCS2 showed potent antitumor potential and showed protective action on endogenous-enzymatic and non-enzymatic antioxidants in cancer-bearing animals. Marked improvement in cellular architecture and ultrastructure of breast/tumor tissues excised from experimental animals was noted through histopathological and field emission scanning electron microscopy (FESEM) analyses. Significant upregulation of antioxidant proteins, Keap1 and HO-1, and downregulation of inflammatory proteins, MAPK, and NF-κB was observed after BCS2 treatment. The in silico computational studies predicted the potent binding of BCS2 with the active pockets of Keap1, HO-1, and MAPK proteins that validated the biological findings.

The study revealed BCS2's potent antioxidant and antitumor potential against mammary carcinoma through the Nrf2-Keap1-HO-1 signaling pathway.

Metabolic Syndrome (MS) is a cluster of conditions that significantly increase the risk of infertility in women. Granulosa cells are crucial for ovarian folliculogenesis and fertility. Understanding molecular alterations in these cells can provide insights into MS-associated infertility.

This study aimed to investigate Differentially Expressed Genes (DEGs) and Proteins (DEPs) in granulosa cells from female patients with MS-associated infertility.

Transcriptome and proteome analyses were integrated to compare granulosa cells from three MS patients with infertility to three control subjects. RNA sequencing and quantitative proteomics analyses were conducted, followed by differential expression analysis, Gene Set Enrichment Analysis (GSEA), and Protein-protein Interaction (PPI) network construction. Functional enrichment of overlapping DEGs and DEPs and potential drug-protein interactions were also explored. Hub genes identified by PPI were validated via quantitative Polymerase Chain Reaction (qPCR) and western blot assays.

Principal Component Analysis (PCA) demonstrated a distinct separation between MS and control groups, indicating significant differences in gene and protein expression. A total of 1,046 upregulated and 23 downregulated DEGs, along with 222 upregulated and 412 downregulated DEPs, were identified in the MS group. GSEA highlighted enrichment in processes, like the cell cycle and immune response. Venn diagram revealed 71 overlapping DEGs and DEPs, mainly related to immune regulation. Key hub proteins and potential therapeutic candidates were identified, with hub genes upregulated at the mRNA level, but downregulated at the protein level in granulosa cells of MS patients.

The integrative analyses revealed significant molecular alterations in granulosa cells from MS patients with infertility. Identified DEGs, DEPs, and hub proteins suggested potential therapeutic targets and pathways for addressing MS-associated infertility.

Prevention of the formation of β-haematin is the target of several existing antimalarials drugs, most notably chloroquine. This target is therefore attractive for the development of new molecules with antimalarial potential.

In this study, we have used a combination of ab-initio molecular dynamics and density functional tight-binding to examine the possible interaction mechanisms between five amodiaquine analogues and four conformations of haematin. Reactivity and stability of these complexes were investigated using bond length (Fe-N and Fe-O), energies (HOMO-LUMO) and molecular dynamics.

Results revealed a good interaction between haem and the compounds, stable geometries of complexes.

The findings from this study are valuable because they can aid the design and understanding of new therapeutic molecules that could be used to treat drug-resistant malaria, a global threat of today.

A new series of triazoles with antifungal activity have been synthesized in a one-step fashion by direct reaction of 2-(2,4-difluorophenyl)-2,3-epoxy-1-(1H-1,2,4-triazol-1-yl)propane with various diamines.

Obtained compounds were profiled for biological activity against pathogenic strains of fungi C. albicans and A. niger. Molecular modeling was used to predict binding modes.

The lead compound was 4 times more active against C. albicans than fluconazole and demonstrated a wider spectrum of activity, inhibiting the growth of A. niger.

The results presented herein can contribute to the development of novel antifungal therapeutic agents.