Search Results (478)

Despite notable progress in drug discovery, cancer treatment remains hindered by limited therapeutic efficacy, poor target specificity, adverse effects, and the development of drug resistance. Molecular hybridization, which integrates two or more bioactive entities into a single molecule, has shown considerable potential to overcome these limitations. Since both azoles and flavonoids have demonstrated anticancer potential, extensive studies have been undertaken to combine the two entities and enhance the bioactivity of the resulting hybrids. In this context, numerous azole–flavonoid hybrids have been synthesized and investigated for their anticancer potential. This review provides an overview of the azole–flavonoid hybrids that are promising candidates for novel anticancer drug development, highlighting their superior antitumor potency compared to reference drugs, multitarget activity, tumor-selective cytotoxicity, efficacy against drug-resistant tumor cells, and structure–activity relationships. The review covers 250 hybrids, primarily triazole–chalcone hybrids but also triazole–flavone, flavanone, flavonol, and isoflavone hybrids, as well as other azole–flavonoid hybrids (imidazole–, pyrazole–, isoxazole–, and thiazole–flavonoid hybrids). Full article

Background: Nanomaterials have emerged as a transformative approach in modern pharmaceutical applications, offering advanced benefits compared to conventional therapies. Among available pharmaceutical nanomaterials, silver nanoparticles (AgNPs) have been reported with broad-spectrum antimicrobial potential and drug delivery potency. Nevertheless, some studies suggested that chemical synthesis of AgNPs might result in redundant chemicals, posing environmental and health risks. To minimize undesired products, a promising approach is to biologically synthesize this potent nanomaterial. Methods: This study ultilized an eco-friendly system for AgNPs synthesis using Aspergillus terreus isolated from the air. Physical properties of biosynthesized AgNPs were evaluated by UV–visible spectroscopy, dynamic light scattering, and scanning electron microscopy analysis. Antibacterial activity of biosynthesized AgNPs was examined by well diffusion and minimum inhibitory concentration, while in vitro cytotoxicity was used to determine the antitumor activity of AgNPs. Results: The biosynthesized AgNPs had a size of around 60 nm, a PDI inferior to 0.2, and a zeta potential of −30 mV. They exhibited potent antibacterial activity against both Gram-positive and Gram-negative pathogens. Additionally, these nanoparticles also exerted a selective antiproliferative effect on MCF-7, A549, and MDA-MB-231 cell lines. Conclusions: Our research presented the potential of biosynthesized AgNPs using Aspergillus terreus for antimicrobial and anticancer applications, offering an eco-friendly and sustainable alternative to traditional chemical methods. Full article

Background: Food rich in tocopherols (T) and tocotrienols (T3) are considered functional due to their ability to reduce oxidative stress and modulate anti-viability and pro-apoptotic pathways with anticancer potential; however, their efficacy differs between T and T3 and among isoforms (α and γ) likely due to differences in intracellular uptake and, consequently, in the activation of anticancer signaling pathways. To address these isoform-dependent differences, HeLa and MCF7 cancer cell lines were used to assess the antiproliferative activity of α-tocopherol (αT), γ-tocopherol (γT) and tocotrienols (Tocomin) as well as their pharmacological interactions according to Loewe and Chou–Talalay models. Methods: The tocol profile of the commercial mixture of T3 (Tocomin) was quantified by normal-phase HPLC. HeLa, MCF7, and ARPE-19 cells were cultured in DMEM supplemented with 10% FBS and exposed to αT, γT, or Tocomin (50–800 µg/mL; DMSO vehicle) for 48 h; viability was measured by the MTT assay and EC50 values were obtained from log(dose)–response fits (n = 3). Fixed-ratio (1:1) combinations were evaluated in HeLa and MCF7, and interactions were quantified using Loewe additivity and Chou–Talalay combination indices, supported by isobologram analysis. Results: Tocomin showed greater potency with αT and γT, and synergy with αT/γT; however, the combination of αT + γT showed antagonism in both cell lines. Conclusions: The higher potency of Tocomin and its synergistic interactions with αT or γT suggest that tocotrienol-rich mixtures may enhance the antiproliferative response, whereas combining αT and γT together may reduce efficacy under the tested conditions. Full article

Michael acceptors, such as chalcones and benzylidenes, are privileged scaffolds for the development of anticancer agents. Taking this into account, we developed a selective Claisen–Schmidt condensation of the dammarane-type triterpenoid hollongdione with pyridine-2-carbaldehyde, enabling controlled synthesis of mono- and bis-substituted triterpenes depending on the reaction conditions. The reaction demonstrated high temperature-dependent regioselectivity, providing C2-mono- 2 or 2,21-bis-substituted 3 triterpenes with yields up to 96% and 95%, respectively. The structures of the newly synthesized triterpene chalcones were elucidated by 1D and 2D NMR spectroscopy and unambiguously confirmed by a single-crystal X-ray diffraction, which established the E configuration of the exocyclic double bond. In biological studies, the bis-2-pyridylidene derivative 3 exhibited a pronounced and broad-spectrum antitumor activity in the NCI-60 panel, inducing cell death in 58 of 59 cancer cell lines. High selectivity toward melanoma, renal, and prostate cancer cell lines was observed, with selectivity indices (SI) of up to 18.82 for melanoma LOX IMVI. In MTT assays, compound 3 displayed a submicromolar cytotoxicity, particularly against the KRAS-mutant PANC-1 cell line (IC₅₀ = 0.22 µM). Anticancer activity was further confirmed in a zebrafish (Danio rerio) xenograft model of human HCT116 colon cancer, where tumor growth inhibition reached 72% without pronounced embryotoxicity (LC₅₀ = 1.4 µM). We have developed an efficient approach for the site-selective modification of hollongdione, providing access to potent anticancer dammarane-type chalcones. The bis-2-pyridylidene derivative 3 emerged as a promising lead compound, demonstrating submicromolar potency, high selectivity towards melanoma, and significant in vivo efficacy in a zebrafish xenograft model. Full article

Background/Objectives: Plant-derived bioactives offer pharmacological potential but are often limited by poor delivery and selectivity. The Pulicaria crispa dichloromethane fraction (DCMF) shows potent but non-selective antiproliferative activity. This study aimed to engineer a functional nanoformulation using a MIL-53(Fe) metal–organic framework (MOF) to achieve sustained release and improve in vitro potency and selectivity against colorectal cancer cells. Methods: DCMF was phytochemically profiled by GC-MS. A DCMF@MIL-53(Fe) nanocomposite was synthesized and characterized for particle size, zeta potential, and entrapment efficiency. In vitro release kinetics were evaluated. Anticancer activity and selectivity were assessed in HCT-116 cells. Mechanistic studies included cell-cycle analysis, cell-death assays, and molecular docking. Results: Tomentosin was identified as the predominant constituent (28.82%). The nanocomposite displayed suitable physicochemical properties (mean size: 218 nm; entrapment efficiency: 83.6%) and a clear transition from burst to sustained drug release over 48 h. Nanoencapsulation resulted in a 53-fold increase in cytotoxic potency, calculated on a DCMF-equivalent basis (IC₅₀ = 0.40 µg/mL), compared with free DCMF (IC₅₀ = 21.51 µg/mL), along with a modest improvement in selectivity. Enhanced activity was associated with G0/G1 cell cycle arrest and a shift toward necrotic, non-apoptotic cell death. Docking of the predominant constituent, tomentosin, supported plausible interactions with CDK4/Cyclin D3 and the MDM2–p53 axis, providing structural context for G1/S checkpoint disruption. Conclusions: MIL-53(Fe) nanoencapsulation converted a non-selective plant extract into a sustained-release formulation with improved in vitro efficacy and selectivity. These findings provide proof-of-concept that rational nano-delivery strategies can mitigate key pharmaceutical limitations of plant-derived fractions and enhance the anticancer potential of traditional medicinal resources. Full article

Gliomas are among the most challenging brain tumors to treat, owing to their marked heterogeneity and the aberrant signaling networks that sustain tumor growth and resistance to therapy. Quercetin, a dietary flavonoid widely found in fruit and vegetables, exhibits documented anticancer activity, prompting the development of optimized derivatives with improved biological potency. In earlier work, we synthesized and evaluated a series of quercetin derivatives and identified the acylated compound 3-O-decanoylquercetin (Q-3-Dec) as particularly effective in reducing glioma cell viability. In this study, we explored Q-3-Dec as a multi-target agent, which concomitantly impairs NF-κB/STAT3-dependent survival signaling, mitochondrial function, and O6-Methylguanine-DNA Methyltransferase (MGMT) expression, a DNA repair enzyme closely associated with chemoresistance, in glioma cells. In U373-MG glioma cells, treatment with 50 μM Q-3-Dec triggered pronounced, time-dependent morphological changes and an early loss of mitochondrial membrane potential after 3 h. With prolonged exposure, Q-3-Dec markedly decreased NF-κB and STAT3 phosphorylation and reduced the expression of the anti-apoptotic proteins Bcl-2 and survivin, alongside a significant decrease in MGMT levels. These combined effects culminated in a progressive increase in cell death, reaching approximately 30% after 48 h. Together, these findings position Q-3-Dec as a multi-node modulator of glioma survival, supporting its potential for further preclinical development to improve future therapeutic strategies against glioma. Full article

The rising global incidence of hepatocellular carcinoma demands innovative therapeutic strategies. This study explores the enhanced anticancer potential of magnesium-doped copper oxide (Mg-doped CuO) nanoparticles, which were synthesized to improve upon the properties of undoped CuO nanoparticles. Mg-doped CuO nanoparticles with doping concentrations ranging from 1% to 5% were prepared using the co-precipitation method and thoroughly characterized by SEM, EDS, and FTIR. Their biological activity was evaluated against HepG2 liver cancer cells and normal human fibroblast cells. The MTT assay demonstrated a significant, concentration-dependent increase in cytotoxicity for Mg-doped CuO nanoparticles compared to undoped CuO, with the 3% Mg-doped CuO formulation showing the greatest potency (IC₅₀ = 21.99 µg/mL at 48 h). Cell cycle analysis revealed that treatment with Mg-doped CuO nanoparticles, particularly at 3% and 5% doping concentrations, induced a substantial G2/M phase arrest, indicating a mechanism of action involving the disruption of cell division. Furthermore, all Mg-doped CuO nanoparticles exhibited markedly higher IC₅₀ values in normal fibroblasts, confirming a favorable selective toxicity towards cancer cells. Apoptosis was identified as a key cell death pathway through acridine orange/propidium iodide staining. These results conclusively show that magnesium doping significantly augments the selective anticancer efficacy of CuO nanoparticles via cell cycle arrest and apoptosis induction, presenting a highly promising nanomaterial targeted liver cancer therapy. Full article

Background: Medicinal plants used in traditional Mexican medicine represent a valuable source of bioactive compounds with potential anticancer activity. Beyond cytotoxic potency, selectivity toward cancer cells over normal cells is a critical toxicological parameter for identifying safer therapeutic candidates. This study aimed to evaluate the selective cytotoxic and antiproliferative effects of extracts from four Mexican medicinal plants across human cancerous and non-cancerous cell lines. Methods: Hexane, acetone, and methanolic extracts from Semialarium mexicanum, Eryngium heterophyllum, Piper auritum, and Cochlospermum vitifolium were evaluated in a panel of human cancer cell lines and non-tumoral models, including primary human uterine fibroblasts (HUFs). Cytotoxicity was assessed after 48 h of treatment using increasing extract concentrations, and selectivity indices were calculated. Cell cycle distribution and nuclear morphology analyses were performed to explore antiproliferative effects. Additionally, GC–MS-based chemical profiling was conducted on selected extracts to obtain a tentative characterization of major bioactive constituents. Results: The extracts exhibited differential cytotoxic profiles depending on plant species and solvent polarity. The hexane extract of Semialarium mexicanum showed the highest cytotoxic potency and selectivity toward cervical cancer cells, with half-maximal inhibitory concentration (IC₅₀); values of 15.9 ± 1.8 µg/mL and 17.2 ± 2.8 µg/mL in HeLa and SiHa cells, respectively, and selectivity index (SI) values > 5 when compared with primary human uterine fibroblasts (HUF). Extracts of Eryngium heterophyllum displayed moderate cytotoxic activity (IC₅₀ = 20–30 µg/mL in HeLa cells) with intermediate selectivity, whereas Cochlospermum vitifolium showed solvent-dependent effects and Piper auritum exhibited limited cytotoxicity. Cell cycle analysis revealed an increased sub-G1 population, and nuclear morphology assays demonstrated chromatin condensation and fragmentation in cancer cells, supporting an antiproliferative mechanism. GC–MS analysis of the hexane extract of Semialarium mexicanum suggested the presence of triterpenoid-related and other lipophilic compounds potentially associated with its selective anticancer activity. Conclusions: These findings provide in vitro evidence of selective anticancer activity of Mexican medicinal plant extracts and establish a basis for future mechanistic studies medicinal plant extracts and lay the groundwork for future mechanistic investigations. Full article

Background/Objectives: Parasporin PS2Aa1, recently designated as Mpp46Aa1, is recognized for its selective anticancer activity against various human cell lines. In this study, specific regions of the native protein were fragmented, and targeted amino acid substitutions were introduced to improve cytotoxic selectivity and potency. Methods: The modified fragments were evaluated individually and in combination with curcumin, a polyphenol with well-documented anticancer properties, and Sacha inchi-derived matrices, known for their antioxidant and antiproliferative activities. Results: Experimental results demonstrated that the substituted variant designated T104L-G108W exhibited superior anticancer activity compared to the native peptide P102-K11. Synergism assays revealed that curcumin-bioconjugated peptides were more effective against the tested cell lines, whereas combinations with Sacha inchi reduced cytotoxicity, suggesting possible interference in the mechanisms of action. Functional assays, including caspase 3/7 and 9 activation, Annexin V-Cy3 staining, and cell viability analysis with 6-CFDA, confirmed increased sensitivity in SiHa and HeLa cell lines, particularly for peptide T104L-G108W. Conclusions: Collectively, these findings support the effectiveness of a substitution-based strategy in improving parasporin fragments and underscore the therapeutic potential of peptide T104L-G108W as a novel anticancer candidate. Furthermore, this study provides preliminary evidence that natural biomolecules can be optimized through targeted modifications and rational combinations, establishing a framework for the development of sustainable and selective therapeutic approaches in cancer treatment. Full article

Oral squamous cell carcinoma (OSCC) remains a major therapeutic challenge due to aggressive progression, high recurrence, and limited selectivity of current treatments. In this study, a series of seven 4-amino-2-substituted tetrahydrobenzothieno[2,3-d]pyrimidines were evaluated for their cytotoxic, antiproliferative, and mechanistic effects against oral cancer cell lines with different metastatic potential (HSC-3 and SCC-9), alongside non-tumorigenic keratinocytes (HaCaTs). Several compounds demonstrated selective anticancer activity, with Compounds 5 and 6 showing the most favorable balance between potency and selectivity. Antiproliferative assays revealed effective inhibition of cancer cell growth, while clonogenic assays confirmed a pronounced reduction in long-term survival, particularly in highly metastatic HSC-3 cells. Mechanistic studies indicated that the anticancer effects are associated with S-phase cell cycle arrest, apoptosis induction, and profound disruption of the actin cytoskeleton. In silico ADME and drug-likeness analyses supported the lead-like properties of the most active derivatives. Overall, these findings identify thienopyrimidine derivatives as promising scaffolds for the development of targeted therapies against OSCC and warrant further optimization and in vivo evaluation. Full article

Natural products are a valuable source of structurally diverse bioactive compounds, many of which have contributed significantly to the discovery of new anticancer drugs. Carnosic acid 1, an abietane-type diterpenoid primarily found in rosemary and sage, has emerged as a promising scaffold due to its ability to modulate key cellular pathways involved in cancer development and progression, including the cell cycle, apoptosis, autophagy, inflammation, and oxidative stress. Despite its multifaceted approach to combat cancer and promising results obtained in vitro and in vivo, its moderate potency limits its clinical application. To address this limitation, several chemical modifications have been performed to generate semisynthetic derivatives with improved efficacy. Several semisynthetic derivatives have demonstrated significantly enhanced anticancer activity across diverse cancer models, highlighting the importance of structural optimization of the carnosic acid 1 backbone. This review provides a comprehensive overview of carnosic acid 1 and its semisynthetic derivatives, focusing on their anticancer activities, underlying molecular mechanisms, and structure–activity relationships, with the aim of guiding the future design and development of carnosic acid 1-derived anticancer drugs. Full article

Background: Gold (Au) complexes have emerged as promising anticancer candidates due to their distinct coordination chemistry and ability to modulate thiol-dependent and redox-regulated cellular pathways, particularly thioredoxin reductase (TrxR). In recent years, structurally diverse Au(I) and Au(III) complexes have been reported with potent in vitro anticancer activity; however, cross-study comparability and design principles remain unclear. Aim: This systematic review critically evaluates anticancer Au(I/III) complexes reported since 2016, with the specific aim of identifying how oxidation state, coordination geometry, and ligand class influence in vitro potency, selectivity, and translational potential. Methods: A PRISMA-guided literature search was performed in Scopus, Web of Science, PubMed, and ScienceDirect for studies published between January 2016 and March 2025. Two independent reviewers screened titles/abstracts and full texts according to predefined inclusion criteria. Only original studies reporting anticancer activity of structurally characterized Au(I/III) complexes in human cancer models were included. After the removal of duplicates, 1100 records were screened at the title and abstract level. Of these, 240 articles were assessed in full text for eligibility. Ultimately, 128 studies reporting anticancer activity of structurally characterized Au(I/III) complexes met the inclusion criteria and were included in the qualitative synthesis. Biological potency data were harmonized to μM units where applicable, and results were synthesized qualitatively due to heterogeneity in experimental design. Results: A total of 128 studies met the inclusion criteria. Au(I) complexes—particularly phosphine- and N-heterocyclic carbene (NHC)-based compounds—consistently showed sub-micromolar cytotoxicity in TrxR-dependent cancer cell lines, whereas Au(III) complexes displayed greater structural diversity but variable stability and redox behavior. In vivo efficacy was reported for a limited subset of compounds and was frequently constrained by solubility, systemic toxicity, or metabolic instability. Conclusions: The available evidence indicates that anticancer activity of gold complexes is strongly dependent on oxidation state, ligand environment, and redox stability. While Au(I) scaffolds show more reproducible in vitro potency, successful translation to in vivo models remains limited. This review defines structure–activity and structure–liability relationships that can guide the rational design of next-generation gold-based anticancer agents. Full article

Drug resistance remains a significant challenge in cancer therapy, accounting for most relapses and contributing substantially to cancer-related mortality worldwide. Several molecular processes are linked to the development of resistance to anticancer drugs, with the most studied mechanisms including epigenetic changes, drug efflux, cell survival signalling pathways, and inactivation of anticancer drugs. Both intrinsic and acquired forms of resistance hinder tumour cell elimination, reducing treatment success. This translates to poorer patient outcomes and the need for more aggressive treatment regimens. Therefore, understanding these molecular processes is crucial for enhancing the efficacy of anticancer therapy. Medicinal plants offer potential to counter various resistance mechanisms through their diverse phytocompounds. These compounds may offer benefits including consistent availability, anticancer potency, few side effects, and minimal drug resistance. However, the bioavailability of these phytochemicals and the lack of extensive clinical trials remain key challenges. Therefore, this review provides in-depth information on the mechanisms that lead to drug resistance during cervical cancer therapy, the challenges related to phytochemical bioavailability, the current status, and future needs for clinical trials evaluating the application of medicinal plants to combat drug resistance in cancer cells. Full article

PARP inhibitors are a clinically validated class of anticancer therapeutics that exploit synthetic lethality to target homologous recombination-deficient tumors, such as those carrying BRCA1/2 mutations. Nevertheless, the rational design of mitochondria-targeted PARP inhibitors capable of selective mitochondrial accumulation and organelle-specific PARP modulation remains an unresolved objective. To enable organelle-specific modulation of PARP activity, we synthesized a series of trialkyl(aryl)phosphonium conjugates of olaparib and rucaparib designed to target mitochondria by cardiolipin binding. Their activity was evaluated by PARP1 inhibition, cardiolipin affinity, and cytotoxicity in BRCA1-deficient HCC1937 breast cancer cells and non-malignant H9C2 cardiomyocytes. All conjugates retained potent PARP1 inhibition (IC₅₀ = 3.4–17 nM), comparable to the parent drugs. Several derivatives, particularly compounds 2d and 6c, exhibited strong cardiolipin binding (EC₅₀ = 12.99 µM and 6.77 µM, respectively) and significantly enhanced cytotoxicity in HCC1937 cells (IC₅₀ = 0.93 and 2.01 µM), outperforming olaparib and rucaparib. Notably, cytotoxicity toward H9C2 cells was lower, indicating a favorable selectivity profile. Phosphonium conjugation preserves PARP1 inhibitory activity while conferring mitochondrial targeting and enhanced anticancer potency. These findings support the development of mitochondria-targeted PARP inhibitors as a next-generation therapeutic strategy with the potential to improve efficacy and overcome resistance in HR-deficient tumors. Full article

Overexpression of protein phosphatase 5 (PP5) is implicated in tumor cell growth, establishing PP5 as a compelling target for small-molecule anticancer therapy. Building on prior success in achieving selectivity within the PP2A domain through scaffold functionalization that maximizes active-site interactions, we propose a parallel strategy for PP5 inhibition. Norcantharidin, the demethylated cousin of cantharidin, is a potent yet unselective phosphatase inhibitor, making its bicyclic framework an attractive platform for systematic derivatization. The approach reported herein exploits anhydride reactivity to generate a carboxylic acid derivative that is transformed into a chloromethyl ester. Chloromethyl ester functionality serves as a strategically activated intermediate enabling downstream functional-group diversification under mild, neutral conditions while preserving scaffold integrity. This modular synthetic strategy establishes a foundation for the development of PP5-selective norcantharidin derivatives with improved tumor selectivity, potency, and synthetic feasibility. Full article