Anti-cancer agents in medicinal chemistry最新文献

Colorectal cancer is the fourth most prevalent cause of cancer-related fatalities, and cancer is still one of the major causes of death globally. Although pyrimidine analogues can target abnormal cellular growth, they have demonstrated potential as therapeutic treatments for a variety of malignancies, including colon cancer. A vital nitrogen-containing aromatic heterocyclic molecule, pyrimidine is an important target for cancer treatments since it is involved in the construction of DNA and RNA. Recent research has investigated the synthesis and assessment of a number of pyrimidine derivatives, demonstrating their capacity to block particular enzymes and pathways linked to the development of cancer. According to the review, a number of pyrimidine-based chemical families, such as 1H-pyrazolo, diarylpyrazolo, and bromo-pyrimidine derivatives, have shown strong anti-cancer properties in preclinical models, especially against lung and colon cancer cell lines. Moreover, these compounds' structure-activity relationship (SAR) studies show that changes made at important positions on the pyrimidine scaffold improve their anticancer efficacy. These findings highlight the significance of further study into pyrimidine analogues as promising candidates for cancer therapy.

The next-generation nanoparticles overcome the drawbacks of early nanoplatforms by integrating multiple functions, such as drug delivery, controlled drug release, and combination therapy, into a single system. This study examines the biomedical applications of quantum dots, carbon nanotubes, superparamagnetic iron oxide nanoparticles, and layered double hydroxides for the delivery of breast cancer drugs. They are termed as "nextgeneration" nanoparticles, as they are advanced nanocarriers that offer a comprehensive and alternative approach towards breast cancer treatment, providing enhanced specificity and efficacy compared to their predecessors. The development of these nanoplatforms has significantly enhanced drug bioavailability and reduced toxicity. A comprehensive analysis of a nanotechnology-based drug delivery system was conducted. The keywords used for this review were "Breast Cancer", "Targeted Drug Delivery", "Quantum Dots", "Carbon Nanotubes", "Layer Double Hydroxides", and "Superparamagnetic Iron Oxide Nanoparticles". The inclusion criteria consisted of studies focusing on breast cancer, targeted drug delivery, and therapeutic applications of these nanocarriers. In contrast, exclusion criteria included studies focusing on the synthesis of nanocarriers and the diagnostic applications of these nanostructures. The study underscores their mechanisms, limitations, and future development directions. Additionally, the study tracks the evolution of the nanocarriers since their early discovery. Next-generation nanocarriers (QDs, CNTs, SPIONs, and LDHs) have strong therapeutic potential owing to their precisely engineered properties, such as size, shape, morphology, and surface modifications. Their trigger-initiated drug release mechanisms enable targeted delivery with a better rate of tumor penetration, while their ability to co-deliver multiple therapeutic agents addresses drug resistance issues and provides synergistic effects. Comparative analyses have revealed that these advanced nanoplatforms significantly outperform early-generation carriers in terms of bioavailability, reduced toxicity, and treatment efficacy across various breast cancer types. Next-generation nanoplatforms offer unprecedented opportunities for targeted and efficient cancer treatment. Continued research and innovation are necessary to address existing challenges and to optimize their therapeutic potential for clinical applications.

Introduction: Cancer progression is increasingly understood to be influenced by neural mechanisms, including neurotransmitter signaling, neurotrophic factor activity, neuroinflammation, and neurogenic inflammation. These neurobiological interactions contribute to tumor proliferation, angiogenesis, and metastasis. Kinase inhibitors, a class of targeted therapies that block dysregulated kinase activity, have demonstrated promise not only in direct tumor suppression but also in modulating neural pathways associated with cancer progression.

Methods: This review examines the role of kinase inhibitors in modulating cancer-associated neural mechanisms. A comprehensive literature search was conducted to identify studies exploring the effects of kinase inhibition on: (1) neurotransmitter signaling pathways; (2) neurotrophic factors such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF); (3) neuroinflammation through glial cell modulation; and (4) neurogenic inflammation. Additionally, we assessed the impact of kinase inhibitors on tumor-induced axonogenesis and stress-related signaling. Clinical relevance was evaluated through analysis of preclinical models, human case studies, and outcomes from relevant clinical trials.

Results: Kinase inhibitors were found to significantly modulate neural factors that facilitate tumor growth. Specifically, they can suppress neurotrophic signaling (e.g., NGF/TrkA, BDNF/TrkB), inhibit glial activation, reduce pro-inflammatory cytokine production, and block neurotransmitter-induced proliferation. Inhibition of stress-responsive kinases such as p38 MAPK and JNK also disrupted tumor-associated axonogenesis and inflammation. Clinical trials demonstrate improved outcomes in cancers such as glioblastoma, breast cancer, and pancreatic cancer when kinase inhibitors are employed with consideration of neural mechanisms.

Discussion: These findings support the emerging concept of targeting the neural tumor microenvironment as a therapeutic strategy. Kinase inhibitors represent a dual-action approach, suppressing both cancer cell intrinsic growth pathways and the neural factors that sustain them. However, several challenges persist, including resistance mechanisms, variability in patient neural profiles, and off-target effects. Future research should focus on the development of neural-specific kinase inhibitors, the use of neural biomarkers for therapy selection, and the integration of neuro-oncology into personalized treatment plans.

Conclusion: Kinase inhibitors offer a promising frontier in cancer treatment by targeting neural mechanisms that contribute to tumor progression. While current evidence is encouraging, further investigation is required to optimize their use within neuro-oncology. Personalized approaches and novel targets within the neural-cancer axis will be essential for translating thi

Recent advancements in medication formulations and drug delivery systems over the past two decades have improved patient adherence and pharmacological responses. Efficient, target-specific medication delivery remains challenging, with many current systems designed to minimize drug loss and degradation. Magnetosomes, as nanocarriers, show promise for delivering antibodies, vaccine DNA, and siRNA, enhancing the stability of chemotherapeutics, and enabling targeted delivery to malignant tumors. Targeted drug delivery is crucial in cancer treatment, as anticancer drugs often cannot differentiate between healthy and malignant cells, causing side effects and systemic toxicity. Magnetosome-based drug delivery offers a potential solution, minimizing adverse effects and promoting drug accumulation at the target site. This review covers the design, development, and advancements in magnetosome-based drug delivery for cancer therapy.

Introduction: Polyamine metabolism is essential for cancer cell growth, with enzymes like ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC) playing key roles in polyamine (PA) biosynthesis. These polyamines (putrescine, spermidine, and spermine) regulate vital cellular processes, including DNA replication, protein synthesis, and cell cycle progression. Dysregulated polyamine metabolism is common in cancer, making ODC and AdoMetDC attractive therapeutic targets. This review highlights polyamines' role in cancer and explores combination therapies targeting polyamine metabolism and critical signaling pathways for improved clinical outcomes.

Methods: A comprehensive analysis of both historical and recent literature on polyamine metabolism in cancer was performed using PubMed, which provides access to over 37 million citations from biomedical literature. Expression data for key polyamine biosynthetic enzymes, ODC and AdoMetDC, were obtained from the UALCAN portal - an interactive web resource for the analysis of cancer OMICS data. The IUPAC names of drugs and inhibitors targeting the polyamine pathway were retrieved from the PubChem database and used to generate molecular structures using the BIOVIA Draw 2025 program. Additionally, the ClinicalTrials.gov database was explored to identify ongoing and completed clinical research studies, as well as to gather detailed information on therapeutic agents targeting polyamine metabolism.

Results: Aberrant polyamine metabolism in cancer is driven by oncogenic pathways like MYC, Akt, and mTOR. MYC upregulates ODC1, promoting polyamine dysregulation. Defects in enzymes such as MTA phosphorylase (MTAP) enhance cancer cell sensitivity to inhibitors of purine/pyrimidine synthesis and the ubiquitin-proteasome pathway, suggesting alternative therapeutic strategies.

Discussion: Therapeutic strategies combining polyamine biosynthesis inhibition with targeting nucleotide synthesis or proteasome function have shown synergistic potential. However, the dual nature of polyamines - supporting both, tumor growth and ferroptotic cell death - poses a therapeutic challenge. Balancing these effects is key to designing effective interventions. Advancing this field requires not only selective inhibitors but also a deeper understanding of context-dependent polyamine functions in tumor biology.

Conclusion: Developing more potent inhibitors with improved drug-like properties is crucial for advancing polyamine- targeted therapies and positioning this field at the forefront of cancer research.

Introduction: Cyclooxygenase, an enzyme that occurs in at least two distinct variants (COX-1 and COX-2), is the target of classical inhibitors, which lack selectivity and inhibit both types of COX. However, a recent approach focuses explicitly on inhibiting COX-2, commonly found in inflamed tissue, resulting in fewer adverse effects than COX-1 inhibitors.

Methods: A series of 4-(4-(methylsulfonyl)phenyl)-6-phenylpyrimidin-2-amine derivatives were synthesized through a two-step process. First, 4-substituted acetophenones underwent base-catalyzed Claisen-Schmidt condensation with 4-(methylsulfonyl)benzaldehyde to yield chalcones, which were then cyclized with guanidine hydrochloride under basic reflux conditions. Molecular docking was performed using AutoDock Vina software. The inhibitory activities of COX-1 and COX-2 were evaluated using enzymatic assays. Antiplatelet aggregation was measured via a turbidimetric method, and antiproliferative activity was assessed using the MTT assay.

Results: The in vitro experiments on COX inhibition revealed that a substantial number of the synthesized compounds presented a strong suppressive effect against COX-2. The assessment of antiplatelet aggregation activity indicated that most of the derivatives effectively inhibited ADP-induced platelet aggregation. Compound 4i exhibited the most potent antiproliferative activity, comparable to cisplatin. The docking studies and molecular modeling results demonstrated that the designed compounds, except for 4b, exhibited a binding behavior comparable to that of celecoxib. In addition, the insertion of the SO2Me moiety within the secondary binding site of COX-2 was observed.

Discussion: These findings suggest that the structural modifications introduced in the synthesized derivatives contribute significantly to their selective COX-2 inhibition and antiplatelet properties. The correlation between docking results and biological assays supports the rationale behind the design of the compound.

Conclusion: The 4-(4-(methylsulfonyl)phenyl)-6-phenylpyrimidin-2-amine exhibits unique properties as a COX-2 inhibitor, displaying effective inhibition of COX-2 while showing minimal interaction with the COX-1 enzyme. Furthermore, our study revealed that most of these compounds exhibited inhibitory effects on ADP-induced platelet aggregation.

Introduction: Colorectal cancer is an important cause of cancer-related mortality, necessitating innovative therapies to improve efficacy and reduce side effects. This study explores the potential of Cisplatin and Rutin-loaded nanoliposomes (Cis-NLs and Rut-NLs) for anti-colorectal cancer activity.

Methods: Cis-NLs and Rut-NLs were prepared using thin-film hydration, achieving encapsulation efficiencies of 95.5% and 62.5%, respectively. Drug release studies revealed controlled profiles, with Cis-NLs showing a complete release (100%) and Rut-NLs reaching 23.48% over 48 hours. Stability assessments demonstrated minimal changes in size, polydispersity index (PDI), and zeta potential over three months. Encapsulation efficiency decreased slightly for Cis-NLs (92.87%) and significantly for Rut-NLs (26.55%). Several tests were performed to evaluate the biological activity of this combination on colorectal cancer cells and HDF cells to check its selectivity.

Results: In vitro cytotoxicity studies on HT29 colorectal cancer cells revealed IC50 values of 1.72 μg/mL for free Cisplatin, 2.35 μg/mL for Cis-NLs, >100 μg/mL for free Rutin, and 63.33 μg/mL for Rut-NLs. A combination of Cis-NLs and Rut-NLs reduced the IC50 to 2.2 μg/mL. Selective toxicity evaluation using human dermal fibroblasts showed an IC50 of 79.24 μM for cisplatin, reduced to 63.3 μM in Cis-NLs, with Rut-NLs demonstrating negligible toxicity.

Discussion: Wound healing assays confirmed significant inhibition of cell migration, with wound closure reduced from 62.41% in controls to 34.35% in treated groups. Utilizing nanotechnology, liposomal formulations were synthesized to enhance drug delivery and therapeutic synergy.

Conclusion: These results highlight the potential of Cisplatin and Rutin-loaded nanoliposomes as a combination therapy for colorectal cancer.

Introduction: Melanoma, an aggressive skin cancer, has seen treatment advancements with immune checkpoint inhibitors (ICIs) like ipilimumab and nivolumab. Despite improved survival rates, resistance remains a challenge. The recent focus on lymphocyte activation gene-3 (LAG-3) inhibitors, such as relatlimab, shows promise in combination therapies, potentially improving outcomes with fewer adverse effects. This review evaluates the safety and efficacy of anti-LAG-3 antibodies in melanoma treatment.

Methods: This systematic review and meta-analysis, following the PRISMA guidelines and registered in PROSPERO (CRD42024565756), assessed anti-LAG-3 antibodies in melanoma treatment. A thorough search across PubMed, Embase, Scopus, and Web of Science up to January 2024 yielded relevant studies. Data on study characteristics, patient demographics, disease characteristics, treatment details, and clinical outcomes were extracted. Quality assessment was performed using the MINOR criteria. The meta-analysis, using STATA and random- effects models, addressed heterogeneity to determine safety and efficacy outcomes.

Results: We examined the clinical benefit of this combination therapeutic approach by measuring several primary endpoints and running a meta-analysis to determine the pooled estimate of 6-month progression-free survival (PFS), 1-year PFS, 6-month duration of response (DoR), 1-year DoR, 1-year overall survival (OS), 2-year OS, partial response (PR), complete response (CR), objective response rate (ORR), disease control rate (DCR), stable disease (SD), and progressive disease (PD) for patients diagnosed with melanoma. Our analysis showed 66% of any grade treatment-related adverse events (trAEs) (95% CI: 51%-81%), 19% of grade ≥ 3 trAEs (95% CI: 11%- 27%), 12% of any grade AEs leading to discontinuation (95% CI: 9%-14%), and 8% of grade ≥ 3 AEs leading to discontinuation (95% CI: 6%-10%). 76% of any grade overall AEs (95% CI: 34%-100%), and 33% of grade ≥ 3 overall AEs (95% CI: 15%-50%). The most common AEs were fatigue, pneumonitis, rash, pruritus, colitis, hepatitis, diarrhea, hypothyroidism, thyroiditis, and adrenal insufficiency.

Discussion: This systematic review and meta-analysis provide comprehensive evidence regarding the safety and efficacy of anti-LAG-3 antibodies in melanoma therapy. Pooled data reveals encouraging outcomes across several key endpoints, including PFS, OS, and ORR. While trAEs were common (66% for any grade and 19% for grade ≥3), most were manageable.

Conclusion: Anti-LAG-3 therapy is an active and safe treatment that shows promising results in melanoma treatment.

Metastatic melanoma is an aggressive malignancy with limited treatment options at advanced stages. Lifileucel, an FDA-approved autologous Tumor-Infiltrating Lymphocyte (TIL) therapy, marks a major advancement in immunotherapy, particularly for patients who fail conventional treatments like immune checkpoint inhibitors and targeted therapies. The mechanism of lifileucel involves the ex vivo expansion of patient-derived TILs to boost immune responses against melanoma cells. These expanded TILs are re-infused into patients, enhancing tumor-specific cytotoxicity and modulating the tumor microenvironment for sustained immune activation. Clinical trials have demonstrated its efficacy, with the overall response rate (ORR) reaching up to 36% in heavily pretreated populations, offering durable responses and improved progression-free survival compared to traditional therapies. The personalized approach of lifileucel, leveraging the patient's own T-cell repertoire, highlights its potential for precision oncology by targeting individual tumor profiles. Its integration with combination therapies, particularly immune checkpoint inhibitors, shows promising synergistic effects, broadening its clinical applicability. In addition to clinical success, the role of lifileucel in influencing the melanogenesis pathway offers insights into optimizing therapeutic strategies for melanoma. Ongoing research focuses on enhancing TIL functionality, overcoming challenges like tumor-induced immune suppression, and extending the applicability of lifileucel to other solid tumors. This breakthrough therapy not only addresses a critical unmet need in melanoma treatment but also represents a paradigm shift toward personalized medicine in oncology. Lifileucel underscores the potential of TILbased approaches to revolutionize cancer care, setting the stage for future advancements in immunotherapy.

Natural products and their derivatives have played a dominant role in the development of therapeutic agents. Traditionally, most of the natural products developed for the effective treatment of different diseases have been sourced from plants. Natural product discovery has seen a shift of focus towards microorganisms due to the chemical diversity of bioactive products they synthesize. Myxobacteria produce a large variety of novel chemical entities with diverse structures and varied bioactivities. In the last few decades, secondary metabolites from different genera of myxobacteria have been recognized as harbouring potent anticancer activity. Several analogs of these anticancer compounds have been prepared to address the limitations such as, poor solubility, high toxicity and low production yield, in order to obtain the compounds in higher quantities with better pharmacological properties and target selectivity. For example, a semi-synthetic derivative of epothilone obtained from a strain of myxobacterium has been approved for clinical use against taxane-resistant breast cancer. The anticancer compounds from myxobacteria target microtubules, the cytoskeleton, vacuolar ATPase, methionine aminopeptidase, exportin, the proteasome or translation elongation factor to exert anticancer activity. The focus of this review is on the promising anticancer compounds produced by myxobacteria, their targets and their mechanisms of action in cancer cells.