Anti-cancer agents in medicinal chemistry最新文献

Introduction: Triple Negative Breast Cancer (TNBC), which makes up 15% of all breast cancers, is widely acknowledged as the most aggressive and challenging subtype of the disease. It is characterized by the absence of HER2 receptors, progesterone, and estrogen, which limits the options for targeted treatment and mainly affects younger women. It is associated with a poor prognosis due to its rapid progression, high recurrence rates, and risk of metastasizing into vital organs like the brain and lungs. These clinical challenges underscore the urgent need for personalized treatment plans and innovative therapeutic strategies.

Methods: Numerous studies have identified dysregulated signaling pathways in TNBC, including the PI3K/AKT/mTOR, JAK/STAT, Wnt/β-catenin, Notch, and MAPK/ERK pathways, which offer therapeutic targets.

Results: Recent developments in clinical and molecular research have presented potential treatment strategies. Pembrolizumab and other immune checkpoint inhibitors have demonstrated significant benefits when used in conjunction with chemotherapy for both early-stage and metastatic TNBC. In advanced patients, sacituzumab, govitecan, and other Antibody-Drug Conjugates (ADCs) have shown remarkable efficacy in delivering cytotoxic medications, improving progression-free survival. Significant obstacles still exist despite these developments, such as tumor heterogeneity and treatment resistance.

Discussion: This review highlights the beneficial effects of small molecule inhibitors and combination therapies in treating the deadliest type of breast cancer, as well as the therapeutic potential of targeting dysregulated signaling pathways and providing insight into potential avenues for developing new therapies.

Conclusion: To significantly enhance outcomes for TNBC patients, future research must concentrate on identifying predictive biomarkers and refining individualized therapy plans.

Introduction: Bone tumors, especially in advanced stages, pose serious diagnostic and therapeutic challenges due to their aggressive nature and the invasiveness of traditional biopsy techniques. Liquid biopsy offers a promising, minimally invasive alternative by analyzing tumor-derived components from bodily fluids, such as circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and extracellular vesicles (EVs). These biomarkers enable dynamic and precise disease monitoring.

Objective: This review aimed to investigate the role of liquid biopsy in the diagnosis, prognosis, and treatment guidance of bone tumors, highlighting recent molecular advances and clinical findings.

Methods: A structured narrative review was conducted using PubMed, covering studies published up to July 2024. Studies involving osteosarcoma, Ewing sarcoma, chondrosarcoma, and chordoma were included, focusing on the clinical implications of CTCs, ctDNA, and EVs from plasma, serum, and other fluids.

Results: Liquid biopsy technologies demonstrated high diagnostic accuracy in bone tumors. In osteosarcoma, CTC detection using qRT-PCR and FISH methods showed sensitivities up to 98.6% and was strongly associated with metastatic disease and recurrence risk. ctDNA profiling identified tumor-specific mutations, hypomethylation markers (e.g., IRX1), and early relapse indicators with up to 97.4% specificity. EV-associated biomarkers, particularly miRNAs, such as miR-25-3p and a 3-miRNA signature, distinguished tumor subtypes and predicted metastasis-free survival. Advanced techniques, like SERS and MALDI-TOF MS profiling of exosomes, achieved diagnostic accuracies near 100%. EV RNA sequencing revealed differential gene expression and fusion events linked to metastatic progression and long-term outcomes.

Conclusion: Liquid biopsy holds strong potential for transforming bone tumor care. Its clinical adoption depends on further validation through standardized methods and large-scale studies.

Introduction: Isatin derivatives are an important class of nitrogen-containing heterocyclic compounds that have exhibited a broad spectrum of pharmacological and biological activities. The condensation reaction of isatin readily forms C=N-bonded compounds due to the high reactivity of the 3-position carbonyl group. Hydrazone compounds also play an important role in research related to pesticide chemistry and medicinal chemistry. Therefore, we propose that the compound incorporates both indigo and hydrazone skeletons, which could confer excellent biological activity. The objective of this study is to synthesize novel isatinhydrazone derivatives that function as CDK2 inhibitors through molecular docking and bioactivity studies.

Methods: A series of isatin-hydrazone derivatives was synthesized and characterized using ¹H NMR, ¹³C NMR, and HRMS. The in vitro cytotoxicities of these compounds were assessed using an MTT assay against A549 (non-small cell lung cancer), HepG2 (hepatocellular carcinoma), and HeLa (cervical cancer) cell lines.

Results: According to the results of the MTT assay, compounds 2e and 2f exhibited potent selectivity and activity against A549 (IC₅₀ = 5 nM) and HeLa cells (IC₅₀ = 6 nM), respectively. Compound 2h demonstrated dual efficacy against A549 (IC₅₀= 8 nM) and HepG2 (IC₅₀= 13 nM). In addition, molecular docking revealed strong binding affinities and stable interactions between active derivatives and key residues within the CDK2 active site.

Conclusion: These novel isatin-hydrazone derivatives, particularly 2e, 2f, and 2h, could be used as potential anticancer agents that inhibit CDK2 kinase activity.

Introduction: During the last 20 years, the prevalence of colon cancer, among the most prevalent gastrointestinal cancers globally, has increased in the majority of nations. The current review compiled phytochemicals reported to manage colon cancer from 2015 to 2020.

Methods: The article is taken from various sources of Web of Science, PubMed, Google Scholar, Scopus, Elsevier, Research Gate, and PubChem Results: Colon cancer is the leading cause of cancer-related death worldwide and impacts both men and women. Because of the present dietary habits and lifestyle, which include eating a lot of meat, drinking alcohol, and not exercising enough, the death rate from colon cancer has increased globally. A robust gastrointestinal tract and the control of regular intestinal activity seem to be significantly influenced by dietary fiber.

Discussion: The prognosis for colon cancer is dismal, as it is frequently discovered at an advanced stage. Despite some evidence suggesting a diet low in fibre predisposes to colon carcinogenesis. The use of phytochemicals may help in the management of colon cancer.

Conclusion: By altering many signalling pathways involved in the control of chronic inflammation, the cell cycle, autophagy, apoptotic metastasis, and angiogenesis, these natural compounds have been shown to have anticolon cancer properties. Compounds such as Ellagitannin, Ursolic acid, Garcinol, Oxymatrine, Emodin, Catalpol, Resveratrol, Zerumbone, Curcumin, Pyrogallol, α-Hederin, Juglone, Zingerone, Brosimone I, Organosilicon, Myricetin, Tenacissoside H, 6,8-Diprenylorobol, Plumbagin, Dioscin, and many more are listed with their mechanisms of action.

Introduction: Skin cancer is a major global health concern, with rising prevalence and limited effectiveness of conventional therapies. Natural phytopharmaceuticals, particularly those derived from Triticum aestivum (wheatgrass), offer promising therapeutic potential due to their antioxidant, anti-inflammatory, and anticancer properties. This review explores the potential of nanogel-encapsulated wheatgrass bioactives to modulate molecular pathways involved in skin cancer development.

Methods: A comprehensive review was conducted of preclinical studies, advances in nanogel-based delivery systems, and the molecular pharmacology of wheatgrass phytoconstituents. Emphasis was placed on their interactions with key cancer-related signaling pathways and the impact of nanogels on pharmacokinetic and pharmacodynamic profiles.

Results: Wheatgrass bioactives were found to regulate oncogenic pathways, including PI3K/Akt, MAPK/ERK, NF-κB, and p53. Nanogel encapsulation enhanced solubility, stability, targeted delivery, and bioavailability. Both in vitro and in vivo studies demonstrated improved cytotoxicity against melanoma and non-melanoma skin cancer cells, with reduced off-target effects.

Discussion: Nanogel-based delivery of wheatgrass phytopharmaceuticals offers a multi-targeted strategy by modulating multiple cancer pathways while addressing challenges associated with natural compound delivery. Despite promising preclinical results, translational limitations remain, including scarce human trials and variability in formulation. Future research should prioritize clinical validation and regulatory standardization.

Conclusion: Nanogel-encapsulated wheatgrass bioactives represent a novel, mechanism-driven, and targetspecific approach for skin cancer therapy, with the potential to advance phytotherapy toward mainstream oncology treatment.

Introduction: Heterocyclic compounds are widely utilized in the development of anticancer medications due to their diverse structures and ability to interact with multiple biological targets within cancer cells. Quinoline is a heterocyclic compound and an essential compound in the domains of industrial and pharmaceutical chemistry because of its various pharmacological effects. Researchers are developing new traditional, synthetic, and innovative green approaches to synthesize mono- or poly-substituted quinoline derivatives for anticancer activity.

Methods: A comprehensive literature survey was conducted using multiple databases, including Google Scholar, PubMed, SpringerLink, ScienceDirect, and others, to investigate the existing literature on synthetic strategies for various quinoline derivatives. This review article intends to present a summary of various traditional synthetic methods alongside innovative green approaches.

Results: Many researchers have demonstrated that quinoline derivatives can be synthesized using various methods, including traditional techniques, hybrid approaches with heterocyclic structures, and innovative green synthetic methods, as well as elucidating their structure-activity relationships for potential use as anticancer agents. The majority of traditional synthetic methods rely on hazardous chemicals, low reaction rates, high temperatures, and high pressures. Currently, the green chemistry approach produces eco-friendly, economical, highyield, pure, and outstanding products in the fields of industry and pharmaceuticals.

Discussion: This section explores various affordable and eco-friendly synthetic techniques that produce potent and specific quinoline compounds, intended for use as anticancer agents.

Conclusion: The progress demonstrated in the green synthetic methods and the development of quinoline-based compounds as new treatment options could aid in identifying new and effective quinoline derivatives for cancer treatment in the future.

Introduction: Breast cancer remains a leading cause of cancer-related mortality in women, primarily due to Breast Cancer Stem Cells (BCSCs), which contribute to tumor progression, metastasis, and resistance to conventional therapies. Vitex negundo Linn. (VN), a medicinal plant abundant in polyphenolic flavonoids such as luteolin (LT), has previously demonstrated anticancer potential. This study investigates the active metabolite profiling of VN targeting BCSCs and evaluates LT's therapeutic potential through in vitro and in silico approaches.

Methods: An integrated network pharmacology and computational approach identified VN metabolites targeting BCSCs, including CDK1, cyclin B1/B2, TOP1, GSK-3β, and PARP1. Mutational analysis in MCF-7 cells followed by luteolin (LT) treatment assessed its impact on stemness, gene expression, ROS generation, cell cycle, and apoptosis. Molecular docking and dynamics confirmed LT's strong binding to CDK1/Cyclin B.

Results: LT significantly reduced the properties of BCSCs by inhibiting the CDK1/Cyclin B complex and downregulating associated genes. It induced ROS-mediated apoptosis and altered cell cycle distribution, notably increasing G1 and S phase populations. Molecular modeling confirmed strong binding of LT to CDK1/Cyclin B, suggesting disruption of cell cycle regulation and self-renewal.

Discussion: LT binds strongly to CDK1 and Cyclin B proteins, suppressing their activity in MCF-7 cells. This disrupts gene expression linked to BCSC self-renewal, induces apoptosis, and causes cell cycle arrest. LT targeting CDK1/Cyclin B complexes offers promising therapeutic potential for future clinical development against BCSCs.

Conclusion: LT from VN shows promise as a therapeutic agent targeting CDK1/Cyclin B in ER+ breast cancer stem cells, supporting its potential for clinical development.

Introduction: Lapatinib, a novel targeted anti-tumor drug in clinical use, demonstrates notable potential for liver cancer treatment. However, its mechanism of action in liver hepatocellular carcinoma (LIHC) remains poorly understood. This investigation sought to clarify the function of secreted phosphoprotein 1 (SPP1) in LIHC and investigate the anti-tumor effects of lapatinib on SPP1 expression.

Methods: We analyzed data from normal liver and LIHC specimens obtained from The Cancer Genome Atlas (TCGA) and the GSE6764 dataset using R version 4.2.1. SPP1 protein expression in LIHC patients and its impact on patient prognosis were evaluated. Western blotting evaluated lapatinib-induced alterations in SPP1 protein levels in hepatoma cells. Cell Counting Kit-8 (CCK-8) assays measured lapatinib's impact on hepatoma cell growth and proliferation.

Results and Discussion: SPP1 level was notably elevated in LIHC specimens versus normal liver tissues (P < 0.01). The survival outcomes were notably inferior in cases displaying elevated SPP1 levels versus those with reduced levels (P < 0.05). CCK-8 analyses demonstrated that a decrease in SPP1 expression leads to a significant inhibition of growth and proliferation in the LIHC cell line HepG2, while lapatinib can inhibit the survival of liver cancer cells. Western blotting analyses revealed that lapatinib treatment reduced SPP1 expression in HepG2 cells, increased the ratio of BAX/Bcl2, and triggered apoptosis in cells.

Conclusion: These observations demonstrate that the expression of SPP1 is associated with disease progression and survival in patients with LIHC. Lapatinib exerts its anti-tumor effects in LIHC by downregulating SPP1 expression and promoting apoptosis in hepatoma cells.

Introduction: The polo-like kinase-1 (PLK1) plays a significant role in cell cycle regulation and proliferation; upon dysregulation, PLK1 activates different oncogenic pathways that lead to breast cancer. Therefore, targeting the PLK1 protein on the kinase domain prevents the possibility of tumor development.

Methods: A machine learning model was developed to screen small molecules against PLK1 using a cancer bioassay dataset. The binding affinity and structural integrity of the complex were assessed using molecular docking and dynamic studies. In vitro evaluation was then performed for the screened compound against the SKBR3 cell line.

Results: The research findings highlighted the silymarin flavonoid to have a greater binding energy with PLK1 (-9.2 Kcal/mol) than other molecules (above -8.5 Kcal/mol). Additionally, the molecular dynamics simulation showed silymarin to be more stable, less flexible, and more compact with PLK1. Further, the binding free energy revealed silymarin to be more stable with PLK1 (-13.25 kcal/mol) than volasertib (-2.87 kcal/mol). The IC50 value of silymarin was found to be 95.76 μg/mL, inducing apoptosis on the SKBR3 cell line.

Discussion: Despite PLK1 being predicted as a potential oncogenic target, the treatment choices were limited. A cheminformatics approach was utilized for screening inhibitors against PLK1. The in silico and in vitro evaluations indicated that silymarin effectively inhibited the PLK1 protein in breast cancer.

Conclusion: These research findings established silymarin as a potential alternative drug targeting PLK1, which is highly expressed in HER2-positive breast cancer, and modulates the oncogenic processes not just in breast cancer, but also in other cancers.

Introduction: Cynara scolymus (Artichoke) is a medicinal plant of significant pharmacological importance, rich in phenolic acids and flavonoids. Therefore, the current research aimed to assess the anticancer properties and potential molecular pathways of Artichoke extract utilizing an HCC rat model induced by Carbon tetrachloride (CCl4).

Methods: Fifty male albino rats were randomly allocated into five groups: a negative control group (NCG), a positive control group (PCG), an Artichoke protective group (APG), an Artichoke treatment group (ATG), and a cisplatin treatment group (CTG). Blood and liver tissue samples were collected for biochemical and molecular analyses at the end of the experiment. We also performed histological examination of the liver and an immunohistochemistry assay for the significant tumor marker alpha-fetoprotein (AFP) and Nrf-2.

Results: Our data showed higher liver enzymes in PCG compared with NCG. Additionally, we also found a significant decrease in Nrf-2, CAT, SOD, caspase 3, and caspase 9 levels and up-regulation of AKT and PI3K in the PCG relative to the negative control group. On the other hand, our findings suggest that Artichoke extract holds protective and therapeutic potential for effectively treating HCC induced by CCl4, especially in the APG.

Discussion: Our findings imply that the impressive antioxidant, apoptotic, and anticancer capabilities of Artichoke extract are due to the combination of the phenolic acids and flavonoids. Consequently, it is advisable to incorporate artichoke as a dietary supplement for individuals with chronic liver conditions.

Conclusion: We conclude that the up-regulation of the Caspase 3 and Caspase 9 pathways and the suppression of PI3K/AKT signalling pathways may be the mechanisms behind the anti-tumor actions of artichoke extract.