Anti-cancer agents in medicinal chemistry最新文献

Background: Cancer is a complex disease marked by changes in the levels and functions of key cellular proteins, including oncogenes and tumor suppressors. Proteomics technology enables the identification of crucial protein targets and signaling pathways involved in cancer cell proliferation and metastasis. Various proteomics techniques have been employed to investigate the molecular mechanisms of cancer, aiding in the confirmation and characterization of heritable disorders.

Method: A comprehensive literature search was conducted using PubMed, ScienceDirect, and Google Scholar with search terms like "Cancer and proteomics" and "Mass spectrometry in oncology," utilizing Boolean operators for refinement. Selection criteria included peer-reviewed articles in English on MS-based biomarker detection, tumor-specific proteins, and drug resistance markers, excluding non-peer-reviewed works and pre-2000 publications unless foundational. Extracted data focused on MS methodologies, biomarker sensitivity, and clinical applications, particularly advances in detecting low-abundance biomarkers and monitoring treatment response. Methodological quality was assessed using PRISMA, evaluating study design, sample size, reproducibility, and statistical analysis. Ethical approval was not required, but adherence to systematic review guidelines and proper citation were ensured.

Result: In this review, we highlighted the advanced analytical technique for cancer diagnosis and management of cancer, and described the objective of novel cancer biomarkers. Mass spectrometry (MS) is transforming cancer diagnostics and personalized medicine by enabling precise biomarker detection and monitoring. Unlike traditional antibody-based methods, MS provides high-throughput, quantitative analysis of tumor-specific proteins in clinical samples like blood and tissue. Advanced MS techniques improve sensitivity, allowing for the identification of low-abundance biomarkers and tumor-associated proteoforms, including post-translational modifications and drug resistance markers. In research, MS-based proteomics supports multi-center biomarker validation studies with standardized protocols, enhancing reproducibility. The integration of proteomic data with genomic and transcriptomic datasets through proteogenomics is refining precision oncology strategies. These advancements are bridging the gap between research and clinical application, making MS a critical tool for early cancer detection, prognosis, and therapy selection.

Conclusion: Advancements in technology and analytical techniques have helped to produce more accurate and sensitive cancer-specific biomarkers. These methods are advancing rapidly, and developing high-throughput platforms has yielded great results. However, The substantial variation in protein concentrations makes cancer protein profiling extremely complicated. This shows that more technic

Background: In various kinds of cancer, including Non-Small Cell Lung Cancer (NSCLC), treatment resistance diminishes the effectiveness of current therapeutic approaches and underscores the need for new treatment strategies.

Aim: This study aimed to investigate the combined and individual effects of the anticancer drug carboplatin and the natural antioxidant curcumin, as well as the apoptotic effects of these drugs on the A549 cancer cells.

Objectives: The synergistic effect of the combined treatment with curcumin and carboplatin on lung cancer cells was evaluated, focusing on early apoptosis, caspase-3/9 activity, and mitochondrial membrane potential.

Methods: The cytotoxic effects were determined using the MTT method. Apoptotic changes were examined using the Annexin V-FITC labeling method. Activation of caspases-9 and -3 and mitochondrial membrane potential were measured using flow cytometry.

Results: The IC50 values of curcumin and carboplatin against A549 cells were determined to be 60±8 μM and 100±9 μM, respectively. The combination of curcumin and carboplatin showed a synergistic effect. After treating A549 cells with carboplatin, curcumin, or the combined use of curcumin+carboplatin for 12 hours, the rates of early apoptotic cells were determined to be 9.5±1.3%, 8.1±0.3%, and 22.2±2.9%, respectively. The rate of early apoptosis in combined use was significantly higher compared to individual use. Similarly, when the combined treatment of curcumin and carboplatin was compared to the administration of carboplatin alone, a higher level of mitochondrial membrane depolarization was observed. There was a slight increase in caspase 9 activity in the combined treatment group compared to the individual treatments. Furthermore, after treating A549 cells with the specified doses, the caspase 3 activity was determined for carboplatin (0.5±0.1%), curcumin (1.9±0.0%), and the combination of both (7.3±0.8%).

Conclusion: These results indicated that the combined use of curcumin and carboplatin enhanced apoptosis and mitochondrial depolarization, demonstrating that the combined treatment of drugs reduced the toxic dose of carboplatin. However, further research is needed to comprehensively understand the potential of this effect in in vivo studies.

Background: Breast cancer is an abnormal cell growth that develops in the breast and spreads throughout the body. Despite cancer being the second leading cause of death, survival rates are increasing as a result of progress in cancer screening and therapy. Breast cancer is the most frequently diagnosed cancer type among women, but in most cases, there are no obvious symptoms. Screening mammograms can be used for early detection of cancer. The size of the tumor and the extent of cancer spread determine the type of needed treatment. There are different forms of treatment, where targeted therapy is generally the least harmful. It targets specific characteristics of cancer cells, such as human epidermal growth factor receptor 2 (HER2). Tyrosine kinase inhibitors are effective targeted treatment of HER2 positive breast cancer. A newer class has emerged, cyclin dependent kinase (CDK4/6), which is used to treat metastatic breast cancer.

Objectives: Although CDK4/6 inhibitors class of therapy has revolutionized the treatment of metastatic breast cancer, some patients showed resistance and decreased efficacy. This study is the first to propose innovative computational strategies to improve the effectiveness and pharmacokinetic properties of existing HER2/CDK4/6 inhibitors anti-cancer agents. Through computer-aided drug design, the activity of existing breast cancer drug candidates has been tested. Structural modifications have been applied for in-silico optimization of their biological activity.

Methods: In this research, twenty-two analogues of the tested compounds have been proposed. Their biological activity and pharmacokinetic properties (ADMET) have been tested using BIOVIA Discovery Studio software.

Results: Out of the designed analogous compounds, seven proposed structures demonstrated superior efficacy compared to the original drugs. The research study docking studies revealed that modifications to lapatinib and tucatinib improved binding affinity to HER2 by 15-25%, with docking scores of -18.34 kcal/mol and -1.04 kcal/mol, respectively. Similarly, CDK4/6 inhibitors exhibited enhanced selectivity, with abemaciclib showing the highest binding energy of -13.2 kcal/mol. ADMET predictions suggested improved solubility and reduced toxicity risks compared to the original drugs.

Conclusion: The research study results demonstrate that the synthesis of more lipophilic analogues of lapatinib or tucatinib and, likewise designing of fluorinated derivatives of CDK4/6 inhibitors play a crucial role in improving the efficacy of these anti-cancer agents. These findings highlight the potential of the proposed modifications as promising candidates for further pharmacological and in vitro and in vivo clinical validation.

Background: Lung cancer is one of the most widespread malignancies among all types of cancers. There is uncertainty in its treatment because of the selectivity. The investigation is aimed to enhance therapeutic efficacy through targeted improvements in drug selectivity and reduced toxicity by analyzing well-accepted cyclooxygenase (COX)-2, which is an enzyme target and a known therapeutic target for anti-inflammatory and antitumor agents.

Objective: The objective of the present research was to identify the most suitable counterpart for celecoxib, which would produce synergistic effects and improve the selectivity index, safety, and efficacy of targeting cancer cells.

Methods: The HOPE-62 cancer cell line and noncancerous LLC-MK2 cell line were used to analyze the activity of the prepared formulations. The effectiveness was compared by calculating the half-maximal inhibitory concentration (IC50) values of carrageenan, celecoxib, and celecoxib embedded with carrageenan. The release pattern of celecoxib from the carrageenan matrix was also determined by using a trans-diffusion cell; moreover, the binding sites of carrageenan and celecoxib were also evaluated through in silico molecular docking studies.

Results: Carrageenan showed promising anticancer activity, with an IC50 value of 17.3±2 μM against the HOPE- 62 cell line. When blended with celecoxib (15.6±2 μM), the combination achieved enhanced efficacy and improved selectivity over celecoxib alone (IC50 of 10.3±1.5 μM). In noncancerous LLC-MK2 cells, the IC50 values were observed to be significantly higher: 1484 ±6 μM in the combined formulation and with IC50 values of 559±3 μM and 878±4 μM, respectively, in celecoxib and carrageenan alone.

Conclusion: The carrageenan-embedded celecoxib exhibited a significant increase in the selectivity index from 32 to 144, which suggests enhanced anticancer activity with a favorable safety profile. Initially, sustained release of celecoxib from the blend was at a higher rate, but steadily maintained rates were. The In-silico docking studies also supported the synergistic activity of the combined form through separate interaction patterns without interfering with others. These findings underscore the therapeutic potential of excipient-drug blending strategies to achieve synergistic effects, excellent selectivity, and reduced toxicity in cancer treatments.

Breast cancer is the most prevalent malignant tumor among women globally, with breast cancer susceptibility genes (BRCA1 and BRCA2, BRCA1/2) mutations significantly increasing the risk of developing aggressive forms of the disease. Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have shown promise in treating BRCA1/2-mutated breast cancer by exploiting deficiencies in homologous recombination (HR) repair. However, the emergence of acquired resistance poses a significant challenge. Our study examines the mechanisms of PARPi resistance in BRCA1/2-mutated breast cancer, synthesizing recent clinical advancements and identifying key resistance pathways, including HR recovery, DNA replication fork stability, and epigenetic modifications. We also highlight potential strategies to overcome these challenges to PARPi resistance, such as combination therapies and novel targets. Our comprehensive analysis aims to inform future clinical practices and guide the development of more effective treatment strategies.

Talimogene laherparepvec (T-VEC), the first FDA-approved oncolytic viral therapy, has transformed cancer immunotherapy since its 2015 approval for unresectable melanoma. Engineered from Herpes Simplex Virus type 1 (HSV-1) with deletions in ICP34.5 and ICP47 genes and GM-CSF insertion, T-VEC selectively replicates within the tumor cells, inducing lysis and releasing tumor-derived antigens while stimulating systemic antitumor immunity through dendritic cell activation. Although extensively studied for melanoma, its potential extends beyond this malignancy, with emerging applications in breast cancer, Head and Neck Squamous Cell Carcinoma (HNSCC), and other solid tumors. This review synthesizes T-VEC's mechanism of action, leveraging dysregulated Ras signalling, impaired interferon pathways in cancer cells, its clinical outcomes, and safety profile across these indications. While prior literature emphasizes melanoma monotherapy and combinations with immune checkpoint inhibitors, less attention has been given to its efficacy in non-melanoma cancers and synergistic potential with chemotherapy or radiation therapy. By exploring recent trials, such as T-VEC with neoadjuvant chemotherapy in triple-negative breast cancer and pembrolizumab in HNSCC, highlighting its versatility. Comparative analysis with other oncolytic viruses like HF-10, oncorine (H101), and measles virus variants positions T-VEC within the virotherapy landscape. Key challenges-systemic delivery, immune clearance, and biomarker development for patient selection-are addressed alongside strategies to enhance immune modulation through novel combinations. This review underscores T-VEC's expanding role in cancer treatment, offering clinicians' and researchers' insights to optimize its therapeutic horizons across diverse malignancies.

Background: Lung cancer remains a leading cause of cancer-related mortality worldwide, primarily due to late-stage diagnosis and resistance to conventional therapies. Recent studies have highlighted the potential of natural compounds in enhancing the efficacy and reducing the side effects of conventional cancer treatments. Baicalin, a bioactive compound from Scutellaria baicalensis, exhibits significant anticancer properties.

Objectives: This study aimed to investigate the role of baicalin in modulating lung cancer cell behavior through the arachidonate 12-lipoxygenase (ALOX12)-mediated ferroptosis pathway.

Methods: We employed cyber pharmacology and molecular docking techniques to predict and validate the interaction between baicalin and ALOX12. In vitro experiments were conducted on A549 lung cancer cells to assess the effects of baicalin on cell proliferation, migration, and invasion. The expression levels of ALOX12, reactive oxygen species (ROS), and ferroptosis markers, such as Glutathione Peroxidase 4 (GPX4) and Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4), were measured.

Results: Baicalin treatment significantly upregulated ALOX12 expression in lung cancer cells, and this upregulation was associated with a reduction in cell proliferation, migration, and invasion. Furthermore, baicalin-induced ferroptosis was characterized by increased ROS levels, iron accumulation, and elevated expression of GPX4 and ACSL4. These findings suggest that baicalin enhances ferroptosis through ALOX12 activation, synergistically inhibiting cancer cell growth.

Conclusion: Baicalin significantly upregulated ALOX12 expression, promoted ferroptosis, and inhibited the proliferation and migration of A549 lung cancer cells. This finding provides evidence for the potential use of baicalin as a therapeutic agent for lung cancer and highlights the importance of ALOX12 in lung cancer treatment strategies.

Background: Monastrol is a known kinesin Eg5 inhibitor. It is a dihydropyrimidine with 4-(mhydroxyphenyl) substituent. In contrast to taxols and vinca alkaloids, which, through targeting microtubules, affect both normal and cancer cells, kinesin inhibitors selectively target cancer cells.

Objectives: In this study, m-hydroxyphenyl in monastrol was replaced with imidazolyl substituent, which has better water solubility and is found in the structure of many drugs and biologically active compounds. The effects of synthesized compounds were also investigated.

Methods: Three series of monastrol-related dihydropyrimidinone derivatives were synthesized through a modified Biginelli reaction. The newly synthesized compounds were characterized by elemental analysis, LCMS, and NMR. Then, the structure-activity relationship (SAR) of synthesized compounds was evaluated by their toxicity, molecular docking scores, and results of molecular dynamic simulation. The compounds with more potential (4i, 4m, 5a, and 6a) were further investigated in vitro and in vivo for their anti-cancer effects.

Results: The synthesized compounds could effectively reduce the ATPase activity of kinesins, which was consistent with the observation of G2/M arrest of cells in flow cytometry and confocal microscopy results. In addition, an increase in cells in the sub-G1 phase, along with the enhancement of the Bax/Bcl-2 ratio and overexpression of caspases 3, 9, and 8, suggested the apoptosis-inducing effects of compounds. Moreover, compounds showed potent anti-angiogenic effects via altering the expression of genes involved in angiogenesis, which was consistent with the reduced length of capillaries in the CAM test. The synthesized compounds could also demonstrate satisfactory in vivo results in the mice tumor model, which was in accordance with the findings of in vitro experiments.

Conclusion: Novel dihydropyrimidinone derivatives synthesized via modified Biginelli reaction present promising potential as anti-cancer agents.

Aims: This study explores the therapeutic potential of Nigella sativa L. and its key bioactive compound, thymoquinone (TQ).

Background: Pancreatic cancer presents a significant health challenge due to its aggressiveness and limited treatment options. N. sativa and its component TQ have demonstrated anticancer properties in other cancers, warranting exploration in pancreatic cancer models.

Objective: To assess the antiproliferative, apoptotic, and anti-invasive effects of N. sativa extracts and TQ on pancreatic cancer cells, with a focus on modulating the NRF2/HO-1 and TNF-α signaling pathways.

Method: MIA PaCa-2 and PANC-1 pancreatic cancer cell lines were treated with essential and fixed oils, methanol extracts (from Türkiye and Syria), and TQ. Cell viability, apoptosis, and invasiveness were assessed via XTT, Annexin V, and Matrigel assays, respectively. Gene expression and cytokine levels were evaluated using RTqPCR and ELISA. HPLC was conducted to confirm TQ concentrations in extracts.

Result: The methanol extract of Türkiye-originated N. sativa seeds (TM) exhibited the highest cytotoxic effect, reducing cell viability in MIA PaCa-2 and PANC-1 at 0.05 mg/mL, while TQ significantly decreased viability at 20 μM. TM reduced MIA PaCa-2 and PANC-1 invasiveness (42±1.23 and 35±0.73, respectively) and contained a higher concentration of TQ (7.9168 ± 0.0561%) compared to the Syria-originated extract (SM).

Conclusion: The findings suggest that TM and TQ exhibit strong anticancer potential by modulating key signaling pathways in pancreatic cancer cells, supporting their potential for further development as therapeutic agents in pancreatic cancer treatment.

Background: Aurone based compounds exhibited antioxidant and anti-inflammatory potential and documented for their anticancer potential. The anticancer potential of aurone derivatives AU3, AU4, AU5, AU7, and AU10 is yet to be studied against breast cancer.

Objective: The present work was undertaken to evaluate the anticancer potential of aurone based test compounds AU3, AU4, AU5, AU7, and AU10 in breast cancer cell lines MCF-7.

Methods: The azaindole based aurones were synthesized by the condensing 4,6-dimethoxybenzofuran-3(2H)-one derivative with various indole aldehydes in the presence of sodium hydroxide. The MCF-7 breast cancer cell line was used to assess the cytotoxic effects of these compounds. Molecular docking studies of the synthesized compounds against the Cyclin-dependent kinase 2 (CDK2)/Cyclin A complex were conducted.

Results: Our experimental findings demonstrated that AU3, AU4, AU5, AU7, and AU10 elicited significant effects on MCF-7 by virtue of its minimum cell viability, with IC50 values of 70.14 μM, 87.85 μM, 133.21 μM, 52.79 μM, and 99.55 μM, respectively, thus, exhibits potential anticancer action. Further, to corroborate the anticancer potential, we investigated mechanisms of action through molecular docking studies with the CDK2/Cyclin A complex (PDB: 6GUC) and their findings demonstrated that test compounds showed robust binding through various interactions, including hydrogen bonds, Pi-interactions, and Alkyl bonds with key residues such as Lys129, Asp127, Gln131, and Asp145. Test compounds AU3 and AU7, exhibited better binding affinities and diverse interaction profiles, suggesting a potent disruption of CDK2/Cyclin A activity.

Conclusion: Thus, in conclusion, our findings revealed that AU3, AU4, AU5, AU7, and AU10 elicited anticancer action and their effects through CDK2/Cyclin A disruption.