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Molecules (Basel, Switzerland) Jun 2024In this research, with an aim to develop novel pyrazole oxime ether derivatives possessing potential biological activity, thirty-two pyrazole oxime ethers, including a...
In this research, with an aim to develop novel pyrazole oxime ether derivatives possessing potential biological activity, thirty-two pyrazole oxime ethers, including a substituted pyridine ring, have been synthesized and structurally identified through H NMR, C NMR, and HRMS. Bioassay data indicated that most of these compounds owned strong insecticidal properties against , , , and at a dosage of 500 μg/mL, and some title compounds were active towards at 500 μg/mL. Furthermore, some of the designed compounds had potent insecticidal effects against , , or at 100 μg/mL, with the mortalities of compounds , , , , , , , , , , and against , in particular, all reaching 100%. Even when the dosage was lowered to 20 μg/mL, compound also expressed 50% insecticidal activity against , and compounds , , , , , and displayed more than 60% inhibition rates against . The current results provided a significant basis for the rational design of biologically active pyrazole oxime ethers in future.
Topics: Pyrazoles; Oximes; Insecticides; Animals; Drug Design; Structure-Activity Relationship; Ethers; Molecular Structure; Pyridines; Moths
PubMed: 38930832
DOI: 10.3390/molecules29122767 -
International Journal of Molecular... Jun 2024The tumor microenvironment (TME) is crucial in tumor development, metastasis, and response to immunotherapy. DNA methylation can regulate the TME without altering the...
Identification and Validation of Tumor Microenvironment-Associated Signature in Clear-Cell Renal Cell Carcinoma through Integration of DNA Methylation and Gene Expression.
The tumor microenvironment (TME) is crucial in tumor development, metastasis, and response to immunotherapy. DNA methylation can regulate the TME without altering the DNA sequence. However, research on the methylation-driven TME in clear-cell renal cell carcinoma (ccRCC) is still lacking. In this study, integrated DNA methylation and RNA-seq data were used to explore methylation-driven genes (MDGs). Immune scores were calculated using the ESTIMATE, which was employed to identify TME-related genes. A new signature connected with methylation-regulated TME using univariate, multivariate Cox regression and LASSO regression analyses was developed. This signature consists of four TME-MDGs, including , , , and , which exhibit high methylation and low expression in tumors. Validation was performed using qRT-PCR which confirmed their downregulation in ccRCC clinical samples. Additionally, the signature demonstrated stable predictive performance in different subtypes of ccRCC. Risk scores are positively correlated with TMN stages, immune cell infiltration, tumor mutation burden, and adverse outcomes of immunotherapy. Interestingly, the expression of four TME-MDGs are highly correlated with the sensitivity of first-line drugs in ccRCC treatment, especially pazopanib. Molecular docking indicates a high affinity binding between the proteins and pazopanib. In summary, our study elucidates the comprehensive role of methylation-driven TME in ccRCC, aiding in identifying patients sensitive to immunotherapy and targeted therapy, and providing new therapeutic targets for ccRCC treatment.
Topics: Carcinoma, Renal Cell; Humans; Tumor Microenvironment; DNA Methylation; Kidney Neoplasms; Gene Expression Regulation, Neoplastic; Pyrimidines; Indazoles; Sulfonamides; Biomarkers, Tumor; Female; Molecular Docking Simulation; Gene Expression Profiling; Male
PubMed: 38928496
DOI: 10.3390/ijms25126792 -
International Journal of Molecular... Jun 2024Cutaneous melanoma is the most dangerous and deadly form of human skin malignancy. Despite its rarity, it accounts for a staggering 80% of deaths attributed to cutaneous...
Cutaneous melanoma is the most dangerous and deadly form of human skin malignancy. Despite its rarity, it accounts for a staggering 80% of deaths attributed to cutaneous cancers overall. Moreover, its final stages often exhibit resistance to drug treatments, resulting in unfavorable outcomes. Hence, ensuring access to novel and improved chemotherapeutic agents is imperative for patients grappling with this severe ailment. Pyrazole and its fused systems derived thereof are heteroaromatic moieties widely employed in medicinal chemistry to develop effective drugs for various therapeutic areas, including inflammation, pain, oxidation, pathogens, depression, and fever. In a previous study, we described the biochemical properties of a newly synthesized group of imidazo-pyrazole compounds. In this paper, to improve our knowledge of the pharmacological properties of these molecules, we conduct a differential proteomic analysis on a human melanoma cell line treated with one of these imidazo-pyrazole derivatives. Our results detail the changes to the SKMEL-28 cell line proteome induced by 24, 48, and 72 h of imidazo-pyrazole treatment. Notably, we highlight the down-regulation of the Ras-responsive element binding protein 1 (RREB1), a member of the zinc finger transcription factors family involved in the tumorigenesis of melanoma. RREB1 is a downstream element of the MAPK pathway, and its activation is mediated by ERK1/2 through phosphorylation.
Topics: Humans; Melanoma; Pyrazoles; Proteomics; Cell Line, Tumor; Transcription Factors; Antineoplastic Agents; Skin Neoplasms; DNA-Binding Proteins; Imidazoles; Gene Expression Regulation, Neoplastic; Proteome
PubMed: 38928466
DOI: 10.3390/ijms25126760 -
International Journal of Molecular... Jun 2024This paper presents the work performed to transition a lab-scale synthesis (1 g) to a large-scale (400 g) synthesis of the 3-5-diamino-1H-Pyrazole Disperazol, a new...
This paper presents the work performed to transition a lab-scale synthesis (1 g) to a large-scale (400 g) synthesis of the 3-5-diamino-1H-Pyrazole Disperazol, a new pharmaceutical for treatment of antibiotic-resistant biofilm infections. The potentially hazardous diazotisation step in the lab-scale synthesis was transformed to a safe and easy-to-handle flow chemistry step. Additionally, the paper presents an OSHA-recommended safety assessment of active compound , as performed by Fauske and Associates, LLC, Burr Ridge, IL, USA.
Topics: Pyrazoles; Pseudomonas aeruginosa; Anti-Bacterial Agents; Biofilms; Humans; Pseudomonas Infections; Risk Assessment
PubMed: 38928443
DOI: 10.3390/ijms25126737 -
International Journal of Molecular... Jun 2024The development of resistance to tyrosine kinase inhibitors (TKIs) is a major cause of treatment failure in metastatic renal cell carcinoma (mRCC). A deeper...
The development of resistance to tyrosine kinase inhibitors (TKIs) is a major cause of treatment failure in metastatic renal cell carcinoma (mRCC). A deeper understanding of the metabolic mechanisms associated with TKI resistance is critical for refining therapeutic strategies. In this study, we established resistance to sunitinib and pazopanib by exposing a parental Caki-1 cell line to increasing concentrations of sunitinib and pazopanib. The intracellular and extracellular metabolome of sunitinib- and pazopanib-resistant mRCC cells were investigated using a nuclear magnetic resonance (NMR)-based metabolomics approach. Data analysis included multivariate and univariate methods, as well as pathway and network analyses. Distinct metabolic signatures in sunitinib- and pazopanib-resistant RCC cells were found for the first time in this study. A common metabolic reprogramming pattern was observed in amino acid, glycerophospholipid, and nicotinate and nicotinamide metabolism. Sunitinib-resistant cells exhibited marked alterations in metabolites involved in antioxidant defence mechanisms, while pazopanib-resistant cells showed alterations in metabolites associated with energy pathways. Sunitinib-resistant RCC cells demonstrated an increased ability to proliferate, whereas pazopanib-resistant cells appeared to restructure their energy metabolism and undergo alterations in pathways associated with cell death. These findings provide potential targets for novel therapeutic strategies to overcome TKI resistance in mRCC through metabolic regulation.
Topics: Humans; Drug Resistance, Neoplasm; Kidney Neoplasms; Protein Kinase Inhibitors; Cell Line, Tumor; Sunitinib; Sulfonamides; Metabolomics; Indazoles; Carcinoma, Renal Cell; Pyrimidines; Metabolome; Cell Proliferation; Tyrosine Kinase Inhibitors
PubMed: 38928035
DOI: 10.3390/ijms25126328 -
International Journal of Molecular... Jun 2024Triazoles are compounds with various biological activities, including fungicidal action. They became popular through cholinesterase studies after the successful...
Triazoles are compounds with various biological activities, including fungicidal action. They became popular through cholinesterase studies after the successful synthesis of the dual binding femtomolar triazole inhibitor of acetylcholinesterase (AChE, EC 3.1.1.7) by Sharpless et al. via click chemistry. Here, we evaluate the anticholinesterase effect of the first isopropanol triazole fungicide mefentrifluconazole (Ravystar), developed to overcome fungus resistance in plant disease management. Mefentrifluconazole is commercially available individually or in a binary fungicidal mixture, i.e., with pyraclostrobin (Ravycare). Pyraclostrobin is a carbamate that contains a pyrazole ring. Carbamates are known inhibitors of cholinesterases and the carbamate rivastigmine is already in use for the treatment of Alzheimer's disease. We tested the type and potency of anticholinesterase activity of mefentrifluconazole and pyraclostrobin. Mefentrifluconazole reversibly inhibited human AChE and BChE with a seven-fold higher potency toward AChE ( = 101 ± 19 μM). Pyraclostrobin (50 μM) inhibited AChE and BChE progressively with rate constants of (t = 2.1 min; = 6.6 × 10 M min) and (t = 1.5 min; = 9.2 × 10 M min), respectively. A molecular docking study indicated key interactions between the tested fungicides and residues of the lipophilic active site of AChE and BChE. Additionally, the physicochemical properties of the tested fungicides were compared to values for CNS-active drugs to estimate the blood-brain barrier permeability. Our results can be applied in the design of new molecules with a lesser impact on humans and the environment.
Topics: Strobilurins; Cholinesterase Inhibitors; Acetylcholinesterase; Humans; Fungicides, Industrial; Triazoles; Molecular Docking Simulation; Butyrylcholinesterase; Pyrazoles
PubMed: 38928014
DOI: 10.3390/ijms25126310 -
Clinical Cardiology Jun 2024This study evaluates the cost-effectiveness of Apixaban and Rivaroxaban, compared to Warfarin, for stroke prevention in patients with non-valvular atrial fibrillation in... (Comparative Study)
Comparative Study
Cost-Effectiveness and Budget Impact Analysis of Apixaban and Rivaroxaban Versus Warfarin in the Prevention of Stroke in Patients With Non-Valvular Atrial Fibrillation (NVAF) in Iran.
INTRODUCTION
This study evaluates the cost-effectiveness of Apixaban and Rivaroxaban, compared to Warfarin, for stroke prevention in patients with non-valvular atrial fibrillation in Iran.
METHOD
A Markov model with a 30-year time horizon was employed to simulate and assess different treatment strategies' cost-effectiveness. The study population comprised Iranian adults with NVAF, identified through specialist consultations, hospital visits, and archival record reviews. Direct medical costs, direct nonmedical, and indirect costs were included. Quality-adjusted life years (QALY) were assessed using an EQ-5D questionnaire. This study utilized a cost-effectiveness threshold of $11 134 per QALY.
RESULTS
Apixaban demonstrated superior cost-effectiveness compared to Rivaroxaban and Warfarin. Over 30 years, total costs were lower in the Apixaban and Rivaroxaban groups compared to the Warfarin group ($126.18 and $109.99 vs. $150.49). However, Apixaban showed higher total QALYs gained compared to others (0.134 vs. 0.133 and 0.116). The incremental cost-effectiveness ratio for comparing Apixaban to Warfarin was calculated at -1332.83 cost per QALY, below the threshold of $11 134, indicating Apixaban's cost-effectiveness. Sensitivity analyses confirmed the robustness of the findings, with ICER consistently remaining below the threshold. Over 5 years (2024-2028) of Apixaban usage, the incremental cost starts at USD 70 250 296 in the first year and gradually rises to USD 71 770 662 in the fifth year. DSA and PSA were assessed to prove the robustness of the results.
CONCLUSION
This study shows that Apixaban is a cost-effective option for stroke prevention in non-valvular atrial fibrillation patients in Iran compared to Warfarin.
Topics: Humans; Atrial Fibrillation; Pyrazoles; Cost-Benefit Analysis; Pyridones; Warfarin; Iran; Stroke; Rivaroxaban; Anticoagulants; Male; Factor Xa Inhibitors; Quality-Adjusted Life Years; Female; Markov Chains; Aged; Drug Costs; Treatment Outcome; Middle Aged; Budgets; Time Factors
PubMed: 38923583
DOI: 10.1002/clc.24311 -
Cancer Medicine Jun 2024A neurotrophic tropomyosin receptor kinase (NTRK)-tyrosine kinase inhibitor (TKI) has shown dramatic efficacy against malignant tumors harboring an NTRK fusion gene....
INTRODUCTION
A neurotrophic tropomyosin receptor kinase (NTRK)-tyrosine kinase inhibitor (TKI) has shown dramatic efficacy against malignant tumors harboring an NTRK fusion gene. However, almost all tumors eventually acquire resistance to NTRK-TKIs.
METHOD
To investigate the mechanism of resistance to NTRK-TKIs, we established cells resistant to three types of NTRK-TKIs (larotrectinib, entrectinib, and selitrectinib) using KM12 colon cancer cells with a TPM3-NTRK1 rearrangement.
RESULT
Overexpression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) was observed in three resistant cells (KM12-LR, KM12-ER, and KM12-SR) by microarray analysis. Lower expression of sterol regulatory element-binding protein 2 (SREBP2) and peroxisome proliferator activated receptor α (PPARα) was found in two cells (KM12-ER and KM12-SR) in which HMGCS2 was overexpressed compared to the parental KM12 and KM12-LR cells. In resistant cells, knockdown of HMGCS2 using small interfering RNA improved the sensitivity to NTRK-TKI. Further treatment with mevalonolactone after HMGCS2 knockdown reintroduced the NTRK-TKI resistance. In addition, simvastatin and silibinin had a synergistic effect with NTRK-TKIs in resistant cells, and delayed tolerance was observed after sustained exposure to clinical concentrations of NTRK-TKI and simvastatin in KM12 cells. In xenograft mouse models, combination treatment with entrectinib and simvastatin reduced resistant tumor growth compared with entrectinib alone.
CONCLUSION
These results suggest that HMGCS2 overexpression induces resistance to NTRK-TKIs via the mevalonate pathway in colon cancer cells. Statin inhibition of the mevalonate pathway may be useful for overcoming this mechanistic resistance.
Topics: Humans; Animals; Drug Resistance, Neoplasm; Mice; Cell Line, Tumor; Protein Kinase Inhibitors; Mevalonic Acid; Xenograft Model Antitumor Assays; Colonic Neoplasms; Receptor, trkA; Hydroxymethylglutaryl-CoA Synthase; Benzamides; Pyrimidines; Pyrazoles; Indazoles
PubMed: 38923428
DOI: 10.1002/cam4.7393 -
Current Oncology (Toronto, Ont.) Jun 2024Niraparib was recently funded in Canada for the maintenance treatment of ovarian cancer following platinum-based chemotherapy. However, the drug's safety profile in the...
Niraparib was recently funded in Canada for the maintenance treatment of ovarian cancer following platinum-based chemotherapy. However, the drug's safety profile in the real world remains uncertain. We conducted a cohort study to describe the patient population using niraparib and the proportion that experienced adverse events between June 2019 and December 2022 in four Canadian provinces (Ontario, Alberta, British Columbia [BC], and Quebec). We used administrative data and electronic medical records from Ontario Health, Alberta Health Services, and BC Cancer, and registry data from Exactis Innovation. We summarized baseline characteristics using descriptive statistics and reported safety outcomes using cumulative incidence. We identified 514 patients receiving niraparib. Mean age was 67 years and most were initiated on a daily dose of 100 or 200 mg/day. Grade 3/4 anemia, neutropenia, and thrombocytopenia occurred in 11-16% of the cohort. In Ontario, the three-month cumulative incidence of grade 3/4 thrombocytopenia was 11.6% (95% CI, 8.3-15.4%), neutropenia was 7.1% (95% CI, 4.6-10.4%), and anemia was 11.3% (95% CI, 8.0-15.2%). Cumulative incidences in the remaining provinces were similar. Initial daily dose and proportions of hematological adverse events were low in the real world and may be related to cautious prescribing and close monitoring by clinicians.
Topics: Humans; Female; Ovarian Neoplasms; Indazoles; Aged; Piperidines; Middle Aged; Canada; Cohort Studies; Poly(ADP-ribose) Polymerase Inhibitors; Aged, 80 and over; Piperazines
PubMed: 38920747
DOI: 10.3390/curroncol31060264 -
Cells Jun 2024Cancer is one of the most important problems of modern societies. Recently, studies have reported the anticancer properties of rosiglitazone related to its ability to...
Cancer is one of the most important problems of modern societies. Recently, studies have reported the anticancer properties of rosiglitazone related to its ability to bind peroxisome proliferator receptor γ (PPARγ), which has various effects on cancer and can inhibit cell proliferation. In this study, we investigated the effect of new 4-thiazolidinone (4-TZD) hybrids Les-4369 and Les-3467 and their effect on reactive oxygen species (ROS) production, metabolic activity, lactate dehydrogenase (LDH) release, caspase-3 activity, and gene and protein expression in human foreskin fibroblast (BJ) cells and lung adenocarcinoma (A549) cells. The ROS production and caspase-3 activity were mainly increased in the micromolar concentrations of the studied compounds in both cell lines. Les-3467 and Les-4369 increased the mRNA expression of , (tumor protein P53), and (ATM serine/threonine kinase) in the BJ cells, while the mRNA expression of these genes (except ) was mainly decreased in the A549 cells treated with both of the tested compounds. Our results indicate a decrease in the protein expression of AhR, PPARγ, and PARP-1 in the BJ cells exposed to 1 µM Les-3467 and Les-4369. In the A549 cells, the protein expression of AhR, PPARγ, and PARP-1 increased in the treatment with 1 µM Les-3467 and Les-4369. We have also shown the PPARγ modulatory properties of Les-3467 and Les-4369. However, both compounds prove weak anticancer properties evidenced by their action at high concentrations and non-selective effects against BJ and A549 cells.
Topics: Humans; A549 Cells; PPAR gamma; Reactive Oxygen Species; Pyrazoles; Thiazolidines; Indoles; Caspase 3; Tumor Suppressor Protein p53; Cell Proliferation; Antineoplastic Agents; Ataxia Telangiectasia Mutated Proteins; Apoptosis; Fibroblasts
PubMed: 38920636
DOI: 10.3390/cells13121007