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Molecules (Basel, Switzerland) Dec 2022Pyrazole, an important pharmacophore and a privileged scaffold of immense significance, is a five-membered heterocyclic moiety with an extensive therapeutic profile,... (Review)
Review
Pyrazole, an important pharmacophore and a privileged scaffold of immense significance, is a five-membered heterocyclic moiety with an extensive therapeutic profile, viz., anti-inflammatory, anti-microbial, anti-anxiety, anticancer, analgesic, antipyretic, etc. Due to the expansion of pyrazolecent red pharmacological molecules at a quicker pace, there is an urgent need to put emphasis on recent literature with hitherto available information to recognize the status of this scaffold for pharmaceutical research. The reported potential pyrazole-containing compounds are highlighted in the manuscript for the treatment of cancer and inflammation, and the results are mentioned in % inhibition of inflammation, % growth inhibition, IC, etc. Pyrazole is an important heterocyclic moiety with a strong pharmacological profile, which may act as an important pharmacophore for the drug discovery process. In the struggle to cultivate suitable anti-inflammatory and anticancer agents, chemists have now focused on pyrazole biomolecules. This review conceals the recent expansion of pyrazole biomolecules as anti-inflammatory and anticancer agents with an aim to provide better correlation among different research going around the world.
Topics: Humans; Anti-Inflammatory Agents; Drug Design; Pyrazoles; Antineoplastic Agents; Inflammation; Structure-Activity Relationship; Neoplasms
PubMed: 36557840
DOI: 10.3390/molecules27248708 -
Molecules (Basel, Switzerland) Sep 2020The synthesis of FcC(O)CH(R)C(O)Fc (Fc = Fe(η-CH)(η-CH); R = H, ; Bu, ; CHCH(OCHCH)OMe, ), [M(κ,'-FcC(O)CHC(O)Fc)] (M = Ti, = 3, ; M = Fe, = 3, ; M = BF, = 1, ),...
The synthesis of FcC(O)CH(R)C(O)Fc (Fc = Fe(η-CH)(η-CH); R = H, ; Bu, ; CHCH(OCHCH)OMe, ), [M(κ,'-FcC(O)CHC(O)Fc)] (M = Ti, = 3, ; M = Fe, = 3, ; M = BF, = 1, ), and 1-R'-3,5-Fc-CHN (R' = H, ; Me, ; Ph, ) is discussed. The solid-state structures of , , , , , , and ([TiCl(κ,'-PhC(O)CHC(O)Ph)]) show that and exist in their β-diketo form. Compound crystallizes as a tetramer based on a hydrogen bond pattern, including one central water molecule. The electrochemical behavior of - and - was studied by cyclic and square-wave voltammetry, showing that the ferrocenyls can separately be oxidized reversibly between -50 and 750 mV (-, , -: two Fc-related events; , : six events, being partially superimposed). For complex , Ti-centered reversible redox processes appear at -985 (Ti/Ti) and -520 mV (Ti/Ti). Spectro-electrochemical UV-Vis/NIR measurements were carried out on , and , whereby only showed an IVCT (intervalence charge-transfer) band of considerable strength ( = 6250 cm, = 4725 cm, = 240 L·mol·cm), due to the rigid COB cycle, enlarging the coupling strength between the Fc groups.
Topics: Electrochemistry; Hydrogen Bonding; Ketones; Molecular Conformation; Pyrazoles; Spectrophotometry, Ultraviolet; Spectroscopy, Near-Infrared
PubMed: 33003450
DOI: 10.3390/molecules25194476 -
International Journal of Molecular... May 2023Some new Bis-pyrazoline hybrids with dual EGFR and BRAF inhibitors have been developed. The target compounds were synthesized and tested in vitro against four cancer...
Some new Bis-pyrazoline hybrids with dual EGFR and BRAF inhibitors have been developed. The target compounds were synthesized and tested in vitro against four cancer cell lines. Compounds , , and demonstrated strong antiproliferative activity with GI values of 1.05 µM, 1.50 µM, and 1.20 µM, respectively. Hybrids showed dual inhibition of EGFR and BRAF. Compounds , , and inhibited EGFR-like erlotinib and exhibited promising anticancer activity. Compound is the most potent inhibitor of cancer cell proliferation and BRAF. Compounds and induced apoptosis by increasing caspase 3, 8, and Bax levels, and resulted in the downregulation of the antiapoptotic Bcl2. The molecular docking studies verified that compounds , , and have the potential to be dual EGFR/BRAF inhibitors. Additionally, in silico ADMET prediction revealed that most synthesized bis-pyrazoline hybrids have low toxicity and adverse effects. DFT studies for the two most active compounds, and , were also carried out. The values of the HOMO and LUMO energies, as well as softness and hardness, were computationally investigated using the DFT method. These findings agreed well with those of the in vitro research and molecular docking study.
Topics: Humans; Apoptosis; Cell Line; Cell Proliferation; Cell Survival; Density Functional Theory; Drug Design; ErbB Receptors; Molecular Docking Simulation; Proto-Oncogene Proteins B-raf; Pyrazoles; Static Electricity; Structure-Activity Relationship; Antineoplastic Agents
PubMed: 37240450
DOI: 10.3390/ijms24109104 -
Biomolecules Jul 2021Cyclooxygenase-2 (COX-2) is an important enzyme involved in prostaglandins biosynthesis from arachidonic acid. COX-2 is frequently overexpressed in human cancers and... (Review)
Review
Cyclooxygenase-2 (COX-2) is an important enzyme involved in prostaglandins biosynthesis from arachidonic acid. COX-2 is frequently overexpressed in human cancers and plays a major tumor promoting function. Accordingly, many efforts have been devoted to efficiently target the catalytic site of this enzyme in cancer cells, by using COX-2 specific inhibitors such as celecoxib. However, despite their potent anti-tumor properties, the myriad of detrimental effects associated to the chronic inhibition of COX-2 in healthy tissues, has considerably limited their use in clinic. In addition, increasing evidence indicate that these anti-cancerous properties are not strictly dependent on the inhibition of the catalytic site. These findings have led to the development of non-active COX-2 inhibitors analogues aiming at preserving the antitumor effects of COX-2 inhibitors without their side effects. Among them, two celecoxib derivatives, 2,5-Dimethyl-Celecoxib and OSU-03012, have been developed and suggested for the treatment of viral (e.g., recently SARS-CoV-2), inflammatory, metabolic diseases and cancers. These molecules display stronger anti-tumor properties than celecoxib and thus may represent promising anti-cancer molecules. In this review, we discuss the impact of these two analogues on cancerous processes but also their potential for cancer treatment alone or in combination with existing approaches.
Topics: Animals; Antineoplastic Agents; Celecoxib; Cell Cycle; Cyclooxygenase 2 Inhibitors; Humans; Neoplasms; Pyrazoles; Sulfonamides
PubMed: 34356673
DOI: 10.3390/biom11071049 -
Transplant International : Official... Feb 2020
Topics: Acute Disease; Adult; Aged; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Nitriles; Pyrazoles; Pyrimidines; Steroids
PubMed: 31755139
DOI: 10.1111/tri.13560 -
Drug Design, Development and Therapy 2020Type 2 diabetes mellitus (T2DM) is an emerging epidemic in Asian countries, especially in India. With the advent of the SGLT2 inhibitor class of drugs demonstrating... (Review)
Review
Type 2 diabetes mellitus (T2DM) is an emerging epidemic in Asian countries, especially in India. With the advent of the SGLT2 inhibitor class of drugs demonstrating benefits beyond glycemic control, viz. weight loss, blood pressure reduction, and cardiovascular and renal protection, the management of T2DM has taken a quantum leap. Remogliflozin etabonate (RE) is the latest addition to the SGLT2 inhibitor class of drugs that have been recently approved in India for the management of T2DM. RE is a potent and selective inhibitor of SGLT2 with the unique distinction of being administered as a prodrug, existence of active metabolites, and short half-life necessitating twice-daily dosing. The Phase III study of RE demonstrated it to be an efficacious and safe agent and non-inferior to the currently available SGLT2 inhibitors. This paper reviews not only the pharmacokinetics, pharmacodynamics, clinical efficacy, and safety profile of RE but also its molecular and clinical development program. This review has taken into consideration all available published as well as unpublished literature on RE and discusses the individual studies performed during its development for characterization of pharmacological profile.
Topics: Diabetes Mellitus, Type 2; Drug Development; Glucosides; Humans; Hypoglycemic Agents; Pyrazoles; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 32612352
DOI: 10.2147/DDDT.S221093 -
Molecules (Basel, Switzerland) Jul 2023The altered activation or overexpression of protein kinases (PKs) is a major subject of research in oncology and their inhibition using small molecules, protein kinases... (Review)
Review
The altered activation or overexpression of protein kinases (PKs) is a major subject of research in oncology and their inhibition using small molecules, protein kinases inhibitors (PKI) is the best available option for the cure of cancer. The pyrazole ring is extensively employed in the field of medicinal chemistry and drug development strategies, playing a vital role as a fundamental framework in the structure of various PKIs. This scaffold holds major importance and is considered a privileged structure based on its synthetic accessibility, drug-like properties, and its versatile bioisosteric replacement function. It has proven to play a key role in many PKI, such as the inhibitors of Akt, Aurora kinases, MAPK, B-raf, JAK, Bcr-Abl, c-Met, PDGFR, FGFRT, and RET. Of the 74 small molecule PKI approved by the US FDA, 8 contain a pyrazole ring: Avapritinib, Asciminib, Crizotinib, Encorafenib, Erdafitinib, Pralsetinib, Pirtobrutinib, and Ruxolitinib. The focus of this review is on the importance of the unfused pyrazole ring within the clinically tested PKI and on the additional required elements of their chemical structures. Related important pyrazole fused scaffolds like indazole, pyrrolo[1,2-b]pyrazole, pyrazolo[4,3-b]pyridine, pyrazolo[1,5-a]pyrimidine, or pyrazolo[3,4-d]pyrimidine are beyond the subject of this work.
Topics: Pyrazoles; Protein Kinase Inhibitors; Antineoplastic Agents; Drug Design; Structure-Activity Relationship; Humans; Animals
PubMed: 37513232
DOI: 10.3390/molecules28145359 -
Scientific Reports May 2023Catalpol, a natural product mainly existed in plenty of Chinese traditional medicines, is an iridoid compound with the comprehensive effects on neuroprotective,...
Catalpol, a natural product mainly existed in plenty of Chinese traditional medicines, is an iridoid compound with the comprehensive effects on neuroprotective, anti-inflammatory, choleretic, hypoglycemic and anticancer. However, there are some disadvantages for catalpol such as a short half-life in vivo, low druggability, stingy binding efficiency to target proteins and so on. It is necessary to make structural modification and optimization which enhance its performance on disease treatments and clinic applications. Pyrazole compounds have been reported to have excellent anticancer activities. Based on the previous research foundation of our research group on iridoids and the anticancer activities of catalpol and pyrazole, a series of pyrazole modified catalpol compounds were synthesized by principle of drug combination for serving as potential cancer inhibitors. These derivatives are characterized by H NMR, C NMR and HRMS. The efficacy of anti-esophageal cancer and anti-pancreatic cancer activities were evaluated by the MTT assay on two esophageal cancer cells Eca-109 and EC-9706, and two pancreatic cancer cells PANC-1, BxPC-3 and normal pancreatic cell line HPDE6-C7, which showed that the compound 3e had strong inhibitory activity against esophageal cancer cells, this providing a theoretical basis for the discovery of catalpol-containing drugs.
Topics: Humans; Iridoid Glucosides; Neoplasms; Cell Line; Pyrazoles
PubMed: 37173367
DOI: 10.1038/s41598-023-33403-9 -
JCO Precision Oncology Jan 2022Larotrectinib is a highly selective and CNS-active tropomyosin receptor kinase (TRK) inhibitor that has demonstrated efficacy across TRK fusion-positive cancers,...
PURPOSE
Larotrectinib is a highly selective and CNS-active tropomyosin receptor kinase (TRK) inhibitor that has demonstrated efficacy across TRK fusion-positive cancers, regardless of the tumor type. The aim of this study was to assess the efficacy and safety of larotrectinib in patients with TRK fusion-positive lung cancers.
MATERIALS AND METHODS
Data from two global, multicenter, registrational clinical trials of patients treated with larotrectinib were analyzed: a phase II adult and young adult basket trial (NCT02576431) and a phase I adult trial (NCT02122913). The primary end point was objective response rate (ORR).
RESULTS
By July 20, 2020, 20 patients with TRK fusion-positive lung cancer had been treated. The ORR by investigator assessment among 15 evaluable patients was 73% (95% CI, 45 to 92); one (7%) patient had a complete response, 10 (67%) had a partial response, three (20%) had stable disease, and one (7%) had progressive disease as best response. The median duration of response, progression-free survival, and overall survival were 33.9 months (95% CI, 5.6 to 33.9), 35.4 months (95% CI, 5.3 to 35.4), and 40.7 months (95% CI, 17.2 to not estimable), respectively. Among patients with baseline CNS metastases, the ORR was 63% (95% CI, 25 to 91). Adverse events were mainly grade 1 or 2.
CONCLUSION
Larotrectinib is highly active with rapid and durable responses, extended survival benefit, and a favorable long-term safety profile in patients with advanced lung cancer harboring gene fusions, including those with CNS metastases. These findings support routine testing for fusions in patients with lung cancer.
Topics: Adult; Aged; Female; Gene Fusion; Humans; Lung Neoplasms; Male; Middle Aged; Protein Kinases; Pyrazoles; Pyrimidines; Treatment Outcome
PubMed: 35085007
DOI: 10.1200/PO.21.00418 -
Journal of Comparative Effectiveness... Oct 2022To extrapolate clinical trial results to estimate and compare expected progression-free and overall life years (LYs) and quality-adjusted LYs (QALYs) for larotrectinib...
To extrapolate clinical trial results to estimate and compare expected progression-free and overall life years (LYs) and quality-adjusted LYs (QALYs) for larotrectinib and entrectinib in patients with colorectal cancer (CRC), soft tissue sarcoma (STS) and brain metastases prior to treatment with larotrectinib or entrectinib. A naive direct comparison of larotrectinib versus entrectinib was made using partitioned survival modeling methods from clinical trial data. Larotrectinib resulted in an additional 1.58 LYs (1.17 QALYs), 5.81 LYs (2.02 QALYs) and 1.01 LYs in CRC, STS and baseline brain metastases, respectively, compared with entrectinib. Larotrectinib provided life expectancy and QALY gains compared with entrectinib. Additional studies will be beneficial as more patients are treated and survival data develop to better inform comparative effectiveness results.
Topics: Benzamides; Brain Neoplasms; Clinical Trials as Topic; Gene Fusion; Humans; Indazoles; Pyrazoles; Pyrimidines
PubMed: 35993247
DOI: 10.2217/cer-2021-0247