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Molecules (Basel, Switzerland) Jul 2019A series of disubstituted 1-pyrazoles with methyl (), amino (), and nitro () groups, as well as ester () or amide () groups in positions 3 and 5 was synthesized, and...
A series of disubstituted 1-pyrazoles with methyl (), amino (), and nitro () groups, as well as ester () or amide () groups in positions 3 and 5 was synthesized, and annular tautomerism was investigated using X-ray, theoretical calculations, NMR, and FT-IR methods. The X-ray experiment in the crystal state showed for the compounds with methyl (, ) and amino () groups the tautomer with ester or amide groups at position 3 (tautomer 3), but for those with a nitro group (, ), tautomer 5. Similar results were obtained in solution by NMR NOE experiments in CDCl, DMSO-, and CDOD solvents. However, tautomer equilibrium was observed for in DMSO. The FT-IR spectra in chloroform and acetonitrile showed equilibria, which can be ascribed to conformational changes of the cis/trans arrangement of the ester/amide group and pyrazole ring. Theoretical analysis using the M06-2X/6-311++G(d,p) method (in vacuo, chloroform, acetonitrile, and water) and measurement of aromaticity (NICS) showed dependence on internal hydrogen bonds, the influence of the environment, and the effect of the substituent. These factors, pyrazole aromaticity and intra- and inter-molecular interactions, seem to have a considerable influence on the choice of tautomer.
Topics: Amides; Crystallography, X-Ray; Esters; Hydrogen Bonding; Models, Molecular; Models, Theoretical; Molecular Conformation; Molecular Structure; Pyrazoles; Spectrum Analysis
PubMed: 31330976
DOI: 10.3390/molecules24142632 -
Molecules (Basel, Switzerland) Aug 2020This review focuses on the cytotoxic effect of new synthetic pyrazolo[4,3-][1,2,4]triazine derivatives against different tumor cell lines. Some annulated... (Review)
Review
This review focuses on the cytotoxic effect of new synthetic pyrazolo[4,3-][1,2,4]triazine derivatives against different tumor cell lines. Some annulated pyrazolotriazines i.e., pyrazolo[4,3-][1,2,4]triazolo[4,3-][1,2,4]triazines and pyrazolo[4,3-]tetrazolo[1,5-][1,2,4]triazine demonstrated significant broad cytotoxic activity in micromolar range concentration, which could have excellent potential to be new candidate therapeutic agents in cancer chemotherapy.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Pyrazoles; Structure-Activity Relationship; Sulfonamides; Triazines
PubMed: 32872493
DOI: 10.3390/molecules25173948 -
Annals of Palliative Medicine Oct 2021Riociguat therapy has been recommended for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), and it might have therapeutic... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Riociguat therapy has been recommended for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), and it might have therapeutic significance for other types of pulmonary hypertension (PH). Our purpose was to evaluate the specific impact of riociguat on all types of PH.
METHODS
We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing the safety and efficacy of riociguat treatment for PH through databases of the Cochrane Library, PubMed, Embase, and Web of Science from inception to the present. Duplicate publications, studies with no full text, incomplete information or inability to extract data, animal experiments and reviews, and systematic reviews were excluded. The software RevMan 5.4 was used for data synthesis.
RESULTS
There were 8 RCTs included in our study, involving 1,606 participants. For PAH and CTEPH patients, riociguat treatment extended 6-minute walk distance (6MWD) by 39.84 meters, decreased mean pulmonary arterial pressure (PAP) by 4.20 mmHg, lowered pulmonary vascular resistance (PVR) by 218.76 dynes/sec/cm-5, cut down right atrial pressure (RAP) by 0.9 mmHg, increased cardiac index (CI) by 0.49 L/min/m2, improved cardiac output (CO) by 0.89 L/min, reduced N-terminal pro-type B natriuretic peptide (NT-proBNP) by 436.21 pg/mL, and decreased adverse events and clinical worsening as compared with placebo. For other types of PH including PH due to left heart disease and PH due to lung disease, riociguat was reported as having improved CI by 0.42 L/min/m2 and CO was increased by 0.92 L/min compared with placebo. Other efficacy outcomes and safety outcomes did not attain statistical difference in other types of PH.
CONCLUSIONS
For PAH and CTEPH, riociguat treatment is safe and effective, but for other types of PH, it can only improve some hemodynamic parameters.
Topics: Chronic Disease; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines
PubMed: 34763472
DOI: 10.21037/apm-21-2656 -
Investigational New Drugs Jun 2023Adavosertib selectively inhibits Wee1, which regulates intra-S and G2/M cell-cycle checkpoints. This study investigated dosing schedules for adavosertib monotherapy,...
Adavosertib selectively inhibits Wee1, which regulates intra-S and G2/M cell-cycle checkpoints. This study investigated dosing schedules for adavosertib monotherapy, determining the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) in patients with advanced solid tumors.Patients received oral adavosertib qd or bid on a 5/9 schedule (5 days on treatment, 9 days off) in 14-day cycles, or qd on one of two 5/2 schedules (weekly, or for 2 of 3 weeks) in 21-day cycles. Safety, efficacy, and pharmacokinetic analyses were performed.Sixty-two patients (female, 64.5%; median age, 61.5 years; most common primary tumors: lung [24.2%], ovary [21.0%]) received treatment (qd schedules, n = 50; bid schedules, n = 12) for 1.8 months (median). Median time to maximum adavosertib concentration was 2.2-4.1 h; mean half-life was 5-12 h. Adverse events (AEs) caused dose reductions, interruptions and discontinuations in 17 (27.4%), 25 (40.3%) and 4 (6.5%) patients, respectively. Most common grade ≥ 3 AEs were anemia, neutropenia (each n = 9, 14.5%) and diarrhea (n = 8, 12.9%). Seven (11.3%) patients experienced 10 treatment-related serious AEs (pneumonia n = 2 [3.2%], dehydration n = 2 [3.2%], anemia n = 1 [1.6%], febrile neutropenia n = 1 [1.6%], and thrombocytopenia n = 1 [1.6%]). Overall objective response rate was 3.4% (2/58); disease control rate was 48.4% (30/62); median progression-free survival was 2.7 months.MTDs were 125 mg (bid 5/9) and 300 mg (qd 5/9 and 5/2 for 2 of 3 weeks); RP2D was 300 mg (qd 5/2 for 2 of 3 weeks). The safety profile was manageable, acceptable, and generally concordant with the known safety profile.
Topics: Female; Humans; Middle Aged; Anemia; Maximum Tolerated Dose; Neoplasms; Pyrazoles; Pyrimidinones; Male
PubMed: 37171722
DOI: 10.1007/s10637-023-01371-6 -
Journal of the American Heart... Sep 2020Background Coronary microvascular dysfunction is common in patients of myocardial infarction with non-obstructive coronary artery disease. Coronary flow reserve (CFR)...
Background Coronary microvascular dysfunction is common in patients of myocardial infarction with non-obstructive coronary artery disease. Coronary flow reserve (CFR) reflects coronary microvascular function and is a powerful independent index of coronary microvascular dysfunction and heart failure. Our previous studies showed that knockout of SIRT3 (Sirtuin 3) decreased CFR and caused a diastolic dysfunction. Few studies focus on the treatment of impaired CFR and heart failure. In the present study, we explored the role of C646, a histone acetyltransferase p300 inhibitor, in regulating CFR and cardiac remodeling in SIRT3 knockout (SIRT3KO) mice. Methods and Results After treating with C646 for 14 days, CFR, pulse-wave velocity, and cardiac function were measured in SIRT3KO mice. SIRT3KO mice treated with C646 showed a significant improvement of CFR, pulse-wave velocity, ejection fraction, and fractional shortening. Treatment with C646 reversed pre-existing cardiac fibrosis, hypertrophy, and capillary rarefaction in SIRT3KO mice. Mechanistically, knockout of Sirtuin 3 resulted in significant increases in p300 expression and H3K56 acetylation. Treatment with C646 significantly reduced levels of p300 and H3K56 acetylation in SIRT3KO mice. Furthermore, treatment with C646 increased endothelial nitric oxide synthase expression and reduced arginase II expression and activity. The expression of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and VCAM-1 (vascular cell adhesion molecule 1) was also significantly suppressed by C646 treatment in SIRT3KO mice. Conclusions C646 treatment attenuated p300 and H3K56 acetylation and improved arterial stiffness and CFR via improvement of endothelial cell (EC) dysfunction and suppression of NF-κB.
Topics: Animals; Benzoates; Blotting, Western; Coronary Circulation; Echocardiography; Fluorescent Antibody Technique; Male; Mice; Mice, Knockout; Microvessels; Nitrobenzenes; Pyrazoles; Pyrazolones; Sirtuin 3; Vascular Stiffness; p300-CBP Transcription Factors
PubMed: 32865093
DOI: 10.1161/JAHA.120.017176 -
Molecules (Basel, Switzerland) Sep 2022A small library of highly functionalized phenylaminopyrazoles, bearing different substituents at position 1, 3, and 4 of the pyrazole ring, was prepared by the one-pot...
A small library of highly functionalized phenylaminopyrazoles, bearing different substituents at position 1, 3, and 4 of the pyrazole ring, was prepared by the one-pot condensation of active methylene reagents, phenylisothiocyanate, and substituted hydrazine (namely, methyl- and benzyl-hydrazine). The identified reaction conditions proved to be versatile and efficient. Furthermore, the evaluation of alternative stepwise protocols affected the chemo- and regio-selectivity outcome of the one-pot procedure. The chemical identities of two -methyl pyrazole isomers, selected as prototypes of the whole series, were unambiguously identified by means of NMR and mass spectrometry studies. Additionally, semiempirical calculations provided a structural rationale for the different chromatographic behavior of the two isomers. The prepared tetra-substituted phenylaminopyrazoles were tested in cell-based assays on a panel of cancer and normal cell lines. The tested compounds did not show any cytotoxic effect on the selected cell lines, thus supporting their pharmaceutical potentials.
Topics: Antineoplastic Agents; Drug Design; Hydrazines; Molecular Structure; Pharmaceutical Preparations; Pyrazoles; Structure-Activity Relationship
PubMed: 36144549
DOI: 10.3390/molecules27185814 -
Molecules (Basel, Switzerland) May 2020The publications covering new, transition metal-free cross-coupling reactions of pyrroles with electrophilic haloacetylenes in solid medium of metal oxides and salts to... (Review)
Review
The publications covering new, transition metal-free cross-coupling reactions of pyrroles with electrophilic haloacetylenes in solid medium of metal oxides and salts to regioselectively afford 2-ethynylpyrroles are discussed. The reactions proceed at room temperature without catalyst and base under solvent-free conditions. These ethynylation reactions seem to be particularly important, since the common Sonogashira coupling does not allow ethynylpyrroles with strong electron-withdrawing substituents at the acetylenic fragments to be synthesized. The results on the behavior of furans, thiophenes, and pyrazoles under the conditions of these reactions are also provided. The reactivity and structural peculiarities of nucleophilic addition to the activated acetylene moiety of the novel C-ethynylpyrroles are considered.
Topics: Aluminum Oxide; Furans; Pyrazoles; Thiophenes
PubMed: 32471258
DOI: 10.3390/molecules25112490 -
European Review For Medical and... Dec 2020Metabolic syndrome is characterized by abdominal obesity, hypertriglyceridemia and hyperglycemia. Fatty acid binding protein 4 (FABP4), as a member of intracellular...
OBJECTIVE
Metabolic syndrome is characterized by abdominal obesity, hypertriglyceridemia and hyperglycemia. Fatty acid binding protein 4 (FABP4), as a member of intracellular lipid chaperones, is not only engaged in lipid transport but involved in inflammation and insulin resistance. The present study was to investigate the effects of BMS309403, a specific FABP4 inhibitor, on metabolic syndrome and its possible molecular mechanisms in islets.
MATERIALS AND METHODS
Leptin receptor knockout (Lepr-/-) rat, a novel and representative animal model of metabolic syndrome, was adopted in this study. Lepr-/- male rats and their wild littermates were grouped and intragastrically administered with BMS309403. Glucose Tolerance Test (GTT) and Insulin Tolerance Test (ITT) were performed on all rats. Serum insulin was detected by ELISA. The metabolic characters, as well as liver and kidney functions, were evaluated by serum biochemical assay. Immunohistochemistry and Western blot were adopted to detect the expression levels of FABP4, CD68, GRP78, ATF6, p-IRE1a, and Cleaved caspase-3.
RESULTS
Lepr-/- rats showed prominent characteristics of metabolic syndrome with increased FABP4, inflammatory infiltration, ER stress and apoptosis in islets. BMS309403 administration attenuated inflammation, ER stress and apoptosis in Lepr-/- rat islets while stimulating insulin secretion as well as improving manifestation of metabolic syndrome without hepatic and renal toxicity.
CONCLUSIONS
FABP4 increased in Lepr-/- rat islets and might be involved in the regulation of islet inflammation and apoptosis via ER stress. FABP4 inhibitor BMS309403 could ameliorate islet inflammation and apoptosis in metabolic syndrome through suppressing ER stress.
Topics: Administration, Oral; Animals; Biphenyl Compounds; Endoplasmic Reticulum Stress; Fatty Acid-Binding Proteins; Glucose Tolerance Test; Inflammation; Islets of Langerhans; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptors, Leptin
PubMed: 33378030
DOI: 10.26355/eurrev_202012_24182 -
International Journal of Molecular... May 2024In a screen of over 200 novel pyrazole compounds, ethyl 1-(2-hydroxypentyl)-5-(3-(3-(trifluoromethyl) phenyl)ureido)-1-pyrazole-4-carboxylate (named GeGe-3) has emerged...
In a screen of over 200 novel pyrazole compounds, ethyl 1-(2-hydroxypentyl)-5-(3-(3-(trifluoromethyl) phenyl)ureido)-1-pyrazole-4-carboxylate (named GeGe-3) has emerged as a potential anticancer compound. GeGe-3 displays potent anti-angiogenic properties through the presumptive targeting of the protein kinase DMPK1 and the Ca2-binding protein calreticulin. We further explored the anticancer potential of GeGe-3 on a range of established cancer cell lines, including PC3 (prostate adenocarcinoma), SKMEL-28 (cutaneous melanoma), SKOV-3 (ovarian adenocarcinoma), Hep-G2 (hepatocellular carcinoma), MDA-MB231, SKBR3, MCF7 (breast adenocarcinoma), A549 (lung carcinoma), and HeLa (cervix epithelioid carcinoma). At concentrations in the range of 10 μM, GeGe-3 significantly restricted cell proliferation and metabolism. GeGe-3 also reduced PC3 cell migration in a standard wound closure and trans-well assay. Together, these results confirm the anticancer potential of GeGe-3 and underline the need for more detailed pre-clinical investigations into its molecular targets and mechanisms of action.
Topics: Humans; Pyrazoles; Antineoplastic Agents; Cell Proliferation; Cell Movement; Cell Line, Tumor; Urea
PubMed: 38791418
DOI: 10.3390/ijms25105380 -
Biochemical Pharmacology Mar 2024Cancer is a disease with a high mortality rate characterized by uncontrolled proliferation of abnormal cells. The hallmarks of cancer evidence the acquired cells... (Review)
Review
Cancer is a disease with a high mortality rate characterized by uncontrolled proliferation of abnormal cells. The hallmarks of cancer evidence the acquired cells characteristics that promote the growth of malignant tumours, including genomic instability and mutations, the ability to evade cellular death and the capacity of sustaining proliferative signalization. Poly(ADP-ribose) polymerase-1 (PARP1) is a protein that plays key roles in cellular regulation, namely in DNA damage repair and cell survival. The inhibition of PARP1 promotes cellular death in cells with homologous recombination deficiency, and therefore, the interest in PARP protein has been rising as a target for anticancer therapies. There are already some PARP1 inhibitors approved by Food and Drug Administration (FDA), such as Olaparib and Niraparib. The last compound presents in its structure an indazole core. In fact, pyrazoles and indazoles have been raising interest due to their various medicinal properties, namely, anticancer activity. Derivatives of these compounds have been studied as inhibitors of PARP1 and presented promising results. Therefore, this review aims to address the importance of PARP1 in cell regulation and its role in cancer. Moreover, it intends to report a comprehensive literature review of PARP1 inhibitors, containing the pyrazole and indazole scaffolds, published in the last fifteen years, focusing on structure-activity relationship aspects, thus providing important insights for the design of novel and more effective PARP1 inhibitors.
Topics: Adenosine Diphosphate Ribose; Cell Cycle; Indazoles; Neoplasms; Pyrazoles; United States; Humans; Animals; Poly (ADP-Ribose) Polymerase-1
PubMed: 38336156
DOI: 10.1016/j.bcp.2024.116045