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Chemical Biology & Drug Design Oct 2021N-formyl peptide receptors (FPR1, FPR2, and FPR3) play key roles in the regulation of inflammatory processes, and recently, it was demonstrated that FPR1 and FPR2 have a...
N-formyl peptide receptors (FPR1, FPR2, and FPR3) play key roles in the regulation of inflammatory processes, and recently, it was demonstrated that FPR1 and FPR2 have a dual role in the progression/suppression of some cancers. Therefore, FPRs represent an important therapeutic target for the treatment of both cancer and inflammatory diseases. Previously, we identified selective or mixed FPR agonists with pyridazinone or pyridinone scaffolds showing a common 4-(bromophenyl)acetamide fragment, which was essential for activity. We report here new pyrazole and pyrazolone derivatives as restricted analogues of the above 6-membered compounds, all exhibiting the same 4-bromophenylacetamide side chain. Most new products had low or absent FPR agonist activity, suggesting that the pyrazole nucleus was not appropriate for FPR agonists. This hypothesis was confirmed by molecular modeling studies, which highlighted that the five-membered scaffold was responsible for a worse arrangement of the molecules in the receptor binding site.
Topics: Acetamides; Binding Sites; Humans; Models, Molecular; Neutrophils; Oxazoles; Protein Binding; Pyrazoles; Pyrazolones; Pyridones; Receptors, Formyl Peptide; Structure-Activity Relationship; Triazoles
PubMed: 34148303
DOI: 10.1111/cbdd.13913 -
Drug Design, Development and Therapy 2017Despite advances in treatments and improved survival, patients with pulmonary hypertension still experience poor exercise and functional capacity, which has a... (Review)
Review
Despite advances in treatments and improved survival, patients with pulmonary hypertension still experience poor exercise and functional capacity, which has a significant detrimental impact on their quality of life. The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine 3',5'-monophosphate (cGMP) pathway has been shown to play an important role in cardiovascular physiology, especially in vasodilation and pulmonary vascular tone. The oral sGC stimulator riociguat has a dual mode of action on the NO-sGC-cGMP pathway: direct stimulation of sGC independent of NO and indirect simulation via sensitization of sGC to endogenous NO. Riociguat is now licensed in >50 countries worldwide, including in Europe, the USA, Canada, and Japan. Approval for the treatment of pulmonary arterial hypertension (PAH) was based on Phase III data from the PATENT studies, in which riociguat significantly improved exercise capacity, pulmonary vascular resistance, a range of secondary end points, and hemodynamic parameters in patients with symptomatic PAH. In the Phase III CHEST studies, riociguat consistently improved exercise capacity in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or persistent/recurrent CTEPH after pulmonary endarterectomy and is now the only drug to be approved for this indication. Riociguat was well tolerated in long-term studies of PAH and CTEPH. This review describes the role of the NO-sGC-cGMP pathway in the pathophysiology of pulmonary hypertension, and reviews the clinical efficacy and safety of riociguat in patients with PAH and inoperable or persistent/recurrent CTEPH. Based on its demonstrated efficacy and established safety profile, riociguat is a promising treatment option for patients with PAH and CTEPH.
Topics: Animals; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Solubility
PubMed: 28458514
DOI: 10.2147/DDDT.S117277 -
Molecules (Basel, Switzerland) Nov 2021Chagas disease, a chronic and silent disease caused by , is currently a global public health problem. The treatment of this neglected disease relies on benznidazole and...
Structural Optimization and Biological Activity of Pyrazole Derivatives: Virtual Computational Analysis, Recovery Assay and 3D Culture Model as Potential Predictive Tools of Effectiveness against .
Chagas disease, a chronic and silent disease caused by , is currently a global public health problem. The treatment of this neglected disease relies on benznidazole and nifurtimox, two nitroheterocyclic drugs that show limited efficacy and severe side effects. The failure of potential drug candidates in Chagas disease clinical trials highlighted the urgent need to identify new effective chemical entities and more predictive tools to improve translational success in the drug development pipeline. In this study, we designed a small library of pyrazole derivatives (44 analogs) based on a hit compound, previously identified as a cysteine protease inhibitor. The in vitro phenotypic screening revealed compounds , , and as promising candidates, with IC values of 6.09 ± 0.52, 2.75 ± 0.62, and 3.58 ± 0.25 µM, respectively, against intracellular amastigotes. All pyrazole derivatives have good oral bioavailability prediction. The structure-activity relationship (SAR) analysis revealed increased potency of 1-aryl-1-pyrazole-imidazoline derivatives with the Br, Cl, and methyl substituents in the -position. The compound stands out for its trypanocidal efficacy in 3D microtissue, which mimics tissue microarchitecture and physiology, and abolishment of parasite recrudescence in vitro. Our findings encourage the progression of the promising candidate for preclinical in vivo studies.
Topics: Cell Culture Techniques; Chagas Disease; Humans; Models, Molecular; Parasitic Sensitivity Tests; Printing, Three-Dimensional; Pyrazoles; Trypanocidal Agents; Trypanosoma cruzi
PubMed: 34771151
DOI: 10.3390/molecules26216742 -
Scientific Reports Mar 2020Bipyrazone, 1,3-dimethyl-4-(2-(methylsulfonyl)-4-(trifluoromethyl) benzoyl)-1H-pyrazol-5-yl 1,3-dimethyl-1H-pyrazole- 4-carboxylate, is a 4-hydroxyphenylpyaunate...
Bipyrazone, 1,3-dimethyl-4-(2-(methylsulfonyl)-4-(trifluoromethyl) benzoyl)-1H-pyrazol-5-yl 1,3-dimethyl-1H-pyrazole- 4-carboxylate, is a 4-hydroxyphenylpyaunate dioxygenase (HPPD)-inhibiting herbicide. Greenhouse and field experiments were conducted to explore the potential of post-emergence (POST) application of bipyrazone in wheat fields in China. In the greenhouse study, bipyrazone at 10 and 20 g active ingredient (a.i.) ha effectively controlled Descurainia sophia L., Capsella bursa-pastoris (L.) Medic., Lithospermum arvense L. and Myosoton aquaticum L. Whereas, all tested 16 wheat cultivars showed high degree of tolerance to bipyrazone at 375 and 750 g a.i. ha. In a dose-response experiment carried on the Shannong 6 wheat cultivar and five weed biotypes, bipyrazone was safe to the wheat cultivar, and C. bursa-pastoris, M. aquaticum and D. sophia were sensitive to this herbicide. The selectivity index (SI) between the Shannong 6 and weeds ranged from 34 to 39. The field experiments confirmed that a mixture of bipyrazone and fluroxypyr-mepthyl is practical for controlling broadleaf weeds, and bipyrazone applied alone at 30 to 40 g a.i. ha can also provide satisfactory control of sensitive broadleaf weeds. These findings suggest that bipyrazone POST application has good potential for broadleaf weed management in wheat fields.
Topics: 4-Hydroxyphenylpyruvate Dioxygenase; Crops, Agricultural; Greenhouse Effect; Herbicide Resistance; Herbicides; Molecular Structure; Plant Proteins; Plant Weeds; Pyrazoles; Triticum
PubMed: 32218463
DOI: 10.1038/s41598-020-62116-6 -
British Journal of Cancer Jan 2020Cancer metabolism has undergone a resurgence in the last decade, 70 years after Warburg described aerobic glycolysis as a feature of cancer cells. A wide range of...
Cancer metabolism has undergone a resurgence in the last decade, 70 years after Warburg described aerobic glycolysis as a feature of cancer cells. A wide range of techniques have elucidated the complexity and heterogeneity in preclinical models and clinical studies. What emerges are the large differences between tissues, tumour types and intratumour heterogeneity. However, synergies with inhibition of metabolic pathways have been found for many drugs and therapeutic approaches, and a critical role of window studies and translational trial design is key to success.
Topics: Animals; Azetidines; Biomarkers, Tumor; Clinical Trials as Topic; Drug Therapy, Combination; Fatty Acid Synthase, Type I; Fatty Acids; Glycolysis; Humans; Mice; Molecular Targeted Therapy; Neoplasms; Nitriles; Pyrazoles; Signal Transduction
PubMed: 31819198
DOI: 10.1038/s41416-019-0666-4 -
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 -
Cellular & Molecular Biology Letters Dec 2021Esterase D (ESD) is a nonspecific esterase that detoxifies formaldehyde. Many reports have stated that ESD activity is associated with a variety of physiological and...
BACKGROUND
Esterase D (ESD) is a nonspecific esterase that detoxifies formaldehyde. Many reports have stated that ESD activity is associated with a variety of physiological and pathological processes. However, the detailed signaling pathway of ESD remains poorly understood.
METHODS
Considering the advantages of the small chemical molecule, our recent work demonstrated that 4-chloro-2-(5-phenyl-1-(pyridin-2-yl)-4,5-dihydro-1H-pyrazol-3-yl) phenol (FPD5) activates ESD, and will be a good tool for studying ESD further. Firstly, we determined the interaction between ESD and FK506 binding protein 25 (FKBP25) by yeast two-hybrid assay and co-immunoprecipitation (CO-IP) and analyzed the phosphorylation levels of mTORC1, P70S6K and 4EBP1 by western blot. Furthermore, we used the sulforhodamine B (SRB) and chick chorioallantoic membrane (CAM) assay to analyze cell viability in vitro and in vivo after treatment with ESD activator FPD5.
RESULTS
We screened FKBP25 as a candidate protein to interact with ESD by yeast two-hybrid assay. Then we verified the interaction between ESD and endogenous FKBP25 or ectopically expressed GFP-FKBP25 by CO-IP. Moreover, the N-terminus (1-90 aa) domain of FKBP25 served as the crucial element for their interaction. More importantly, ESD reduced the K48-linked poly-ubiquitin chains of FKBP25 and thus stabilized cytoplasmic FKBP25. ESD also promoted FKBP25 to bind more mTORC1, suppressing the activity of mTORC1. In addition, ESD suppressed tumor cell growth in vitro and in vivo through autophagy.
CONCLUSIONS
These findings provide novel evidence for elucidating the molecular mechanism of ESD and ubiquitination of FKBP25 to regulate autophagy and cancer cell growth. The ESD/FKBP25/mTORC1 signaling pathway is involved in inhibiting tumor cell growth via regulating autophagy.
Topics: Animals; Autophagy; Cell Cycle; Cell Line; Cell Line, Tumor; Chickens; HEK293 Cells; HeLa Cells; Humans; Mechanistic Target of Rapamycin Complex 1; Phosphorylation; Pyrazoles; Signal Transduction; Tacrolimus; Tacrolimus Binding Proteins; Thiolester Hydrolases; Ubiquitination
PubMed: 34875997
DOI: 10.1186/s11658-021-00297-2 -
Bioorganic & Medicinal Chemistry Apr 2019A series of N-acyl pyrazoles was examined as candidate serine hydrolase inhibitors in which the active site acylating reactivity and the leaving group ability of the...
A series of N-acyl pyrazoles was examined as candidate serine hydrolase inhibitors in which the active site acylating reactivity and the leaving group ability of the pyrazole could be tuned not only through the nature of the acyl group (reactivity: amide > carbamate > urea), but also through pyrazole C4 substitution with electron-withdrawing or electron-donating substituents. Their impact on enzyme inhibitory activity displayed pronounced effects with the activity improving substantially as one alters both the nature of the reacting carbonyl group (urea > carbamate > amide) and the pyrazole C4 substituent (CN > H > Me). It was further demonstrated that the acyl chain of the N-acyl pyrazole ureas can be used to tailor the potency and selectivity of the inhibitor class to a targeted serine hydrolase. Thus, elaboration of the acyl chain of pyrazole-based ureas provided remarkably potent, irreversible inhibitors of fatty acid amide hydrolase (FAAH, apparent K = 100-200 pM), dual inhibitors of FAAH and monoacylglycerol hydrolase (MGLL), or selective inhibitors of MGLL (IC = 10-20 nM) while simultaneously minimizing off-target activity (e.g., ABHD6 and KIAA1363).
Topics: Amidohydrolases; Animals; Drug Design; Enzyme Inhibitors; Monoacylglycerol Lipases; Pyrazoles; Rats; Recombinant Proteins; Structure-Activity Relationship; Urea
PubMed: 30879861
DOI: 10.1016/j.bmc.2019.03.020 -
Antioxidants & Redox Signaling Nov 2012To define the mechanisms underlying pyrazole-induced oxidative stress and the protective role of peroxiredoxins (Prxs) and sulfiredoxin (Srx) against such stress.
AIMS
To define the mechanisms underlying pyrazole-induced oxidative stress and the protective role of peroxiredoxins (Prxs) and sulfiredoxin (Srx) against such stress.
RESULTS
Pyrazole increased Srx expression in the liver of mice in a nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent manner and induced Srx translocation from the cytosol to the endoplasmic reticulum (ER) and mitochondria. Pyrazole also induced the expression of CYP2E1, a primary reactive oxygen species (ROS) source for ethanol-induced liver injury, in ER and mitochondria. However, increased CYP2E1 levels only partially accounted for the pyrazole-mediated induction of Srx, prompting the investigation of CYP2E1-independent ROS generation downstream of pyrazole. Indeed, pyrazole increased ER stress, which is known to elevate mitochondrial ROS. In addition, pyrazole up-regulated CYP2E1 to a greater extent in mitochondria than in ER. Accordingly, among Prxs I to IV, PrxIII, which is localized to mitochondria, was preferentially hyperoxidized in the liver of pyrazole-treated mice. Pyrazole-induced oxidative damage to the liver was greater in PrxIII(-/-) mice than in wild-type mice. Such damage was also increased in Srx(-/-) mice treated with pyrazole, underscoring the role of Srx as the guardian of PrxIII.
INNOVATION
The roles of Prxs, Srx, and ER stress have not been previously studied in relation to pyrazole toxicity.
CONCLUSION
The concerted action of PrxIII and Srx is important for protection against pyrazole-induced oxidative stress arising from the convergent induction of CYP2E1-derived and ER stress-derived ROS in mitochondria.
Topics: Animals; Chemical and Drug Induced Liver Injury; Male; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Oxidation-Reduction; Oxidoreductases Acting on Sulfur Group Donors; Peroxiredoxin III; Pyrazoles
PubMed: 22490042
DOI: 10.1089/ars.2011.4334 -
Angewandte Chemie (International Ed. in... Nov 2019C-Nucleosides are characterized by a C-C rather than a C-N linkage between the heterocyclic base and the ribofuranose ring. While the biosynthesis of...
C-Nucleosides are characterized by a C-C rather than a C-N linkage between the heterocyclic base and the ribofuranose ring. While the biosynthesis of pseudouridine-C-nucleosides has been studied, less is known about the pyrazole-C-nucleosides such as the formycins and pyrazofurin. Herein, genome screening of Streptomyces candidus NRRL 3601 led to the discovery of the pyrazofurin biosynthetic gene cluster pyf. In vitro characterization of gene product PyfQ demonstrated that it is able to catalyze formation of the C-glycoside carboxyhydroxypyrazole ribonucleotide (CHPR) from 4-hydroxy-1H-pyrazole-3,5-dicarboxylic acid and phosphoribosyl pyrophosphate (PRPP). Similarly, ForT, the PyfQ homologue in the formycin pathway, can catalyze the coupling of 4-amino-1H-pyrazole-3,5-dicarboxylic acid and PRPP to form carboxyaminopyrazole ribonucleotide. Finally, PyfP and PyfT are shown to catalyze amidation of CHPR to pyrazofurin 5'-phosphate thereby establishing the latter stages of both pyrazofurin and formycin biosynthesis.
Topics: Amides; Bacterial Proteins; Formycins; Glycosides; Multigene Family; Nucleosides; Pyrazoles; Ribonucleosides; Ribose; Streptomyces
PubMed: 31518483
DOI: 10.1002/anie.201910356