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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 -
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 -
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 -
International Journal of Molecular... Aug 2023Pyrazole derivatives, as a class of heterocyclic compounds, possess unique chemical structures that confer them with a broad spectrum of pharmacological activities. They... (Review)
Review
Pyrazole derivatives, as a class of heterocyclic compounds, possess unique chemical structures that confer them with a broad spectrum of pharmacological activities. They have been extensively explored for designing potent and selective anticancer agents. In recent years, numerous pyrazole derivatives have been synthesized and evaluated for their anticancer potential against various cancer cell lines. Structure-activity relationship studies have shown that appropriate substitution on different positions of the pyrazole ring can significantly enhance anticancer efficacy and tumor selectivity. It is noteworthy that many pyrazole derivatives have demonstrated multiple mechanisms of anticancer action by interacting with various targets including tubulin, EGFR, CDK, BTK, and DNA. Therefore, this review summarizes the current understanding on the structural features of pyrazole derivatives and their structure-activity relationships with different targets, aiming to facilitate the development of potential pyrazole-based anticancer drugs. We focus on the latest research advances in anticancer activities of pyrazole compounds reported from 2018 to present.
Topics: Antineoplastic Agents; Pyrazoles; Cell Line; Structure-Activity Relationship; Tubulin
PubMed: 37628906
DOI: 10.3390/ijms241612724 -
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 -
Molecules (Basel, Switzerland) Apr 2021Cannabinoids comprise different classes of compounds, which aroused interest in recent years because of their several pharmacological properties. Such properties include... (Review)
Review
Cannabinoids comprise different classes of compounds, which aroused interest in recent years because of their several pharmacological properties. Such properties include analgesic activity, bodyweight reduction, the antiemetic effect, the reduction of intraocular pressure and many others, which appear correlated to the affinity of cannabinoids towards CB and/or CB receptors. Within the search aiming to identify novel chemical scaffolds for cannabinoid receptor interaction, the CB antagonist/inverse agonist pyrazole-based derivative rimonabant has been modified, giving rise to several tricyclic pyrazole-based compounds, most of which endowed of high affinity and selectivity for CB or CB receptors. The aim of this review is to present the synthesis and summarize the SAR study of such tricyclic pyrazole-based compounds, evidencing, for some derivatives, their potential in the treatment of neuropathic pain, obesity or in the management of glaucoma.
Topics: Cannabinoids; Molecular Structure; Protein Binding; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Structure-Activity Relationship
PubMed: 33917187
DOI: 10.3390/molecules26082126 -
International Journal of Molecular... Mar 2023Multi-drug resistant bacterial strains (MDR) have become an increasing challenge to our health system, resulting in multiple classical antibiotics being clinically...
Multi-drug resistant bacterial strains (MDR) have become an increasing challenge to our health system, resulting in multiple classical antibiotics being clinically inactive today. As the de-novo development of effective antibiotics is a very costly and time-consuming process, alternative strategies such as the screening of natural and synthetic compound libraries is a simple approach towards finding new lead compounds. We thus report on the antimicrobial evaluation of a small collection of fourteen drug-like compounds featuring indazoles, pyrazoles and pyrazolines as key heterocyclic moieties whose synthesis was achieved in continuous flow mode. It was found that several compounds possessed significant antibacterial potency against clinical and MDR strains of the and genera, with the lead compound () reaching MIC values of 4 µg/mL on those species. In addition, time killing experiments performed on compound on MDR strains highlight its activity as bacteriostatic. Additional evaluations regarding the physiochemical and pharmacokinetic properties of the most active compounds are reported and showcased, promising drug-likeness, which warrants further explorations of the newly identified antimicrobial lead compound.
Topics: Pyrazoles; Indazoles; Structure-Activity Relationship; Anti-Infective Agents; Anti-Bacterial Agents; Microbial Sensitivity Tests
PubMed: 36982392
DOI: 10.3390/ijms24065319 -
Molecules (Basel, Switzerland) Feb 2021The remarkable prevalence of pyrazole scaffolds in a versatile array of bioactive molecules ranging from apixaban, an anticoagulant used to treat and prevent blood clots... (Review)
Review
The remarkable prevalence of pyrazole scaffolds in a versatile array of bioactive molecules ranging from apixaban, an anticoagulant used to treat and prevent blood clots and stroke, to bixafen, a pyrazole-carboxamide fungicide used to control diseases of rapeseed and cereal plants, has encouraged both medicinal and organic chemists to explore new methods in developing pyrazole-containing compounds for different applications. Although numerous synthetic strategies have been developed in the last 10 years, there has not been a comprehensive overview of synthesis and the implication of recent advances for treating neurodegenerative disease. This review first presents the advances in pyrazole scaffold synthesis and their functionalization that have been published during the last decade (2011-2020). We then narrow the focus to the application of these strategies in the development of therapeutics for neurodegenerative diseases, particularly for Alzheimer's disease (AD) and Parkinson's disease (PD).
Topics: Alzheimer Disease; Animals; Humans; Molecular Structure; Parkinson Disease; Pyrazoles
PubMed: 33668128
DOI: 10.3390/molecules26051202 -
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 -
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