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Molecules (Basel, Switzerland) Jan 2020The increasing risk of radiation exposure underlines the need for novel radioprotective agents. Hence, a series of novel 1-(2-hydroxyethyl)piperazine derivatives were...
The increasing risk of radiation exposure underlines the need for novel radioprotective agents. Hence, a series of novel 1-(2-hydroxyethyl)piperazine derivatives were designed and synthesized. Some of the compounds protected human cells against radiation-induced apoptosis and exhibited low cytotoxicity. Compared to the previous series of piperazine derivatives, compound exhibited a radioprotective effect on cell survival in vitro and low toxicity in vivo. It also enhanced the survival of mice 30 days after whole-body irradiation (although this increase was not statistically significant). Taken together, our in vitro and in vivo data indicate that some of our compounds are valuable for further research as potential radioprotectors.
Topics: Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Humans; Maximum Tolerated Dose; Models, Molecular; Molecular Conformation; Molecular Structure; Piperazines; Radiation, Ionizing; Radiation-Protective Agents; Structure-Activity Relationship; Survival Analysis
PubMed: 31991816
DOI: 10.3390/molecules25030532 -
International Journal of Molecular... Aug 2023The oral delivery of peptide pharmaceuticals has long been a fundamental challenge in drug development. A new chemical platform was designed based on branched... (Review)
Review
The oral delivery of peptide pharmaceuticals has long been a fundamental challenge in drug development. A new chemical platform was designed based on branched piperazine-2,5-diones for creating orally available biologically active peptidomimetics. The platform includes a bio-carrier with "built-in" functionally active peptide fragments or bioactive molecules that are covalently attached via linkers. The developed platform allows for a small peptide to be taken with a particular biological activity and to be transformed into an orally stable compound displaying the same activity. Based on this approach, various peptidomimetics exhibiting hemostimulating, hemosuppressing, and adjuvant activity were prepared. In addition, new examples of a rare phenomenon when enantiomeric molecules demonstrate reciprocal biological activity are presented. Finally, the review summarizes the evolutionary approach of the short peptide pharmaceutical development from the immunocompetent organ separation to orally active cyclopeptides and peptidomimetics.
Topics: Peptides, Cyclic; Pharmaceutical Preparations; Peptidomimetics; Peptides; Piperazine
PubMed: 37686336
DOI: 10.3390/ijms241713534 -
ACS Chemical Neuroscience Jan 2022In an attempt to extend recent studies showing that some clinically evaluated histamine H receptor (HR) antagonists possess nanomolar affinity at sigma-1 receptors...
In an attempt to extend recent studies showing that some clinically evaluated histamine H receptor (HR) antagonists possess nanomolar affinity at sigma-1 receptors (σR), we selected 20 representative structures among our previously reported HR ligands to investigate their affinity at σRs. Most of the tested compounds interact with both sigma receptors to different degrees. However, only six of them showed higher affinity toward σR than σR with the highest binding preference to σR for compounds , , and . Moreover, all these ligands share a common structural feature: the piperidine moiety as the fundamental part of the molecule. It is most likely a critical structural element for dual H/σ receptor activity as can be seen by comparing the data for compounds and (hHR = 3.17 and 7.70 nM, σR = 1531 and 3.64 nM, respectively), where piperidine is replaced by piperazine. We identified the putative protein-ligand interactions responsible for their high affinity using molecular modeling techniques and selected compounds and as lead structures for further evaluation. Interestingly, both ligands turned out to be high-affinity histamine H and σ receptor antagonists with negligible affinity at the other histamine receptor subtypes and promising antinociceptive activity . Considering that many literature data clearly indicate high preclinical efficacy of individual selective σ or HR ligands in various pain models, our research might be a breakthrough in the search for novel, dual-acting compounds that can improve existing pain therapies. Determining whether such ligands are more effective than single-selective drugs will be the subject of our future studies.
Topics: Analgesics; Histamine; Histamine Antagonists; Histamine H3 Antagonists; Ligands; Piperazine; Piperidines; Receptors, Histamine H3; Receptors, sigma; Structure-Activity Relationship; Sigma-1 Receptor
PubMed: 34908391
DOI: 10.1021/acschemneuro.1c00435 -
Cell Proliferation Jan 2023ER breast cancer (ER BC) is the most common subtype of BC. Recently, CDK4/6 inhibitors combined with aromatase inhibitors have been approved by FDA as the first-line...
BACKGROUND
ER breast cancer (ER BC) is the most common subtype of BC. Recently, CDK4/6 inhibitors combined with aromatase inhibitors have been approved by FDA as the first-line therapy for patients with ER BC, and showed promising therapeutic efficacy in clinical treatment. However, resistance to CDK4/6 inhibitors is frequently observed. A better understanding of the drug resistance mechanism is beneficial to improving therapeutic strategies by identifying optimal combinational treatments.
METHODS
Western blotting, qPCR, flow cytometry and a series of cell experiments were performed to evaluate the phenotype of MCF-7/R cells. RNA sequencing, non-targeted metabolomics, shRNA knockdown and tumour cell-bearing mouse models were used to clarify the drug resistance mechanism.
RESULTS
Here, we found that ER BC cells have shown an adaptive resistance to palbociclib-induced cell cycle arrest by activating an alternative signal pathway, independent of the CDK4/6-RB signal transduction. Continuing treatment of palbociclib evoked cellular senescence of ER BC cells. Subsequently, the senescence-like phenotype promoted stemness of ER BC cells, accompanied by increased chemoresistance and tumour-initiating potential. Based on transcriptome analysis, we found that PFKFB4 played an important role in stemness transformation and drug resistance. A close correlation was determined between PFKFB4 expression by ER BC cells and cell senescence and stemness. Mechanistically, metabolomic profiling revealed that PFKFB4 reprogramed glucose metabolism and promoted cell stemness by enhancing glycolysis. Strikingly, diminishing PFKFB4 levels improved drug sensitivity and overcame chemoresistance during palbociclib treatment in ER BC.
CONCLUSIONS
These findings not only demonstrated the novel mechanism underlying which ER BC cells resisted to palbociclib, but also provided a possible therapeutic strategy in the intervention of ER BC to overcome drug resistance.
Topics: Humans; Animals; Mice; Female; Receptors, Estrogen; Cell Line, Tumor; MCF-7 Cells; Piperazines; Breast Neoplasms; Drug Resistance, Neoplasm; Cyclin-Dependent Kinase 4; Phosphofructokinase-2
PubMed: 36127291
DOI: 10.1111/cpr.13337 -
Emergencias : Revista de La Sociedad... Jun 2022To detect the presence of unsuspected and/or undeclared cathinone and piperazine-type designer drugs in methamphetamine (METH) and amphetamine users treated in emergency... (Observational Study)
Observational Study
OBJECTIVES
To detect the presence of unsuspected and/or undeclared cathinone and piperazine-type designer drugs in methamphetamine (METH) and amphetamine users treated in emergency departments, and to compare clinical and toxicologic profiles.
MATERIAL AND METHODS
Retrospective observational study of emergency department patients treated for confirmed acute intoxication by recreational drugs (METH and amphetamines) between March 2019 and December 2020. We ordered high-performance liquid chromatography with tandem mass spectrometry to detect cathinones (methylone, fluoromethcathinone, mexedrone, fluoromethamphetamine, mephedrone, methylenedioxypyrovalerone) and synthetic piperazines (meta-chlorophenylpiperazine and trifluoromethylphenylpiperazine). Demographic, clinical, and toxicologic variables were analyzed with SPSS software (version 23).
RESULTS
Thirty-nine patients were included: 24 (61.5%) had used METH and 15 (38.5%) an amphetamine. Synthetic cathinones were detected in samples from 11 patients (28.2%), 10 (90.9%) in the METH group and 1 (9.1%) in the amphetamine group (P = .028). The METH users had taken mephedrone (8 patients) or methylone (2 patients); the amphetamine user had taken mephedrone. None of the patients had declared use of a cathinone; nor was use suspected. The mean (SD) number of substances involved was higher among users of cathinones (3.5 [1.13] vs 2.5 [1.40] in those who took no cathinones; P = .036). Among the cathinone users, 90.9% were men, 90.9% had used METH, and 45.5% had practiced chemsex. HIV positivity was significantly associated with cathinone use (in 45.5% vs 10.7% of those not using cathinones; P = .028). All 5 of the patients who had taken cathinones and also practiced chemsex were HIV positive. Significantly more patients who had taken cathinones presented with anxiety (72.7% vs 21.43%; P = .007). No differences in clinical management were found.
CONCLUSION
Detection of METH in intoxicated patients should raise suspicion of probable use of a synthetic cathinone. Patients in whom new psychoactive substances are detected should be kept under observation, and clinical protocols should include referring them to addiction treatment centers.
Topics: Alkaloids; Amphetamine; Emergency Service, Hospital; Female; Humans; Male; Methamphetamine; Piperazine; Piperazines
PubMed: 35736521
DOI: No ID Found -
International Journal of Molecular... Sep 2023Ferroptosis is a newly characterized form of programmed cell death. The fundamental biochemical feature of ferroptosis is the lethal accumulation of iron-catalyzed lipid...
Ferroptosis is a newly characterized form of programmed cell death. The fundamental biochemical feature of ferroptosis is the lethal accumulation of iron-catalyzed lipid peroxidation. It has gradually been recognized that ferroptosis is implicated in the pathogenesis of a variety of human diseases. Increasing evidence has shed light on ferroptosis regulation by amino acid metabolism. Herein, we report that arginine deprivation potently inhibits erastin-induced ferroptosis, but not RSL3-induced ferroptosis, in several types of mammalian cells. Arginine presence reduces the intracellular glutathione (GSH) level by sustaining the biosynthesis of fumarate, which functions as a reactive α,β-unsaturated electrophilic metabolite and covalently binds to GSH to generate succinicGSH. siRNA-mediated knockdown of argininosuccinate lyase, the critical urea cycle enzyme directly catalyzing the biosynthesis of fumarate, significantly decreases cellular fumarate and thus relieves erastin-induced ferroptosis in the presence of arginine. Furthermore, fumarate is decreased during erastin exposure, suggesting that a protective mechanism exists to decelerate GSH depletion in response to pro-ferroptotic insult. Collectively, this study reveals the ferroptosis regulation by the arginine metabolism and expands the biochemical functionalities of arginine.
Topics: Animals; Humans; Ferroptosis; Apoptosis; Piperazines; Lipid Peroxidation; Mammals
PubMed: 37834044
DOI: 10.3390/ijms241914595 -
Bioorganic & Medicinal Chemistry Letters Dec 2017A small library of fluoroethoxy-1,4-diphenethyl piperidine and fluoroethoxy-1,4-diphenethyl piperazine derivatives were designed, synthesized and evaluated for their...
A small library of fluoroethoxy-1,4-diphenethyl piperidine and fluoroethoxy-1,4-diphenethyl piperazine derivatives were designed, synthesized and evaluated for their ability to inhibit [H]dopamine (DA) uptake at the vesicular monoamine transporter-2 (VMAT2) and dopamine transporter (DAT), [H]serotonin (5-HT) uptake at the serotonin transporter (SERT), and [H]dofetilide binding at the human-ether-a-go-go-related gene (hERG) channel. The majority of the compounds exhibited potent inhibition of [H]DA uptake at VMAT2, Ki changes in the nanomolar range (K = 0.014-0.073 µM). Compound 15d exhibited the highest affinity (K = 0.014 µM) at VMAT2, and had 160-, 5-, and 60-fold greater selectivity for VMAT2 vs. DAT, SERT and hERG, respectively. Compound 15b exhibited the greatest selectivity (>60-fold) for VMAT2 relative to all the other targets evaluated, and 15b had high affinity for VMAT2 (K = 0.073 µM). Compound 15b was considered the lead compound from this analog series due to its high affinity and selectivity for VMAT2.
Topics: Dopamine; Dopamine Plasma Membrane Transport Proteins; ERG1 Potassium Channel; Humans; Kinetics; Piperazines; Piperidines; Protein Binding; Serotonin; Serotonin Plasma Membrane Transport Proteins; Structure-Activity Relationship; Vesicular Monoamine Transport Proteins
PubMed: 29153425
DOI: 10.1016/j.bmcl.2017.10.039 -
Journal of Natural Products Jan 2022We have previously reported that neoechinulin B (), a prenylated indole diketopiperazine alkaloid, shows antiviral activities against hepatitis C virus (HCV) via the...
We have previously reported that neoechinulin B (), a prenylated indole diketopiperazine alkaloid, shows antiviral activities against hepatitis C virus (HCV) via the inactivation of the liver X receptors (LXRs) and the resultant disruption of double-membrane vesicles. In this study, a two-step synthesis of the diketopiperazine scaffold of was achieved by the base-induced coupling of 1,4-diacetyl-3-{[-butyldimethylsilyl)oxy]methyl}piperazine-2,5-dione with aldehydes, followed by the treatment of the resultant coupling products with tetra--butylammonium fluoride. Compound and its 16 derivatives - were prepared using this method. Furthermore, variecolorin H, a related alkaloid, was obtained by the acid treatment of in MeOH. The antiviral evaluation of and its derivatives revealed that , , , , , , and exhibited both anti-HCV and anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activities. The results of this study indicate that the exomethylene moiety on the diketopiperazine ring is important for the antiviral activities. The antiviral compounds can inhibit the production of HCV and SARS-CoV-2 by inactivating LXRs.
Topics: Alkaloids; Antiviral Agents; Cell Line, Tumor; Diketopiperazines; Hepacivirus; Humans; Liver X Receptors; Molecular Structure; Piperazines; SARS-CoV-2; Structure-Activity Relationship; Transcription, Genetic
PubMed: 34967639
DOI: 10.1021/acs.jnatprod.1c01120 -
Journal of Food and Drug Analysis Mar 2022Drug substances are at risk of contamination with N-nitrosamines (NAs), well-known carcinogenic agents, during synthesis processes and/or long-term storage. Therefore,...
Drug substances are at risk of contamination with N-nitrosamines (NAs), well-known carcinogenic agents, during synthesis processes and/or long-term storage. Therefore, in this study, we developed an efficient data-based screening approach to systemically assess marketed products and investigated its scalability for benefiting both regulatory agencies and pharmaceutical industries. A substructure-based screening method employing DataWarrior, an open-source software, was established to evaluate the risks of NA impurities in drug substances. Eight NA substructures containing susceptible amino sources for N-nitrosation have been identified as screening targets: dimethylamine (DMA), diethylamine, isopropylethylamine, diisopropylamine, N-methyl-2-pyrrolidone, dibutylamine, methylphenylamine, and tetrazoles. Our method detected 192 drug substances with a theoretical possibility of NA impurity, 141 of which had not been reported previously. In addition, the DMA moiety was significantly dominant among the eight NA substructures. The results were validated using data from the literature, and a high detection sensitivity of 0.944 was demonstrated. Furthermore, our approach has the advantage of scalability, owing to which 31 additional drugs with suspected NA-contaminated substructures were identified using the substructures of 1-methyl-4-piperazine in rifampin and 1-cyclopentyl-4-piperazine in rifapentine. In conclusion, the reported substructure-based approach provides an effective and scalable method for the screening and investigation of NA impurities in various pharmaceuticals and might be used as an ancillary technique in the field of pharmaceutical quality control for risk assessments of potential NA impurities.
Topics: Drug Contamination; Nitrosamines; Piperazines; Quality Control; Risk Assessment
PubMed: 35647726
DOI: 10.38212/2224-6614.3400 -
Psychiatria Polska Dec 2018Although the development of second-generation antipsychotics was a cornerstone in the treatment of schizophrenia, several unmet treatment needs in the field still exist.... (Review)
Review
Although the development of second-generation antipsychotics was a cornerstone in the treatment of schizophrenia, several unmet treatment needs in the field still exist. It is particularly important to note that available antipsychotics have limited efficacy in the treatment of negative symptoms and cognitive impairment. At this point, it should be noted that primary negative symptoms, i.e., those that are not due to depression, extrapyramidal symptoms or psychotic withdrawal, might affect even one-fourth of patients with schizophrenia and are associated with poor clinical and functional outcomes. Cariprazine, is an emerging antipsychotic drug, D3/D2 receptor partial agonist, with affinity to several serotonin receptors. In this article, we provide an overview of pharmacokinetic and pharmacodynamic properties of cariprazine, showing its unique receptor profile. Next, we discuss results of double-blind, placebo-controlled, randomized clinical trials and post hoc analyses of cariprazine that have been published to date. These studies have provided evidence for efficacy of cariprazine in the treatment of schizophrenia exacerbations compared to placebo, with safety and good tolerability. In addition, one clinical trial published to date revealed superior efficacy of cariprazine compared to risperidone in the treatment of predominant negative symptoms that had been also associated with concomitant improvement of functional performance. Overall, current evidence in the field supports the use of cariprazine in exacerbation of schizophrenia and suggests promising efficacy in the treatment of predominant negative symptoms.
Topics: Antipsychotic Agents; Dose-Response Relationship, Drug; Female; Humans; Male; Medication Adherence; Piperazines; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Treatment Outcome
PubMed: 30659560
DOI: 10.12740/PP/OnlineFirst/80710