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Cell Reports Mar 2020Ferroptosis is a type of regulated cell death driven by the iron-dependent accumulation of oxidized polyunsaturated fatty acid-containing phospholipids. There is no...
Ferroptosis is a type of regulated cell death driven by the iron-dependent accumulation of oxidized polyunsaturated fatty acid-containing phospholipids. There is no reliable way to selectively stain ferroptotic cells in tissue sections to characterize the extent of ferroptosis in animal models or patient samples. We address this gap by immunizing mice with membranes from lymphoma cells treated with the ferroptosis inducer piperazine erastin and screening ∼4,750 of the resulting monoclonal antibodies generated for their ability to selectively detect cells undergoing ferroptosis. We find that one antibody, 3F3 ferroptotic membrane antibody (3F3-FMA), is effective as a selective ferroptosis-staining reagent. The antigen of 3F3-FMA is identified as the human transferrin receptor 1 protein (TfR1). We validate this finding with several additional anti-TfR1 antibodies and compare them to other potential ferroptosis-detecting reagents. We find that anti-TfR1 and anti-malondialdehyde adduct antibodies are effective at staining ferroptotic tumor cells in multiple cell culture and tissue contexts.
Topics: Animals; Antibodies, Monoclonal; Antigens; Biomarkers; Cell Line; Cell Line, Tumor; Cell Membrane; Ferroptosis; Golgi Apparatus; Humans; Injections; Mice; Piperazine; Piperazines; Receptors, Transferrin; Xenograft Model Antitumor Assays
PubMed: 32160546
DOI: 10.1016/j.celrep.2020.02.049 -
Nucleic Acids Research Jul 2021Because undesirable pharmacokinetics and toxicity of candidate compounds are the main reasons for the failure of drug development, it has been widely recognized that...
Because undesirable pharmacokinetics and toxicity of candidate compounds are the main reasons for the failure of drug development, it has been widely recognized that absorption, distribution, metabolism, excretion and toxicity (ADMET) should be evaluated as early as possible. In silico ADMET evaluation models have been developed as an additional tool to assist medicinal chemists in the design and optimization of leads. Here, we announced the release of ADMETlab 2.0, a completely redesigned version of the widely used AMDETlab web server for the predictions of pharmacokinetics and toxicity properties of chemicals, of which the supported ADMET-related endpoints are approximately twice the number of the endpoints in the previous version, including 17 physicochemical properties, 13 medicinal chemistry properties, 23 ADME properties, 27 toxicity endpoints and 8 toxicophore rules (751 substructures). A multi-task graph attention framework was employed to develop the robust and accurate models in ADMETlab 2.0. The batch computation module was provided in response to numerous requests from users, and the representation of the results was further optimized. The ADMETlab 2.0 server is freely available, without registration, at https://admetmesh.scbdd.com/.
Topics: Drug-Related Side Effects and Adverse Reactions; Internet; Pharmaceutical Preparations; Pharmacokinetics; Phthalazines; Piperazines; Software
PubMed: 33893803
DOI: 10.1093/nar/gkab255 -
Nature Communications Aug 2022In humans, lipid nanoparticles (LNPs) have safely delivered therapeutic RNA to hepatocytes after systemic administration and to antigen-presenting cells after...
In humans, lipid nanoparticles (LNPs) have safely delivered therapeutic RNA to hepatocytes after systemic administration and to antigen-presenting cells after intramuscular injection. However, systemic RNA delivery to non-hepatocytes remains challenging, especially without targeting ligands such as antibodies, peptides, or aptamers. Here we report that piperazine-containing ionizable lipids (Pi-Lipids) preferentially deliver mRNA to immune cells in vivo without targeting ligands. After synthesizing and characterizing Pi-Lipids, we use high-throughput DNA barcoding to quantify how 65 chemically distinct LNPs functionally delivered mRNA (i.e., mRNA translated into functional, gene-editing protein) in 14 cell types directly in vivo. By analyzing the relationships between lipid structure and cellular targeting, we identify lipid traits that increase delivery in vivo. In addition, we characterize Pi-A10, an LNP that preferentially delivers mRNA to the liver and splenic immune cells at the clinically relevant dose of 0.3 mg/kg. These data demonstrate that high-throughput in vivo studies can identify nanoparticles with natural non-hepatocyte tropism and support the hypothesis that lipids with bioactive small-molecule motifs can deliver mRNA in vivo.
Topics: Humans; Lipids; Liposomes; Nanoparticles; Piperazine; RNA, Messenger; RNA, Small Interfering
PubMed: 35970837
DOI: 10.1038/s41467-022-32281-5 -
Cell Research Jul 2022
Topics: Cell Line, Tumor; Ferroptosis; Piperazines
PubMed: 35352032
DOI: 10.1038/s41422-022-00642-w -
Natural Product Reports Feb 2023Covering: up to the end of July, 2022Fungi are prolific producers of piperazine alkaloids, which have been shown to exhibit an array of remarkable biological activities.... (Review)
Review
Covering: up to the end of July, 2022Fungi are prolific producers of piperazine alkaloids, which have been shown to exhibit an array of remarkable biological activities. Since the first fungal piperazine, herquline A, was reported from Fg-372 in 1979, a plethora of structurally diverse piperazines have been isolated and characterised from various fungal strains. Significant advancements have been made in recent years towards unravelling the biosynthesis of fungal piperazines and numerous synthetic routes have been proposed. This review provides a comprehensive summary of the current knowledge of the discovery, classification, bioactivity and biosynthesis of piperazine alkaloids reported from fungi, and discusses the perspectives for exploring the structural diversity of fungal piperazines genome mining of the untapped piperazine biosynthetic pathways.
Topics: Piperazines; Piperazine; Alkaloids; Fungi
PubMed: 36374102
DOI: 10.1039/d2np00070a -
Chemical Biology & Drug Design Jun 2024The versatile basic structure of piperazine allows for the development and production of newer bioactive molecules that can be used to treat a wide range of diseases.... (Review)
Review
The versatile basic structure of piperazine allows for the development and production of newer bioactive molecules that can be used to treat a wide range of diseases. Piperazine derivatives are unique and can easily be modified for the desired pharmacological activity. The two opposing nitrogen atoms in a six-membered piperazine ring offer a large polar surface area, relative structural rigidity, and more acceptors and donors of hydrogen bonds. These properties frequently result in greater water solubility, oral bioavailability, and ADME characteristics, as well as improved target affinity and specificity. Various synthetic protocols have been reported for piperazine and its derivatives. In this review, we focused on recently published synthetic protocols for the synthesis of the piperazine and its derivatives. The structure-activity relationship concerning different biological activities of various piperazine-containing drugs has also been highlighted to provide a good understanding to researchers for future research on piperazines.
Topics: Piperazines; Humans; Structure-Activity Relationship; Chemistry, Pharmaceutical; Animals
PubMed: 38888058
DOI: 10.1111/cbdd.14537 -
Journal of Medicine and Life Apr 2022Cytokine response to () infection was measured after starting treatments with piperazine. This study aims to determine the impact of cytokine production after infection...
Cytokine response to () infection was measured after starting treatments with piperazine. This study aims to determine the impact of cytokine production after infection with before and after treatment with piperazine. Blood and stool samples of 50 patients with infection and 28 healthy individuals (control) were collected. In this study, IFNγ, IL-5, IL-12, and IL-13 in serum (using ELISA-based methods) were measured. Stool samples were examined using the Kato-Katz technique to detect parasites. Blood and stool samples were analyzed 14 days after starting piperazine treatment for infection. The medium concentration of IFNγ, IL-5, IL-12, and IL-13 in the serum samples with infection is higher than that of the control group. IFNγ, IL-5, IL-12, and IL-13 levels were significantly higher in the infected individuals (10.5±7.4 pg/ml, 14.6±5.1 pg/ml, 8.5±3.2 pg/ml and 13.6±7.5 pg/ml respectively) than the control group (4.7±2.4 pg/ml, 7.8±4.06 pg/ml, 6.3±3.4 pg/ml and 3.5±2.7 pg/ml respectively). Also, piperazine treatment can significantly reduce cytokines levels (IFN-γ: P=0.043, IL-5: P=0.02, and IL-12, p=0.001). This study shows that piperazine treatment can reduce cytokines profiles in patients with infection.
Topics: Ancylostomiasis; Cytokines; Humans; Interleukin-12; Interleukin-13; Interleukin-5; Piperazines
PubMed: 35646178
DOI: 10.25122/jml-2021-0383 -
The American Journal of Cardiology Dec 2023Heart failure is a complex clinical syndrome with a detrimental impact on mortality and morbidity. Energy substrate utilization and myocardial ion channel regulation... (Review)
Review
Heart failure is a complex clinical syndrome with a detrimental impact on mortality and morbidity. Energy substrate utilization and myocardial ion channel regulation have gained research interest especially after the introduction of sodium-glucose co-transporter 2 inhibitors in the treatment of heart failure. Ranolazine or N-(2,6-dimethylphenyl)-2-(4-[2-hydroxy-3-(2-methoxyphenoxy) propyl] piperazin-1-yl) acetamide hydrochloride is an active piperazine derivative which inhibits late sodium current thus minimizing calcium overload in the ischemic cardiomyocytes. Ranolazine also prevents fatty acid oxidation and favors glycose utilization ameliorating the "energy starvation" of the failing heart. Heart failure with preserved ejection fraction is characterized by diastolic impairment; according to the literature ranolazine could be beneficial in the management of increased left ventricular end-diastolic pressure, right ventricular systolic dysfunction and wall shear stress which is reflected by the high natriuretic peptides. Fewer data is evident regarding the effects of ranolazine in heart failure with reduced ejection fraction and mainly support the control of the sodium-calcium exchanger and function of sarcoendoplasmic reticulum calcium adenosine triphosphatase. Ranolazine's therapeutic mechanisms in myocardial ion channels and energy utilization are documented in patients with chronic coronary syndromes. Nevertheless, ranolazine might have a broader effect in the therapy of heart failure and further mechanistic research is required.
Topics: Humans; Ranolazine; Piperazines; Acetanilides; Heart Failure; Sodium
PubMed: 37844876
DOI: 10.1016/j.amjcard.2023.09.066 -
Mini Reviews in Medicinal Chemistry 2021Schizophrenia is a chronic neuropsychiatric disorder that affects nearly 1% of the global population. There are various anti-psychotic drugs available for the treatment... (Review)
Review
Schizophrenia is a chronic neuropsychiatric disorder that affects nearly 1% of the global population. There are various anti-psychotic drugs available for the treatment of schizophrenia, but they have certain side effects; therefore, there is a need to explore and develop novel potential lead compounds against schizophrenia. The currently available drugs e.g. typical and atypical antipsychotics act on different dopamine and serotonin receptors and as per literature reports, various piperidine and piperazine derivatives have shown promising activity against these receptors. When different heterocyclic groups are attached to basic piperidine and piperazine rings, the antipsychotic activity is greatly potentiated. In this direction, various antipsychotic drugs have been synthesized at the laboratory level, and few are under clinical trial studies, such as Lu AE58054, PF-04802540, ORG25935, DMXB-A, Bitopertin, and ABT-126. In the present review, we include the studies related to the effect of different substituents on piperidine/piperazine derivatives and their anti-psychotic activity. Various series of synthesized compounds by other researchers with piperidine/piperazine nucleus have been reviewed and diagrammatically represented in the form of SAR (structure-activity relationships), which will help the scientists for the development of potential lead compounds.
Topics: Animals; Antipsychotic Agents; Humans; Piperazine; Piperidines; Structure-Activity Relationship
PubMed: 32912125
DOI: 10.2174/1389557520666200910092327 -
Journal of Agricultural and Food... Sep 2022Applications of piperazine and homopiperazine in drug design are well-established, and these heterocycles have found use as both scaffolding and terminal elements and... (Review)
Review
Applications of piperazine and homopiperazine in drug design are well-established, and these heterocycles have found use as both scaffolding and terminal elements and also as a means of introducing a water-solubilizing element into a molecule. In the accompanying review (10.1021/acs.jafc.2c00726), we summarized applications of piperazine and homopiperazine and their fused ring homologues in bioactive compound design along with illustrations of the use of 4-substituted piperidines and a sulfoximine-based mimetic. In this review, we discuss applications of pyrrolidine- and fused-pyrrolidine-based mimetics of piperazine and homopiperazine and illustrate derivatives of azetidine that include stretched and spirocyclic motifs, along with applications of a series of diaminocycloalkanes.
Topics: Drug Design; Piperazine; Piperidines; Pyrrolidines
PubMed: 35675052
DOI: 10.1021/acs.jafc.2c00729