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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 -
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 -
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 -
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 -
Drug Research Feb 2021Piperazine, a nitrogen-containing heterocyclic has acquired an inimitable position in medicinal chemistry because of its versatile structure, which has fascinated... (Review)
Review
Piperazine, a nitrogen-containing heterocyclic has acquired an inimitable position in medicinal chemistry because of its versatile structure, which has fascinated researchers to design novel piperazine based molecules having various biological actions. The subsistence of various compounds possessing diverse pharmacological activities in the literature further confirms this fact. Currently available analgesics and anti-inflammatory drugs are associated with side effects that limit their use. Moreover, the literature reveals the incredible anti-inflammatory and analgesic potential of piperazine derivatives along with their method of synthesis, therefore; the present review has been designed to collate the development made in this area that will surely be advantageous in designing novel piperazine based candidates with enhanced efficacy and less toxicity. An extensive literature survey was carried by scrutinizing peer reviewed articles from worldwide scientific databases available on GOOGLE, SCOPUS, PUBMED, and only relevant studies published in English were considered.
Topics: Analgesics; Animals; Anti-Inflammatory Agents; Humans; Piperazine
PubMed: 33336346
DOI: 10.1055/a-1323-2813 -
Journal of Agricultural and Food... Sep 2022Piperazine and homopiperazine are well-studied heterocycles in drug design that have found gainful application as scaffolds and terminal elements and for enhancing the... (Review)
Review
Piperazine and homopiperazine are well-studied heterocycles in drug design that have found gainful application as scaffolds and terminal elements and for enhancing the aqueous solubility of a molecule. The optimization of drug candidates that incorporate these heterocycles in an effort to refine potency, selectivity, and developability properties has stimulated the design and evaluation of a wide range of bioisosteres that can offer advantage. In this review, we summarize the design and application of bioisosteres of piperazine and homopiperazine that have almost exclusively been in the drug design arena. While there are ∼100 approved drugs that incorporate a piperazine ring, only a single marketed agricultural product is built on this heterocycle. As part of the review, we discuss some of the potential reasons underlying the relatively low level of importance of this heterocycle to the design of agrochemicals and highlight the potential opportunities for their use in contemporary research programs.
Topics: Drug Design; Piperazine; Structure-Activity Relationship
PubMed: 35675050
DOI: 10.1021/acs.jafc.2c00726 -
ChemMedChem Jun 2021Depression is the single largest contributor to global disability with a huge economic and social burden on the world. There are a number of antidepressant drugs on the... (Review)
Review
Depression is the single largest contributor to global disability with a huge economic and social burden on the world. There are a number of antidepressant drugs on the market, but treatment-resistant depression and relapse of depression in a large number of patients have increased problems for clinicians. One peculiarity observed in most of the marketed antidepressants is the presence of a piperazine substructure. Although piperazine is also used in the optimization of other pharmacological agents, it is almost extensively used for the development of novel antidepressants. One common understanding is that this is due to its favorable CNS pharmacokinetic profile; however, in the case of antidepressants, piperazine plays a much bigger role and is involved in specific binding conformations of these agents. Therefore, in this review, a critical analysis of the significance of the piperazine moiety in the development of antidepressants has been performed. An overview of current developments in the designing and synthesis of piperazine-based antidepressants (2015 onwards) along with SAR studies is also provided. The various piperazine-based therapeutic agents in early- or late-phase human testing for depression are also discussed. The preclinical compounds discussed in this review will help researchers understand how piperazine actually influences the design and development of novel antidepressant compounds. The SAR studies discussed will provide crucial clues about the structural features and optimizations required to enhance the efficacy and potency of piperazine-based antidepressants.
Topics: Antidepressive Agents; Depression; Drug Development; Humans; Molecular Structure; Piperazine; Structure-Activity Relationship
PubMed: 33751807
DOI: 10.1002/cmdc.202100045