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1.
Cell ; 156(1-2): 317-331, 2014 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-24439385

RESUMO

Ferroptosis is a form of nonapoptotic cell death for which key regulators remain unknown. We sought a common mediator for the lethality of 12 ferroptosis-inducing small molecules. We used targeted metabolomic profiling to discover that depletion of glutathione causes inactivation of glutathione peroxidases (GPXs) in response to one class of compounds and a chemoproteomics strategy to discover that GPX4 is directly inhibited by a second class of compounds. GPX4 overexpression and knockdown modulated the lethality of 12 ferroptosis inducers, but not of 11 compounds with other lethal mechanisms. In addition, two representative ferroptosis inducers prevented tumor growth in xenograft mouse tumor models. Sensitivity profiling in 177 cancer cell lines revealed that diffuse large B cell lymphomas and renal cell carcinomas are particularly susceptible to GPX4-regulated ferroptosis. Thus, GPX4 is an essential regulator of ferroptotic cancer cell death.


Assuntos
Carbolinas/farmacologia , Morte Celular/efeitos dos fármacos , Glutationa Peroxidase/antagonistas & inibidores , Piperazinas/farmacologia , Animais , Carcinoma de Células Renais/tratamento farmacológico , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Glutationa/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Xenoenxertos , Humanos , Linfoma de Células B/tratamento farmacológico , Camundongos , Transplante de Neoplasias , Neoplasias/tratamento farmacológico , Fosfolipídeo Hidroperóxido Glutationa Peroxidase
2.
Cell ; 149(5): 1060-72, 2012 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-22632970

RESUMO

Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration.


Assuntos
Morte Celular , Ferro/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Cicloexilaminas/farmacologia , Fibroblastos/citologia , Fibroblastos/metabolismo , Ácido Glutâmico/metabolismo , Hipocampo/citologia , Humanos , Técnicas In Vitro , Metabolismo dos Lipídeos , Neoplasias/patologia , Fenilenodiaminas/farmacologia , Piperazinas/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo
3.
Molecules ; 29(1)2024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-38202832

RESUMO

The N-phenylquinoneimine scaffold is a versatile synthetic platform that has gained significant attention in the field of drug discovery due to its structural diversity and capacity to interact with biologically relevant targets. This review explores established synthetic methodologies and highlights the significant biological activities exhibited by compounds derived from this scaffold, their implications for medicinal chemistry, and the development of novel therapeutics.


Assuntos
Química Farmacêutica , Descoberta de Drogas
4.
Molecules ; 25(7)2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32244744

RESUMO

Lung cancer is the leading cause of death in men and women worldwide, affecting millions of people. Between the two types of lung cancers, non-small cell lung cancer (NSCLC) is more common than small cell lung cancer (SCLC). Besides surgery and radiotherapy, chemotherapy is the most important method of treatment for lung cancer. Indole scaffold is considered one of the most privileged scaffolds in heterocyclic chemistry. Indole may serve as an effective probe for the development of new drug candidates against challenging diseases, including lung cancer. In this review, we will focus on discussing the existing indole based pharmacophores in the clinical and pre-clinical stages of development against lung cancer, along with the synthesis of some of the selected anti-lung cancer drugs. Moreover, the basic mechanism of action underlying indole based anti-lung cancer treatment, such as protein kinase inhibition, histone deacetylase inhibition, DNA topoisomerase inhibition, and tubulin inhibition will also be discussed.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Desenvolvimento de Medicamentos , Indóis , Animais , Estudos Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Humanos , Estrutura Molecular , Terapia de Alvo Molecular , Transdução de Sinais , Relação Estrutura-Atividade
5.
Nat Chem Biol ; 12(7): 497-503, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27159577

RESUMO

Apoptosis is one type of programmed cell death. Increasingly, non-apoptotic cell death is recognized as being genetically controlled, or 'regulated'. However, the full extent and diversity of alternative cell death mechanisms remain uncharted. Here we surveyed the landscape of pharmacologically accessible cell death mechanisms. In an examination of 56 caspase-independent lethal compounds, modulatory profiling showed that 10 compounds induced three different types of regulated non-apoptotic cell death. Optimization of one of those ten resulted in the discovery of FIN56, a specific inducer of ferroptosis. Ferroptosis has been found to occur when the lipid-repair enzyme GPX4 is inhibited. FIN56 promoted degradation of GPX4. FIN56 also bound to and activated squalene synthase, an enzyme involved in isoprenoid biosynthesis, independent of GPX4 degradation. These discoveries show that dysregulation of lipid metabolism is associated with ferroptosis. This systematic approach is a means to discover and characterize novel cell death phenotypes.


Assuntos
Apoptose/efeitos dos fármacos , Ferro/metabolismo , Oximas/farmacologia , Sulfonamidas/farmacologia , Relação Dose-Resposta a Droga , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Oximas/química , Oximas/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/metabolismo
6.
Molecules ; 23(7)2018 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-30041415

RESUMO

Oxidative stress has been linked to neurodegenerative diseases such as Huntington's, Parkinson's, Alzheimer's and amyotrophic lateral sclerosis diseases. Larrea tridentata (LT) also known as Creosote Bush is an evergreen shrub found in the Chihuahuan desert which has been used medicinally by Native American tribes in southwestern North America and the Amerindians of South America. However, studies of the antioxidant capacity of the crude extract of LT towards the discovery of novel molecular therapies bearing antioxidants and drug-like properties are lacking. In this study, we assessed the antioxidant properties of Larrea tridentata, collected specifically from the Chihuahuan desert in the region of El Paso del Norte, TX, USA. LT phytochemicals were obtained from three different extracts (ethanol; ethanol: water (60:40) and water). Then the extracts were evaluated in eight different assays (DPPH, ABTS, superoxide; FRAP activity, nitric oxide, phenolic content, UV visible absorption and cytotoxicity in non-cancerous HS27 cells). The three extracts were not affecting the HS27 cells at concentrations up to 120 µg/mL. Among the three extracts, we found that the mixture of ethanol: water (60:40) LT extract has the most efficient antioxidant properties (IC50 (DPPH at 30 min) = 111.7 ± 3.8 µg/mL; IC50 (ABTS) = 8.49 ± 2.28 µg/mL; IC50 (superoxide) = 0.43 ± 0.17 µg/mL; IC50 (NO) = 230.4 ± 130.4 µg/mL; and the highest phenolic content was estimated to 212.46 ± 7.05 mg GAE/L). In addition, there was a strong correlation between phenolic content and the free-radical scavenging activity assays. HPLC-MS study identified nine compounds from the LT-ethanol: water extract including Justicidin B and Beta peltain have been previously reported as secondary metabolites of Larrea tridentata.


Assuntos
Antioxidantes/farmacologia , Larrea/química , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Antioxidantes/química , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Flavonoides/química , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia , Humanos , Espectrometria de Massas , Estrutura Molecular , Óxido Nítrico/metabolismo , Fenóis/química , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Folhas de Planta
7.
Molecules ; 23(7)2018 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-29973498

RESUMO

Leishmania major (L. major) is a protozoan parasite that causes cutaneous leishmaniasis. About 12 million people are currently infected with an annual incidence of 1.3 million cases. The purpose of this study was to synthesize a small library of novel thiophene derivatives, and evaluate its parasitic activity, and potential mechanism of action (MOA). We developed a structure⁻activity relationship (SAR) study of the thiophene molecule 5A. Overall, eight thiophene derivatives of 5A were synthesized and purified by silica gel column chromatography. Of these eight analogs, the molecule 5D showed the highest in vitro activity against Leishmania major promastigotes (EC50 0.09 ± 0.02 µM), with an inhibition of the proliferation of intracellular amastigotes higher than 75% at only 0.63 µM and an excellent selective index. Moreover, the effect of 5D on L. major promastigotes was associated with generation of reactive oxygen species (ROS), and in silico docking studies suggested that 5D may play a role in inhibiting trypanothione reductase. In summary, the combined SAR study and the in vitro evaluation of 5A derivatives allowed the identification of the novel molecule 5D, which exhibited potent in vitro anti-leishmanial activity resulting in ROS production leading to cell death with no significant cytotoxicity towards mammalian cells.


Assuntos
Antiprotozoários/síntese química , Leishmania major/efeitos dos fármacos , NADH NADPH Oxirredutases/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/síntese química , Tiofenos/síntese química , Animais , Antiprotozoários/química , Antiprotozoários/farmacologia , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Leishmania major/metabolismo , Leishmaniose Cutânea/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteínas de Protozoários/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacologia
8.
Proc Natl Acad Sci U S A ; 111(47): 16836-41, 2014 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-25385600

RESUMO

Receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis is thought to be the pathophysiologically predominant pathway that leads to regulated necrosis of parenchymal cells in ischemia-reperfusion injury (IRI), and loss of either Fas-associated protein with death domain (FADD) or caspase-8 is known to sensitize tissues to undergo spontaneous necroptosis. Here, we demonstrate that renal tubules do not undergo sensitization to necroptosis upon genetic ablation of either FADD or caspase-8 and that the RIPK1 inhibitor necrostatin-1 (Nec-1) does not protect freshly isolated tubules from hypoxic injury. In contrast, iron-dependent ferroptosis directly causes synchronized necrosis of renal tubules, as demonstrated by intravital microscopy in models of IRI and oxalate crystal-induced acute kidney injury. To suppress ferroptosis in vivo, we generated a novel third-generation ferrostatin (termed 16-86), which we demonstrate to be more stable, to metabolism and plasma, and more potent, compared with the first-in-class compound ferrostatin-1 (Fer-1). Even in conditions with extraordinarily severe IRI, 16-86 exerts strong protection to an extent which has not previously allowed survival in any murine setting. In addition, 16-86 further potentiates the strong protective effect on IRI mediated by combination therapy with necrostatins and compounds that inhibit mitochondrial permeability transition. Renal tubules thus represent a tissue that is not sensitized to necroptosis by loss of FADD or caspase-8. Finally, ferroptosis mediates postischemic and toxic renal necrosis, which may be therapeutically targeted by ferrostatins and by combination therapy.


Assuntos
Apoptose , Túbulos Renais/citologia , Animais , Peso Corporal , Caspase 8/genética , Caspase 8/fisiologia , Proteína de Domínio de Morte Associada a Fas/genética , Proteína de Domínio de Morte Associada a Fas/fisiologia , Camundongos , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/fisiologia , Traumatismo por Reperfusão/prevenção & controle
9.
Bioorg Med Chem Lett ; 25(22): 5315-20, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26410073

RESUMO

Leishmania major (L. major) is a protozoan parasite causal agent of Leishmaniasis. It is estimated that 12 million people are currently infected and around 2 million infections occur each year. Current treatments suffer of high toxicity for the patient, low efficacy toward the parasite, high cost, and are losing effectiveness due to parasite resistance. Discovering novel small molecule with high specificity/selectivity and drug-like properties for anti-leishmanial activity remains a significant challenge. The purpose of this study is to communicate the design and synthesis strategies of novel chemical compounds based of the arylalkylamine scaffold with selective toxicity towards L. major and less toxicity to human cells in vitro. Here, we have developed a structure activity relationship (SAR) study of arylalkylamine AA1 in order to study their anti-parasitic effect in L. major. Overall, 27 arylalkylamine compounds derived from AA1 were synthesized and purified by silica gel column chromatography. The purity of each analog was confirmed by spectroscopic methods ((1)H, (13)C NMR and LC/MS). Among these analogs, the compound AA9 showed the best toxic activity on L. major (LD50=3.34 µM), which represents a 9 fold higher lethality as compared with its parental AA1 (Fer-1) compound (LD50=28.75 µM). In addition, AA9 showed no significant toxicity at 80 µM on U20S Human Osteoblasts, Raw 264.7 Macrophages or intraperitoneal macrophages. In summary, our combined SAR study and biological evaluation data of AA1-AA27 compounds allow the identification of novel arylalkylamine compound AA9 that exhibits potent cytotoxicity against L. major promastigote with minimum toxic effect on human cells.


Assuntos
Aminas/farmacologia , Antiparasitários/farmacologia , Leishmania major/efeitos dos fármacos , Aminas/síntese química , Aminas/química , Aminas/toxicidade , Antiparasitários/síntese química , Antiparasitários/química , Antiparasitários/toxicidade , Arilalquilamina N-Acetiltransferase/química , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Osteoblastos/efeitos dos fármacos
10.
J Am Chem Soc ; 136(12): 4551-6, 2014 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-24592866

RESUMO

Ferrostatin-1 (Fer-1) inhibits ferroptosis, a form of regulated, oxidative, nonapoptotic cell death. We found that Fer-1 inhibited cell death in cellular models of Huntington's disease (HD), periventricular leukomalacia (PVL), and kidney dysfunction; Fer-1 inhibited lipid peroxidation, but not mitochondrial reactive oxygen species formation or lysosomal membrane permeability. We developed a mechanistic model to explain the activity of Fer-1, which guided the development of ferrostatins with improved properties. These studies suggest numerous therapeutic uses for ferrostatins, and that lipid peroxidation mediates diverse disease phenotypes.


Assuntos
Cicloexilaminas/farmacologia , Doença de Huntington/tratamento farmacológico , Nefropatias/tratamento farmacológico , Leucomalácia Periventricular/tratamento farmacológico , Lipídeos de Membrana/metabolismo , Fenilenodiaminas/farmacologia , Morte Celular/efeitos dos fármacos , Cicloexilaminas/uso terapêutico , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Leucomalácia Periventricular/metabolismo , Leucomalácia Periventricular/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Fenilenodiaminas/uso terapêutico
11.
Proc Natl Acad Sci U S A ; 108(39): E771-80, 2011 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-21896738

RESUMO

Cell death is a complex process that plays a vital role in development, homeostasis, and disease. Our understanding of and ability to control cell death is impeded by an incomplete characterization of the full range of cell death processes that occur in mammalian systems, especially in response to exogenous perturbations. We present here a general approach to address this problem, which we call modulatory profiling. Modulatory profiles are composed of the changes in potency and efficacy of lethal compounds produced by a second cell death-modulating agent in human cell lines. We show that compounds with the same characterized mechanism of action have similar modulatory profiles. Furthermore, clustering of modulatory profiles revealed relationships not evident when clustering lethal compounds based on gene expression profiles alone. Finally, modulatory profiling of compounds correctly predicted three previously uncharacterized compounds to be microtubule-destabilizing agents, classified numerous compounds that act nonspecifically, and identified compounds that cause cell death through a mechanism that is morphologically and biochemically distinct from previously established ones.


Assuntos
Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Linhagem Celular , Humanos , Microtúbulos/efeitos dos fármacos , Transdução de Sinais , Proteína Killer-Antagonista Homóloga a bcl-2 , Proteína X Associada a bcl-2/fisiologia
12.
Cancers (Basel) ; 16(3)2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38339398

RESUMO

Copper, an essential element for various biological processes, demands precise regulation to avert detrimental health effects and potential cell toxicity. This paper explores the mechanisms of copper-induced cell death, known as cuproptosis, and its potential health and disease implications, including cancer therapy. Copper ionophores, such as elesclomol and disulfiram, increase intracellular copper levels. This elevation triggers oxidative stress and subsequent cell death, offering potential implications in cancer therapy. Additionally, copper ionophores disrupt mitochondrial respiration and protein lipoylation, further contributing to copper toxicity and cell death. Potential targets and biomarkers are identified, as copper can be targeted to those proteins to trigger cuproptosis. The role of copper in different cancers is discussed to understand targeted cancer therapies using copper nanomaterials, copper ionophores, and copper chelators. Furthermore, the role of copper is explored through diseases such as Wilson and Menkes disease to understand the physiological mechanisms of copper. Exploring cuproptosis presents an opportunity to improve treatments for copper-related disorders and various cancers, with the potential to bring significant advancements to modern medicine.

13.
Cancers (Basel) ; 15(14)2023 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-37509391

RESUMO

Squalene synthase (SQS) has emerged as a promising therapeutic target for various diseases, including cancers, owing to its pivotal role in the mevalonate pathway and the antioxidant properties of squalene. Primarily, SQS orchestrates the head-to-head condensation reaction, catalyzing the fusion of two farnesyl pyrophosphate molecules, leading to the formation of squalene, which has been depicted as a highly effective oxygen-scavenging agent in in vitro studies. Recent studies have depicted this isoprenoid as a protective layer against ferroptosis due to its potential regulation of lipid peroxidation, as well as its protection against oxidative damage. Therefore, beyond its fundamental function, recent investigations have unveiled additional roles for SQS as a regulator of lipid peroxidation and programmed cell death pathways, such as ferroptosis-a type of cell death characterized by elevated levels of lipid peroxide, one of the forms of reactive oxygen species (ROS), and intracellular iron concentration. Notably, thorough explorations have shed light on the distinctive features that set SQS apart from other members within the isoprenoid synthase superfamily. Its unique biochemical structure, intricately intertwined with its reaction mechanism, has garnered significant attention. Moreover, considerable evidence substantiates the significance of SQS in various disease contexts, and its intriguing association with ferroptosis and lipid peroxidation. The objective of this report is to analyze the existing literature comprehensively, corroborating these findings, and provide an up-to-date perspective on the current understanding of SQS as a prospective therapeutic target, as well as its intricate relationship with ferroptosis. This review aims to consolidate the knowledge surrounding SQS, thereby contributing to the broader comprehension of its potential implications in disease management and therapeutic interventions.

14.
Artigo em Inglês | MEDLINE | ID: mdl-36525934

RESUMO

Treatments against leishmaniasis are limited and the development of new molecules is crucial. One class of developmental drug that has shown activity against the parasite Leishmania are thiophene derivatives. Here we synthetized thirty-eight novel thiophene compounds and characterized their activity and potential for resistance against L. infantum. Half of the molecules had an EC50 in the low micromolar range, the piperidine derivatives being more potent than the tetramethylpyran derivatives. Resistance was challenging to select for, and resistant cells could only be raised against one (GC1-19) of the four most active compounds. Using chemogenomic screens we show that a gene conversion event at the ABCG2 locus as well as the overexpression of a tryparedoxin peroxidase are responsible for a weak but significant resistance to the GC1-19 drug candidate. Together, our results suggest that thiophene is a scaffold of interest for further drug development against leishmaniasis.


Assuntos
Antiprotozoários , Leishmania infantum , Leishmaniose Visceral , Leishmaniose , Parasitos , Animais , Leishmania infantum/genética , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Leishmaniose/tratamento farmacológico , Leishmaniose Visceral/tratamento farmacológico
15.
Bioorg Med Chem Lett ; 22(17): 5707-13, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22832321

RESUMO

A series of Pictet-Spengler condensation derivatives (tetrahydro-ß-carbolines) was designed, synthesized and evaluated for lethality against a panel of seven cancer cell lines. Seven compounds (2a, 13, 20, 21, 27, 29 and 34) showed lethality in at least five cell lines. Among these, compound 27 showed a unique selectivity towards oncogenic-RAS expressing BJ-TERT/LT/ST/RAS(V12) tumor cells, compared to non-transformed BJ-TERT cells. Further investigation revealed that 27 induces cell death without activation of caspases. This represents a useful new probe of non-apoptotic cell death and oncogenic-RAS synthetic lethality.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Carbolinas/química , Carbolinas/farmacologia , Genes ras/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Antineoplásicos/síntese química , Carbolinas/síntese química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias/genética
16.
Biomedicines ; 10(4)2022 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-35453641

RESUMO

The selenoprotein glutathione peroxidase 4 (GPX4) is one of the main antioxidant mediators in the human body. Its central function involves the reduction of complex hydroperoxides into their respective alcohols often using reduced Glutathione (GSH) as a reducing agent. GPX4 has become a hotspot therapeutic target in biomedical research following its characterization as a chief regulator of ferroptosis, and its subsequent recognition as a specific pharmacological target for the treatment of an extensive variety of human diseases including cancers and neurodegenerative disorders. Several recent studies have provided insights into how GPX4 is distinguished from the rest of the glutathione peroxidase family, the unique biochemical properties of GPX4, how GPX4 is related to lipid peroxidation and ferroptosis, and how the enzyme may be modulated as a potential therapeutic target. This current report aims to review the literature underlying all these insights and present an up-to-date perspective on the current understanding of GPX4 as a potential therapeutic target.

17.
Pharmaceuticals (Basel) ; 15(1)2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-35056123

RESUMO

Despite the scientific advancements, organophosphate (OP) poisoning continues to be a major threat to humans, accounting for nearly one million poisoning cases every year leading to at least 20,000 deaths worldwide. Oximes represent the most important class in medicinal chemistry, renowned for their widespread applications as OP antidotes, drugs and intermediates for the synthesis of several pharmacological derivatives. Common oxime based reactivators or nerve antidotes include pralidoxime, obidoxime, HI-6, trimedoxime and methoxime, among which pralidoxime is the only FDA-approved drug. Cephalosporins are ß-lactam based antibiotics and serve as widely acclaimed tools in fighting bacterial infections. Oxime based cephalosporins have emerged as an important class of drugs with improved efficacy and a broad spectrum of anti-microbial activity against Gram-positive and Gram-negative pathogens. Among the several oxime based derivatives, cefuroxime, ceftizoxime, cefpodoxime and cefmenoxime are the FDA approved oxime-based antibiotics. Given the pharmacological significance of oximes, in the present paper, we put together all the FDA-approved oximes and discuss their mechanism of action, pharmacokinetics and synthesis.

18.
J Am Chem Soc ; 133(7): 2136-9, 2011 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-21265533

RESUMO

Understanding electron transport across π-π-stacked systems will help to answer fundamental questions about biochemical redox processes and benefit the design of new materials and molecular devices. Herein we employed the STM break-junction technique to measure the single-molecule conductance of multiple π-π-stacked aromatic rings. We studied electron transport through up to four stacked benzene rings held together in an eclipsed fashion via a paracyclophane scaffold. We found that the strained hydrocarbons studied herein couple directly to gold electrodes during the measurements; hence, we did not require any heteroatom binding groups as electrical contacts. Density functional theory-based calculations suggest that the gold atoms of the electrodes bind to two neighboring carbon atoms of the outermost cyclophane benzene rings in η(2) fashion. Our measurements show an exponential decay of the conductance with an increasing number of stacked benzene rings, indicating a nonresonant tunneling mechanism. Furthermore, STM tip-substrate displacement data provide additional evidence that the electrodes bind to the outermost benzene rings of the π-π-stacked molecular wires.


Assuntos
Benzeno/química , Elétrons , Ouro/química , Dimerização , Eletrodos , Compostos Policíclicos/química
19.
Antioxidants (Basel) ; 10(3)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809613

RESUMO

Maintaining the physiological level of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the body is highly important in the fight against radical species in the context of human health [...].

20.
J Am Chem Soc ; 131(43): 15604-5, 2009 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-19824661

RESUMO

Free-radical polymers of 4-vinylimidazole and copolymers with 1-dodecyl-4-vinylimidazole were used as enzyme mimics to transaminate pyruvic acid to alanine, phenylpyruvic acid to phenylalanine, and indole-3-pyruvic acid to tryptophan in water at pH 7.5 and 20 degrees C using pyridoxamines carrying hydrophobic side chains as coenzyme mimics. The best enzyme mimic accelerated the transamination of indole-3-pyruvic acid by a factor of 4 million relative to the rate without the polymer, a higher rate ratio than we had previously achieved with a polyaziridine-based enzyme mimic. The properties of various polyvinylimidazoles were compared, including those prepared with the RAFT modification of the polymerization process.


Assuntos
Imidazóis/química , Polivinil/química , Piridoxamina/metabolismo , Transaminases/metabolismo , Água/química , Mimetismo Molecular , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectrofotometria Ultravioleta , Especificidade por Substrato
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