RESUMEN

Purpose: Tuberculosis (TB) remains a major health threat worldwide, and the spread of drug-resistant (DR) TB impedes the reduction of the global disease burden. Ebselen (EbSe) targets bacterial thioredoxin reductase (bTrxR) and causes an imbalance in the redox status of bacteria. Previous work has shown that the synergistic action of bTrxR and sensitization to common antibiotics by EbSe is a promising strategy for the treatment of DR pathogens. Thus, we aimed to evaluate whether EbSe could enhance anti-TB drugs against Mycobacterium marinum (M. marinum) which is genetically related to Mycobacterium tuberculosis (Mtb) and resistant to many antituberculosis drugs. Methods: Minimum inhibitory concentrations (MIC) of isoniazid (INH), rifampicin (RFP), and streptomycin (SM) against M. marinum were determined by microdilution. The Bliss Independence Model was used to determine the adjuvant effects of EbSe over the anti-TB drugs. Thioredoxin reductase activity was measured using the DTNB assay, and its effects on bacterial redox homeostasis were verified by the elevation of intracellular ROS levels and intracellular GSH levels. The adjuvant efficacy of EbSe as an anti-TB drug was further evaluated in a mouse model of M. marinum infection. Cytotoxicity was observed in the macrophage cells Raw264.7 and mice model. Results: The results reveal that EbSe acts as an antibiotic adjuvant over SM on M. marinum. EbSe + SM disrupted the intracellular redox microenvironment of M. marinum by inhibiting bTrxR activity, which could rescue mice from the high bacterial load, and accelerated recovery from tail injury with low mammalian toxicity. Conclusion: The above studies suggest that EbSe significantly enhanced the anti-Mtb effect of SM, and its synergistic combination showed low mammalian toxicity in vitro and in vivo. Further efforts are required to study the underlying mechanisms of EbSe as an antibiotic adjuvant in combination with anti-TB drug MS.

Asunto(s)

Homeostasis , Isoindoles , Pruebas de Sensibilidad Microbiana , Compuestos de Organoselenio , Oxidación-Reducción , Estreptomicina , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/química , Isoindoles/farmacología , Animales , Ratones , Homeostasis/efectos de los fármacos , Estreptomicina/farmacología , Antituberculosos/farmacología , Antituberculosos/química , Mycobacterium marinum/efectos de los fármacos , Azoles/farmacología , Azoles/química , Relación Dosis-Respuesta a Droga , Antibacterianos/farmacología , Antibacterianos/química , Relación Estructura-Actividad , Estructura Molecular , Ratones Endogámicos BALB C

RESUMEN

Breast cancer has the highest incidence rate among all malignancies worldwide. Its high mortality is mainly related to the occurrence of multidrug resistance, which significantly limits therapeutic options. In this regard, there is an urgent need to develop compounds that would overcome this phenomenon. There are few reports in the literature that selenium compounds can modulate the activity of P-glycoprotein (MDR1). Therefore, we performed in silico studies and evaluated the effects of the novel selenoesters EDAG-1 and EDAG-8 on BCRP, MDR1, and MRP1 resistance proteins in MCF-7 and MDA-MB-231 breast cancer cells. The cytometric analysis showed that the tested compounds (especially EDAG-8) are inhibitors of BCRP, MDR1, and MRP1 efflux pumps (more potent than the reference compounds-novobiocin, verapamil, and MK-571). An in silico study correlates with these results, suggesting that the compound with the lowest binding energy to these transporters (EDAG-8) has a more favorable spatial structure affecting its anticancer activity, making it a promising candidate in the development of a novel anticancer agent for future breast cancer therapy.

Asunto(s)

Neoplasias de la Mama , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Resistencia a Antineoplásicos/efectos de los fármacos , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/química , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/química , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Células MCF-7 , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/antagonistas & inhibidores , Simulación del Acoplamiento Molecular , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/antagonistas & inhibidores , Ésteres/farmacología , Ésteres/química , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores

RESUMEN

In the context of structural investigation and optimization of various potential EGFR inhibitors, a novel series of asymmetrical piperazine-tethered trisubstituted thiophene-3-carboxamide selenide derivatives were synthesized and evaluated for their antiproliferative potential against selected human cancer cell lines. These derivatives, built based on a previously identified hit molecule, were synthesized via multiple-step reactions, including optimization of the C-Se cross-coupling reaction. Two compounds, 17i and 18i, displayed significant cytotoxicity (IC50 value: 4.82 ± 0.80 µM and 1.43 ± 0.08 µM) against HCT116 and A549 cancer cell lines, respectively. Quantitative analysis of apoptotic stages using Annexin V-FITC/PI double staining validated their apoptotic potential. Further, compound 18i demonstrated a remarkable inhibition of EGFR kinase, with an IC50 concentration of 42.3 nM. The lead compound 18i, with remarkable in vitro cytotoxicity, apoptosis induction capability, and EGFR inhibition, emerges as a promising candidate for anticancer therapy.

Asunto(s)

Antineoplásicos , Apoptosis , Proliferación Celular , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB , Simulación del Acoplamiento Molecular , Piperazina , Piperazinas , Inhibidores de Proteínas Quinasas , Tiofenos , Humanos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Tiofenos/química , Tiofenos/farmacología , Tiofenos/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Estructura Molecular , Piperazina/química , Piperazina/farmacología , Piperazina/síntesis química , Apoptosis/efectos de los fármacos , Piperazinas/química , Piperazinas/farmacología , Piperazinas/síntesis química , Compuestos de Organoselenio/química , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/síntesis química , Línea Celular Tumoral

RESUMEN

A series of organoselenium compounds based on the hybridization of artesunate (ART) scaffolds and Se functionalities (-SeCN and -SeCF3) were synthesized. The redox properties of artesunate-SeCN and artesunate-SeCF3 derivatives were conducted by 2, 2-didiphenyl-1-picrylhydrazyl (DPPH), and the results showed that compounds 2c, 2f and 3e have a good free radical scavenging activity. Their cytotoxicity was evaluated against four types of cancer cell lines, SW480 (human colon adenocarcinoma cells), HCT116 (human colorectal adenocarcinoma cells), HepG2 (human hepatocellular carcinoma cells), MCF-7 (human breast cancer cells). The MTT results showed that compared with ART and 5-FU, compound 2c exhibited potent in vitro antiproliferative activity in SW480, HCT116, and MCF-7 cancer cell lines, and was thus chose for further antitumor mechanism investigation. The antitumor mechanism study revealed that compound 2c induced ferroptosis in HCT116 cells by inhibiting the expression of GPX4 protein, accompanying by the up-regulation of intracellular ROS levels. Mitochondria in HCT116 cells exhibit depolarization of mitochondrial membrane potential (MMP) and ultrastructural changes in morphology, which indicated that 2c resulted in mitochondrial dysfunction and ferroptosis. Moreover, 2c could increase the levels of lipid peroxidation and ferrous ion, which further confirm that compound 2c may exert its antitumor effect through ferroptosis. Overall, these results suggest that the artesunate-Se candidates could provide promising new lead derivatives for further potential anticancer drug development.

Asunto(s)

Antineoplásicos , Artesunato , Proliferación Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Ferroptosis , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Humanos , Artesunato/farmacología , Artesunato/síntesis química , Artesunato/química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Ferroptosis/efectos de los fármacos , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/antagonistas & inhibidores , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Estructura Molecular , Relación Dosis-Respuesta a Droga , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/química , Compuestos de Organoselenio/síntesis química

RESUMEN

The medicinal properties of transition metal complexes are greatly influenced by the nature and physico-chemical features of the ligand present in the complex structure. Due to the unique biological properties of the organoselenium compounds reflected in the variety of pharmacological activities (such as antioxidative, antiviral, antimicrobial and anticancer), the last years have brought increased interest for their use as a ligands compounds in the design and syntheses of range of transition metal-based coordination compounds that have been explored as antitumor and antimicrobial agents. Our aim in this review is to provide the overview of an recent development of the transition metal complexes bearing organoselenium ligands in the structure that could be promising choice for the treatment of various diseases, particularly cancer and infective diseases. For this purpose, the complexes of Co, Ni, Cu, Zn, Ru, Pd, Pt, Au and Sn as the most explored examples will be included and discussed.

Asunto(s)

Complejos de Coordinación , Compuestos de Organoselenio , Elementos de Transición , Compuestos de Organoselenio/química , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/síntesis química , Elementos de Transición/química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Humanos , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Animales , Neoplasias/tratamiento farmacológico , Antiinfecciosos/química , Antiinfecciosos/farmacología , Antiinfecciosos/síntesis química

RESUMEN

Antiretrovirals have improved considerably since the introduction of 3'-azido-3'-deoxythymidine (zidovudine or AZT), a molecule with also anticancer effects. Subsequently, a variety of other nucleosides have been synthesized. However, these medications are often associated with serious adverse events and the onset or exacerbation of degenerative processes, diseases, and syndromes, affecting mainly the mitochondria. In this study, we used Caenorhabditis elegans to investigate the toxicity potential of AZT and three new organoselenium derivatives with modifications in the 5' position of the sugar ring in place of the 5'-OH group, with the insertion of a neutral, an electron-withdrawing and an electron-donating group attached to the aryl selenol moiety: 5'-seleno-(4-chloro-phenyl)-3-(amino)-thymidine (ASAT-4-Cl), 5'-seleno-(phenyl)-3-(amino)-thymidine (ASAT-Ph), and 5'-seleno-(4-methoxyphenyl)-3-(amino)- thymidine (ASAT-4-OMe). Analyzes included worm survival, behavior parameters, high-resolution respirometry, citrate synthase activity, and ATP levels. Although all compounds negatively affected C. elegans, ASAT-4-Cl and ASAT-Ph showed lower toxicity compared to AZT, especially in mitochondrial viability and ATP production. Therefore, more studies must be carried out on the use of these new compounds as pharmacological interventions.

Asunto(s)

Caenorhabditis elegans , Compuestos de Organoselenio , Zidovudina , Animales , Caenorhabditis elegans/efectos de los fármacos , Zidovudina/toxicidad , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/toxicidad , Mitocondrias/efectos de los fármacos , Fármacos Anti-VIH/toxicidad

RESUMEN

Recombinant high-density lipoprotein (rHDL) as anti-atherosclerosis (AS) vehicle has unique advantages including multiple anti-atherogenic functions and homing features to plaques. However, rHDL may be converted into dysfunctional forms due to complex treatment during preparation. Herein, oxidation-induced dysfunction of non-split HDL and rHDL was initially investigated. It was found that although both non-split HDL and rHDL showed oxidative dysfunction behavior, non-split HDL demonstrated superior oxidation defense compared to rHDL due to its intact composition and avoidance of overprocessing such as split and recombination. Unfortunately, in vivo oxidative stress could compromise the functionality of HDL. Therefore, surface engineering of non-split HDL and rHDL with cascade antioxidant enzyme analogues Ebselen and mitochondrial-targeted TPGS-Tempo was conducted to construct a dual-line defense HDL nano system (i.e., T@E-HDLs/rHDL), aiming to restore plaque redox balance and preserving the physiological function of HDL. Results indicated that both T@E-HDLs and rHDLs performed without distinction and exhibited greater resistance to oxidative stress damage as well as better functions than unmodified HDLs in macrophage foam cells. Overall, the modification of dual antioxidants strategy bridges the gap between non-split HDL and rHDL, and provides a promising resolution for the dilemmas of oxidative stress in plaques and HDL self dysfunction.

Asunto(s)

Antioxidantes , Lipoproteínas HDL , Estrés Oxidativo , Proteínas Recombinantes , Estrés Oxidativo/efectos de los fármacos , Lipoproteínas HDL/metabolismo , Lipoproteínas HDL/farmacología , Antioxidantes/farmacología , Proteínas Recombinantes/farmacología , Animales , Humanos , Ratones , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Oxidación-Reducción/efectos de los fármacos , Isoindoles/farmacología , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/química

RESUMEN

H2Se is the precursor for the biosynthesis of selenocompounds and is a potential gasotransmitter. Chemical tools for H2Se delivery and detection are important for Se-related biology research. Key challenges in the field include developing compound platforms that are triggered to release H2Se under various stimuli and developing fluorogenic donors that allow for real-time tracking of H2Se delivery. Here we report a new general platform for triggered H2Se donors based on controllable deprotection of a thiol, which can quickly activate an intramolecular arylselenoamide (t1/2 < 1 min) to release H2Se efficiently. Furthermore, we leverage this platform to develop the first examples of fluorogenic H2Se donors, which can be used to monitor H2Se release by fluorescence in real time. We anticipate that the well-defined donation chemistries will significantly advance the development of H2Se donors and stimulate further in-depth studies of H2Se biomedicine.

Asunto(s)

Colorantes Fluorescentes , Compuestos de Sulfhidrilo , Compuestos de Sulfhidrilo/química , Colorantes Fluorescentes/química , Amidas/química , Humanos , Estructura Molecular , Compuestos de Organoselenio/química , Compuestos de Selenio

RESUMEN

α-Alkoxy bridgehead radicals enable intermolecular construction of sterically congested C-C bonds due to their sterically accessible nature. We implemented these radical species into total syntheses of various densely oxygenated natural products and demonstrated their exceptional versatility. Herein, we employed different precursors to generate the same α-alkoxy bridgehead radical and compared the efficacy of the precursors for coupling reactions. Specifically, the bridgehead radical of the trioxaadamantane structure was formed from α-alkoxy carboxylic acid, selenide/telluride, and acyl selenide/acyl telluride, and reacted with 4-((tert-butyldimethylsilyl)oxy)cyclopent-2-en-1-one and 5-oxo-1-cyclopentene-1-carbonitrile. The efficiency of the bridgehead radical formation and subsequent coupling reaction significantly depended on the structures of the precursors and acceptors as well as the reaction conditions. Our findings provide new insights for selecting the appropriate substrates of key coupling reactions in the total synthesis of complex natural products.

Asunto(s)

Ácidos Carboxílicos , Telurio , Ácidos Carboxílicos/química , Ácidos Carboxílicos/síntesis química , Telurio/química , Estructura Molecular , Radicales Libres/química , Compuestos de Selenio/química , Compuestos de Selenio/síntesis química , Compuestos de Organoselenio/química , Compuestos de Organoselenio/síntesis química , Productos Biológicos/química , Productos Biológicos/síntesis química

RESUMEN

Renal ischemia/reperfusion injury (RIRI) is an inevitable complication following kidney transplantation surgery, accompanied by the generation of a large amount of free radicals. A cascade of events including oxidative stress, extreme inflammation, cellular apoptosis, and thrombosis disrupts the microenvironment of renal cells and the hematological system, ultimately leading to the development of acute kidney injury (AKI). The current research primarily focuses on reducing inflammation and mitigating damage to renal cells through antioxidative approaches. However, studies on simultaneously modulating the renal hematologic system remain unreported. Herein, potent and novel drug-loaded nanomicelles can be efficiently self-assembled with magnolol (MG) and ebselen (EBS) by π-π conjugation, hydrophobic action and the surfactant properties of Tween-80. The ultrasmall MG/EBS nanomicelles (average particle size: 10-25 nm) not only fully preserve the activity of both drugs, but also greatly enhance drug utilization (encapsulation rates: MG: 90.1%; EBS: 49.3%) and reduce drug toxicity. Furthermore, EBS, as a glutathione peroxidase mimic and NO catalyst, combines with the multifunctional MG to scavenge free radicals and hydroperoxides, significantly inhibiting inflammation and thrombosis while effectively preventing apoptosis of vascular endothelial cells and renal tubular epithelial cells. This study provides a new strategy and theoretical foundation for the simultaneous regulation of kidney cells and blood microenvironment stability.

Asunto(s)

Compuestos de Bifenilo , Lignanos , Micelas , Compuestos de Organoselenio , Daño por Reperfusión , Daño por Reperfusión/prevención & control , Daño por Reperfusión/tratamiento farmacológico , Compuestos de Bifenilo/química , Compuestos de Bifenilo/administración & dosificación , Compuestos de Bifenilo/farmacología , Lignanos/farmacología , Lignanos/química , Lignanos/administración & dosificación , Humanos , Compuestos de Organoselenio/química , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/administración & dosificación , Isoindoles/farmacología , Isoindoles/administración & dosificación , Isoindoles/química , Apoptosis/efectos de los fármacos , Nanopartículas/química , Nanopartículas/administración & dosificación , Azoles/química , Azoles/farmacología , Azoles/administración & dosificación , Animales , Riñón/efectos de los fármacos , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/administración & dosificación , Tamaño de la Partícula , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Portadores de Fármacos/química , Estrés Oxidativo/efectos de los fármacos

RESUMEN

Disrupted gut microbiota homeostasis is an important cause of inflammatory colitis. Studies have shown that effective supplementation with probiotics can maintain microbial homeostasis and alleviate colitis. Here, to increase the viability of probiotics in the harsh gastrointestinal environments and enable targeted delivery, a redox-sensitive selenium hyaluronic acid (HA-Se) hydrogel encapsulating probiotics was developed. HA was modified with selenocystamine dihydrochloride and crosslinked by an amide reaction to generate a redox-sensitive hydrogel with stable mechanical properties, a low hemolysis rate and satisfactory biocompatibility. The HA-Se hydrogel exhibited suitable sensitivity to 10 mM GSH or 100 µM H2O2. The encapsulation of Limosilactobacillus reuteri (LR) in the HA-Se hydrogel (HA-Se-LR) significantly increased the survival rate of the probiotics in simulated gastric and intestinal fluid. HA-Se-LR administration increased the survival rate of mice with dextran sulfate sodium (DSS)-induced colitis, significantly alleviated oxidative stress and inflammation, and increased the effect of LR on microbiota α diversity. These results indicate that the HA-Se hydrogel constructed in this study can be used as a delivery platform to treat colitis, expanding the targeted applications of the natural polymer HA in disease treatment and the administration of probiotics as drugs to alleviate disease symptoms.

Asunto(s)

Colitis , Cistamina , Sulfato de Dextran , Modelos Animales de Enfermedad , Ácido Hialurónico , Hidrogeles , Limosilactobacillus reuteri , Oxidación-Reducción , Probióticos , Animales , Ácido Hialurónico/química , Hidrogeles/química , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Ratones , Cistamina/química , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/química , Estrés Oxidativo/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Cistina/análogos & derivados

RESUMEN

Cisplatin is a widely-used chemotherapeutic agent for the treatment of various solid neoplasms including colon cancer. Cisplatin-induced DNA damage is restricted due to dose-related adverse reactions as well as primary resistance mechanisms. Therefore, it is imperative to utilize novel therapeutic approaches to circumvent cisplatin limitations and attenuate its normal tissues toxicity. In this study, we exploited a novel PEGylated liposomes with greater efficiency to treat colon cancer. For this, an organoselenium compound (diselanediylbis decanoic acid (DDA)) was synthesized, and liposomes composed of Egg PC or HSPC, as well as DOPE, mPEG2000-DSPE, cholesterol and DDA at varying molar ratios were prepared by using thin-film method. Cisplatin loading was performed through incubation with liposomes. Characterization of nanoliposomes indicated a favarable size range of 91-122 nm and negative zeta potential of -9 to -22 mv. The organoselenium compound significantly improved cisplatin loading efficiency within the liposomes (83.4 %). Results also revealed an efficient bioactivity of cisplatin liposome on C26 cells compared to the normal cells. Further, DDA bearing liposomes significantly improved drug residence time in circulation, reduced toxicity associated with the normal tissues, and enhanced drug accumulation within the oxidative tumor microenvironment. Collectively, results indicated that cisplatin encasement within liposomes by using this method could significantly improve the therapeutic efficacy in vivo, and merits further investigations.

Asunto(s)

Antineoplásicos , Cisplatino , Neoplasias del Colon , Liposomas , Compuestos de Organoselenio , Cisplatino/farmacología , Cisplatino/química , Liposomas/química , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Animales , Antineoplásicos/farmacología , Antineoplásicos/química , Compuestos de Organoselenio/química , Compuestos de Organoselenio/farmacología , Ratones , Humanos , Sistemas de Liberación de Medicamentos , Tamaño de la Partícula , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Ratones Endogámicos BALB C

RESUMEN

Substitution of disulfide bonds with a diselenide bonds in peptides and proteins is an often-used strategy to increase the stability of naturally occurring peptides and proteins. In this paper, diselenide metathesis between model diselenide dimer peptides, as well as that in diselenide(s)-substituted biologically active peptides, were analyzed. Surprisingly, depending on the tertiary structure of the peptides, we observed that the metathesis reaction occurs under physiological conditions even in the absence of reducing agents, light and heating.

Asunto(s)

Péptidos , Selenocisteína , Selenocisteína/química , Péptidos/química , Péptidos/síntesis química , Compuestos de Organoselenio/química , Compuestos de Organoselenio/síntesis química

RESUMEN

Breast cancer is a major malignancy among women, characterized by a high mortality rate. The available literature evidence indicates that selenium, as a trace element, has chemopreventive properties against many types of cancer; as such, compounds containing it in their structure may potentially exhibit anticancer activity. Accordingly, we have undertaken a study to evaluate the effects of novel selenoesters (EDAG-1, -7, -8, -10) on MCF-7 and MDA-MB-231 breast cancer cells. Our analysis included investigations of cell proliferation and viability as well as cytometric determinations of apoptosis/autophagy induction, changes in mitochondrial membrane polarity (ΔΨm), caspase 3/7, 8, and 9 activities, and Bax, Bcl-2, p53, Akt, AMPK, and LC3A/B proteins. The obtained data revealed that the tested derivatives are highly cytotoxic and inhibit cell proliferation even at nanomolar doses (0.41-0.79 µM). Importantly, their strong proapoptotic properties (↑ caspase 3/7) are attributable to the effects on both the extrinsic (↑ caspase 8) and intrinsic (↓ ΔΨm and Bcl-2, ↑ Bax, p53, and caspase 9) pathways of apoptosis. Moreover, the tested compounds are autophagy activators (↓ Akt, ↑ autophagosomes and autolysosomes, AMPK, LC3A/B). In summary, the potent anticancer activity suggests that the tested compounds may be promising drug candidates for future breast cancer therapy.

Asunto(s)

Antineoplásicos , Apoptosis , Autofagia , Proliferación Celular , Neoplasias de la Mama Triple Negativas , Humanos , Apoptosis/efectos de los fármacos , Femenino , Proliferación Celular/efectos de los fármacos , Autofagia/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Línea Celular Tumoral , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/uso terapéutico , Compuestos de Organoselenio/química , Supervivencia Celular/efectos de los fármacos , Ésteres/química , Ésteres/farmacología , Células MCF-7

RESUMEN

Diorganyl diselenides have emerged as privileged structures because they are easy to prepare, have distinct reactivity, and have broad biological activity. They have also been used in the synthesis of natural products as an electrophile in the organoselenylation of aromatic systems and peptides, reductions of alkenes, and nucleophilic substitution. This review summarizes the advancements in methods for the transformations promoted by diorganyl diselenides in the main functions of organic chemistry. Parallel, it will also describe the main findings on pharmacology and toxicology of diorganyl diselenides, emphasizing anti-inflammatory, hypoglycemic, chemotherapeutic, and antimicrobial activities. Therefore, an examination detailing the reactivity and biological characteristics of diorganyl diselenides provides valuable insights for academic researchers and industrial professionals.

Asunto(s)

Compuestos de Organoselenio , Compuestos de Organoselenio/química , Compuestos de Organoselenio/síntesis química , Compuestos de Organoselenio/farmacología , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , Antiinfecciosos/química , Antiinfecciosos/farmacología , Antiinfecciosos/síntesis química , Antiinflamatorios/química , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Productos Biológicos/química , Productos Biológicos/síntesis química , Productos Biológicos/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología

RESUMEN

A wide range of 3-selenylindoles were synthesized via an eco-friendly approach that uses Oxone® as the oxidant in the presence of a catalytic amount of iodine. This mild and economical protocol showed broad functional group tolerance and operational simplicity. A series of novel selenylindoles bearing a benzenesulfonamide moiety were also synthesized and evaluated as carbonic anhydrase inhibitors of the human (h) isoforms hCa I, II, IX, and XII, which are involved in pathologies such as glaucoma and cancer. Several derivatives showed excellent inhibitory activity towards these isoforms in the nanomolar range, lower than that shown by acetazolamide.

Asunto(s)

Bencenosulfonamidas , Inhibidores de Anhidrasa Carbónica , Anhidrasas Carbónicas , Indoles , Yodo , Oxidación-Reducción , Sulfonamidas , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacología , Sulfonamidas/síntesis química , Humanos , Anhidrasas Carbónicas/metabolismo , Indoles/química , Indoles/farmacología , Indoles/síntesis química , Yodo/química , Compuestos de Organoselenio/química , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/síntesis química , Relación Estructura-Actividad , Estructura Molecular

RESUMEN

Sleep is a fundamental state for maintaining the organism homeostasis. Disruptions in sleep patterns predispose to the appearance of memory impairments and mental disorders, including depression. Recent pre-clinical studies have highlighted the antidepressant-like properties of the synthetic compound 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1). To further investigate the neuromodulatory effects of SeBZF1, this study aimed to assess its therapeutic efficacy in ameliorating neurobehavioral impairments induced by sleep deprivation (SD) in mice. For this purpose, a method known as multiple platforms over water was used to induce rapid eye movement (REM) SD. Two hours after acute SD (24 h), male Swiss mice received a single treatment of SeBZF1 (5 mg/kg, intragastric route) or fluoxetine (a positive control, 20 mg/kg, intraperitoneal route). Subsequently, behavioral tests were conducted to assess spontaneous motor function (open-field test), depressive-like behavior (tail suspension test), and memory deficits (Y-maze test). Brain structures were utilized to evaluate oxidative stress markers, monoamine oxidase (MAO) and acetylcholinesterase (AChE) activities. Our findings revealed that SD animals displayed depressive-like behavior and memory impairments, which were reverted by SeBZF1 and fluoxetine treatments. SeBZF1 also reverted the increase in lipoperoxidation levels and glutathione peroxidase activity in the pre-frontal cortex in mice exposed to SD. Besides, the increase in hippocampal AChE activity induced by SD was overturned by SeBZF1. Lastly, cortical MAO-B activity was reestablished by SeBZF1 in mice that underwent SD. Based on the main findings of this study, it can be inferred that the compound SeBZF1 reverses the neurobehavioral alterations induced by sleep deprivation in male Swiss mice.

Asunto(s)

Benzofuranos , Privación de Sueño , Animales , Masculino , Ratones , Privación de Sueño/tratamiento farmacológico , Benzofuranos/farmacología , Benzofuranos/uso terapéutico , Conducta Animal/efectos de los fármacos , Depresión/tratamiento farmacológico , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/uso terapéutico , Trastornos de la Memoria/tratamiento farmacológico , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Aprendizaje por Laberinto/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos

RESUMEN

A series of phenyl ß-carbonyl selenides with o-ester functionality substituted on the oxygen atom with chiral and achiral alkyl groups was synthesized. All compounds are the first examples of this type of organoselenium derivatives with an ester substituent in the ortho position. The obtained derivatives were tested as antioxidants and anticancer agents to see the influence of an ester functionality on the bioactivity of ß-carbonyl selenides by replacing the o-amide group with an o-ester group. The best results as an antioxidant agent were observed for O-((1R,2S,5R)-(-)-2-isopropyl-5-methylcyclohexyl)-2-((2-oxopropyl)selanyl)benzoate. The most cytotoxic derivative against breast cancer MCF-7 cell lines was O-(methyl)-2-((2-oxopropyl)selanyl)benzoate and against human promyelocytic leukemia HL-60 was O-(2-pentyl)-2-((2-oxopropyl)selanyl)benzoate.

Asunto(s)

Antineoplásicos , Antioxidantes , Ésteres , Compuestos de Organoselenio , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antioxidantes/química , Antioxidantes/farmacología , Antioxidantes/síntesis química , Ésteres/química , Ésteres/farmacología , Ésteres/síntesis química , Compuestos de Organoselenio/química , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/síntesis química , Células MCF-7 , Células HL-60 , Relación Estructura-Actividad , Estructura Molecular

RESUMEN

While research has identified several inhibitors of the main protease (Mpro) of SARS-CoV-2, a significant portion of these compounds exhibit reduced activity in the presence of reducing agents, raising concerns about their effectiveness in vivo. Furthermore, the conventional biosafety level 3 (BSL-3) for cellular assays using viral particles poses a limitation for the widespread evaluation of Mpro inhibitor efficacy in a cell-based assay. Here, we established a BSL-1 compatible cellular assay to evaluate the in vivo potential of Mpro inhibitors. This assay utilizes mammalian cells expressing a tagged Mpro construct containing N-terminal glutathione S-transferase (GST) and C-terminal hemagglutinin (HA) tags and monitors Mpro autodigestion. Using this method, GC376 and boceprevir effectively inhibited Mpro autodigestion, suggesting their potential in vivo activity. Conversely, carmofur and ebselen did not exhibit significant inhibitory effects in this assay. We further investigated the inhibitory potential of selenoneine on Mpro using this approach. Computational analyses of binding energies suggest that noncovalent interactions play a critical role in facilitating the covalent modification of the C145 residue, leading to Mpro inhibition. Our method is straightforward, cost-effective, and readily applicable in standard laboratories, making it accessible to researchers with varying levels of expertise in infectious diseases.

Asunto(s)

Antivirales , Azoles , Proteasas 3C de Coronavirus , Isoindoles , Compuestos de Organoselenio , Prolina , SARS-CoV-2 , Antivirales/farmacología , Antivirales/química , Humanos , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/enzimología , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/química , Isoindoles/farmacología , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/metabolismo , Azoles/farmacología , Azoles/química , Prolina/análogos & derivados , Prolina/farmacología , Prolina/química , Simulación del Acoplamiento Molecular , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/química , Tratamiento Farmacológico de COVID-19 , COVID-19/virología , Células HEK293 , Lactamas , Leucina/análogos & derivados , Ácidos Sulfónicos

RESUMEN

Nonalcoholic fatty liver disease (NAFLD), a metabolic disease associated with obesity and type 2 diabetes. Due to its complex pathogenesis, there are still limitations in the knowledge of the disease. To date, no drug has been approved to treat NAFLD. This study aims to explore the role and mechanism of Ebselen (EbSe) in NAFLD. A high-fat diet-induced mouse model of NAFLD was employed to investigate EbSe function in NAFLD mice by EbSe gavage and to regularly monitor the mouse body weight. HE and oil red O staining were performed, respectively, to detect the pathological damage and lipid accumulation in mouse liver tissues. The biochemical and ELISA kits were employed to measure the levels of ALT, AST, TG, TC, LDL-C, HDL-C and pro-inflammatory cytokines within mouse serum or liver tissue. The expression of key proteins of PPARα, fatty acid ß oxidation-related protein, PI3K/Akt and TLR4/JNK signaling pathway was detected by western blot. EbSe significantly downregulated body weight, liver weight and liver lipid accumulation in NAFLD mice and downregulated ALT, AST, TG, TC, LDL-C and increased HDL-C serum levels. EbSe upregulated the expression levels of PPARα and fatty acid ß oxidation-associated proteins CPT1α, ACOX1, UCP2 and PGC1α. EbSe promoted Akt and PI3K phosphorylation, and inhibited TLR4 expression and JNK phosphorylation. EbSe can upregulate PPARα to promote fatty acid ß-oxidation and improve hepatic lipid metabolism. Meanwhile, EbSe also activated PI3K/Akt and inhibited TLR4/JNK signaling pathway. EbSe is predicted to be an effective therapeutic drug for treating NAFLD.

Asunto(s)

Isoindoles , Metabolismo de los Lípidos , Hígado , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico , Compuestos de Organoselenio , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Receptor Toll-Like 4 , Animales , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Receptor Toll-Like 4/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Masculino , Ratones , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/uso terapéutico , Isoindoles/farmacología , Hígado/metabolismo , Hígado/efectos de los fármacos , Azoles/farmacología , Azoles/uso terapéutico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Dieta Alta en Grasa , Transducción de Señal/efectos de los fármacos , Modelos Animales de Enfermedad