RESUMEN

PURPOSE: Napabucasin (NP) is a natural compound that can suppress cancer cell proliferation and cell cycle by inhibition of the signal transducer and activator of transcription 3 (STAT3) gene. We examined the effects of NP on the proliferation and invasion of neuroblastoma cells (SH-SY5Y). METHODS: Human neuroblastoma SH-SY5Y cell line was used in this study. NP was administered to groups at the doses of 0.3-1 µM. Cell viability was analyzed by MTT assay. Real-time quantitative reverse transcription polymerase chain reaction and western blot analysis assessed the expressions of interleukin (IL)-6 dependent Jak2/Stat3 signaling pathway. The MTT cell viability method was applied to determine the antagonistic-synergistic effects and inhibitory concentration (IC50) doses of doxorubicin (DX) and NP. RESULTS: It was determined that 0.3-1 µM doses of NP killed the cells almost completely after 48 hours, and also that Jak2/Stat3 expressions decreased dose-dependently via IL-6. At the protein level, NP and DX were found to reduce Jak2 and Stat3 levels. CONCLUSIONS: NP showed that it suppresses the proliferation of neuroblastoma cells. Due to its inhibitory effect on Jak2 and Stat3, it can be used to prevent invasion of SH-SY5Y cells. NP, which can inactivate Jak2/Stat3, can be used as a treatment agent by combining with DX in proliferation pathway in neuroblastoma.

Asunto(s)

Benzofuranos , Proliferación Celular , Supervivencia Celular , Doxorrubicina , Janus Quinasa 2 , Neuroblastoma , Factor de Transcripción STAT3 , Transducción de Señal , Humanos , Janus Quinasa 2/metabolismo , Janus Quinasa 2/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Transducción de Señal/efectos de los fármacos , Doxorrubicina/farmacología , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/patología , Supervivencia Celular/efectos de los fármacos , Benzofuranos/farmacología , Interleucina-6/metabolismo , Western Blotting , Reacción en Cadena en Tiempo Real de la Polimerasa , Reproducibilidad de los Resultados , Naftoquinonas

RESUMEN

Organic compounds with antibacterial and antiparasitic properties are gaining significance for biomedical applications. This study focuses on the solvent-free synthesis (green synthesis) of 1,4-naphthoquinone or 2,3-dichloro-1,4-naphthoquinone with different phenylamines using silica gel as an acid solid support. The study also includes in silico PASS predictions and the discovery of antibacterial and antiparasitic properties of phenylaminonaphthoquinone derivatives 1-12, which can be further applied in drug discovery and development. These activities were discussed in terms of molecular descriptors such as hydrophobicity, molar refractivity, and half-wave potentials. The in vitro antimicrobial potential of the synthesized compounds 1-12 was evaluated against a panel of six bacterial strains (three Gram-positive: Staphylococcus aureus, Proteus mirabilis, and Enterococcus faecalis; and three Gram-negative bacteria: Escherichia coli, Salmonella typhimurium, and Klebsiella pneumoniae). Six compounds (1, 3, 5, 7, 10, and 11) showed better activity toward S. aureus with MIC values between 3.2 and 5.7 µg/mL compared to cefazolin (MIC = 4.2 µg/mL) and cefotaxime (MIC = 8.9 µg/mL), two cephalosporin antibiotics. Regarding in vitro antiplasmodial activity, compounds 1 and 3 were the most active against the Plasmodium falciparum strain 3D7 (chloroquine-sensitive), displaying IC50 values of 0.16 and 0.0049 µg/mL, respectively, compared to chloroquine (0.33 µg/mL). In strain FCR-3 (chloroquine-resistant), most of the compounds showed good activity, with compounds 3 (0.12 µg/mL) and 11 (0.55 µg/mL) being particularly noteworthy. Additionally, docking studies were used to better rationalize the action and prediction of the binding modes of these compounds. Finally, absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions were performed.

Asunto(s)

Antibacterianos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Naftoquinonas , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Naftoquinonas/farmacología , Naftoquinonas/química , Naftoquinonas/síntesis química , Antiparasitarios/farmacología , Antiparasitarios/síntesis química , Antiparasitarios/química , Tecnología Química Verde/métodos , Bacterias Gramnegativas/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos

RESUMEN

BACKGROUND: This study investigates the potential of eleven 1H-1,2,3-triazol-1,4-naphthoquinone conjugates as virulence factor inhibitors (like Pyocyanin) and their affinity for PhzM, a crucial enzyme for Pyocyanin biosynthesis in Pseudomonas aeruginosa infections. METHODS: A straightforward synthetic pathway enabled the production of these compounds, which were characterized and structurally confirmed through spectroscopic analyses. Evaluation of their impact on PhzM thermal stability identified promising candidates for PhzM binders. RESULTS: Concentration-response behavior elucidated their binding affinity, revealing them as the first reported micromolar affinity ligands for PhzM. Structure-activity relationship analysis emphasized the role of specific molecular moieties in binding affinity modulation, paving the way for future advanced inhibitors' development. CONCLUSION: These findings highlight the potential of naphthoquinone-triazole derivatives as leads for novel therapeutics against P. aeruginosa infections.

Asunto(s)

Antibacterianos , Pruebas de Sensibilidad Microbiana , Naftoquinonas , Pseudomonas aeruginosa , Piocianina , Triazoles , Naftoquinonas/farmacología , Naftoquinonas/química , Naftoquinonas/síntesis química , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/metabolismo , Piocianina/antagonistas & inhibidores , Piocianina/biosíntesis , Piocianina/metabolismo , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacología , Triazoles/metabolismo , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Estructura Molecular , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/microbiología , Humanos , Relación Dosis-Respuesta a Droga

RESUMEN

Lapachol (2-hydroxy-3-(3-methylbut-2-en-1-yl)naphthalene-1,4-dione) is a 1,4-naphthoquinone-derived natural product that presents numerous bioactivities and was shown to have cytotoxic effects against several human tumor cells. Indium(III) complexes with a variety of ligands also exhibit antineoplastic activity. Indium(III) complexes [In(lap)Cl2].4H2O (1), [In(lap)2Cl(Et3N)] (2), [In(lap)3]·2H2O (3) [In(lap)(bipy)Cl2] bipy = 2,2'-bipyridine (4) and [In(lap)(phen)Cl2] phen = 1,10-phenanthroline (5) were obtained with 2-hydroxy-3-(3-methylbut-2-en-1-yl)naphthalene-1,4-dione (lapachol). Crystal structure determinations for (4) and (5) revealed that the indium(III) center is coordinated to two O atoms from lapachol, two N atoms from 1,10-phenanthroline or 2,2'-bipyridine, and two chloride anions, in a distorted octahedral geometry. Although both complexes (4) and (5) interacted with CT-DNA in vitro by an intercalative mode, only 5 exhibited cytotoxicity against MCF-7 and MDA-MB breast tumor cells. 1,10-phenanthroline and complex (5) presented cytotoxic effects against MCF-7 and MDA-MB cells, with complex (5) being threefold more active than 1,10-phenanthroline on MCF-7 cells. In addition, complex (5) significantly reduced the formation of MDA-MB-231 colonies in a clonogenicity assay. The foregoing results suggest that further studies on the cytotoxic effects and cellular targets of complex (5) are of utmost relevance.

Asunto(s)

Antineoplásicos , Neoplasias de la Mama , ADN , Indio , Naftoquinonas , Humanos , Naftoquinonas/química , Naftoquinonas/farmacología , Indio/química , Indio/farmacología , ADN/química , Antineoplásicos/farmacología , Antineoplásicos/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Línea Celular Tumoral , Femenino , Ensayos de Selección de Medicamentos Antitumorales , Cristalografía por Rayos X , Células MCF-7 , Modelos Moleculares , Estructura Molecular

RESUMEN

We have conducted an experimental and computational evaluation of new doxorubicin (4a-c) and ß-lapachone (5a-c) analogs. These novel anticancer analogs were previously synthesized, but had not been tested or characterized until now. We have evaluated their antiproliferative and DNA cleavage inhibition properties using breast (MCF-7 and MDA-MB-231) and prostate (PC3) cancer cell lines. Additionally, cell cycle analysis was performed using flow cytometry. Computational studies, including molecular docking, pharmacokinetic properties, and an analysis of DFT and QTAIM chemical descriptors, were performed to gain insights into the electronic structure and elucidate the molecular binding of the new ß-lapachone and doxorubicin analogs with a DNA sequence and Topoisomerase II (Topo II)α. Our results show that 4a analog displays the highest antiproliferative activity in cancer cell lines by inducing cell death. We observed that stacking interactions and hydrogen bonding are essential to stabilize the molecule-DNA-Topo IIα complex. Moreover, 4a and 5a analogs inhibited Topo's DNA cleavage activity. Pharmacodynamic results indicated that studied molecules have favorable adsorption and permeability properties. The calculated chemical descriptors indicate that electron accumulation in quinone rings is relevant to the reactivity and biological activity. Based on our results, 4a is a strong candidate for becoming an anticancer drug.

Asunto(s)

Antineoplásicos , Proliferación Celular , ADN-Topoisomerasas de Tipo II , Doxorrubicina , Simulación del Acoplamiento Molecular , Naftoquinonas , Naftoquinonas/química , Naftoquinonas/farmacología , Humanos , Doxorrubicina/farmacología , Doxorrubicina/química , ADN-Topoisomerasas de Tipo II/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células MCF-7 , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores de Topoisomerasa II/farmacología , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/metabolismo , División del ADN/efectos de los fármacos

RESUMEN

Breast cancer stands as one of the foremost cause of cancer-related deaths globally, characterized by its varied molecular subtypes. Each subtype requires a distinct therapeutic strategy. Although advancements in treatment have enhanced patient outcomes, significant hurdles remain, including treatment toxicity and restricted effectiveness. Here, we explore the anticancer potential of novel 1,4-naphthoquinone/4-quinolone hybrids on breast cancer cell lines. The synthesized compounds demonstrated selective cytotoxicity against Luminal and triple-negative breast cancer (TNBC) cells, which represent the two main molecular types of breast cancer that depend most on cytotoxic chemotherapy, with potency comparable to doxorubicin, a standard chemotherapeutic widely used in breast cancer treatment. Notably, these derivatives exhibited superior selectivity indices (SI) when compared to doxorubicin, indicating lower toxicity towards non-tumor MCF10A cells. Compounds 11a and 11b displayed an improvement in IC50 values when compared to their precursor, 1,4-naphthoquinone, for both MCF-7 and MDA-MB-231 and a comparable value to doxorubicin for MCF-7 cells. Also, their SI values were superior to those seen for the two reference compounds for both cell lines tested. Mechanistic studies revealed the ability of the compounds to induce apoptosis and inhibit clonogenic potential. Additionally, the irreversibility of their effects on cell viability underscores their promising therapeutic utility. In 3D-cell culture models, the compounds induced morphological changes indicative of reduced viability, supporting their efficacy in a more physiologically relevant model of study. The pharmacokinetics of the synthesized compounds were predicted using the SwissADME webserver, indicating that these compounds exhibit favorable drug-likeness properties and potential as antitumor agents. Overall, our findings underscore the promise of these hybrid compounds as potential candidates for breast cancer chemotherapy, emphasizing their selectivity and efficacy.

Asunto(s)

Antineoplásicos , Neoplasias de la Mama , Naftoquinonas , Humanos , Naftoquinonas/farmacología , Naftoquinonas/química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Células MCF-7 , Quinolonas/farmacología , Quinolonas/química , Apoptosis/efectos de los fármacos , Técnicas de Cultivo Tridimensional de Células/métodos , Doxorrubicina/farmacología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos

RESUMEN

Candida spp. can be found in the human microbiome. However, immunocompromised patients are likely to develop invasive Candida infections, with mortality rates higher than 50%. The discovery of C. auris, a species that rapidly acquire antifungal resistance, increased the concern about Candida infections. The limited number of antifungal agents and the high incidence of resistance to them make imperative the development of new antifungal drugs. ß-lapachone is a biological active naphthoquinone that displays antifungal activity against C. albicans and C. glabrata. The aim of this study was to evaluate if this substance affects C. auris growth and elucidate its mechanism of action. A fluconazole-resistant C. auris isolate was used in this study. The antifungal activity of ß-lapachone was determined through microbroth dilution assays, and its mechanism of action was evaluated using fluorescent probes. Interaction with fluconazole and amphotericin B was assessed by disk diffusion assay and checkerboard. ß-lapachone inhibited planktonic C. auris cell growth by 92.7%, biofilm formation by 84.9%, and decrease the metabolism of preformed biofilms by 87.1% at 100 µg/ml. At 100 µg/ml, reductions of 30% and 59% of Calcofluor White and Nile red fluorescences were observed, indicating that ß-lapachone affects cell wall chitin and neutral lipids content, respectively. Also, the ratio 590 nm/529 nm of JC-1 decreased 52%, showing that the compound affects mitochondria. No synergism was observed between ß-lapachone and fluconazole or amphotericin B. Data show that ß-lapachone may be a promising candidate to be used as monotherapy to treat C. auris resistant infections.

Asunto(s)

Antifúngicos , Biopelículas , Candida auris , Farmacorresistencia Fúngica , Fluconazol , Pruebas de Sensibilidad Microbiana , Naftoquinonas , Naftoquinonas/farmacología , Antifúngicos/farmacología , Farmacorresistencia Fúngica/efectos de los fármacos , Fluconazol/farmacología , Biopelículas/efectos de los fármacos , Humanos , Candida auris/efectos de los fármacos , Candida auris/genética , Anfotericina B/farmacología , Candidiasis/microbiología , Candidiasis/tratamiento farmacológico

RESUMEN

In pursuit of potential agents to treat Chagas disease and leishmaniasis, we report the design, synthesis, and identification novel naphthoquinone hydrazide-based molecular hybrids. The compounds were subjected to in vitro trypanocide and leishmanicidal activities. N'-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)-3,5-dimethoxybenzohydrazide (13) showed the best performance against Trypanosoma cruzi (IC50 1.83 µM) and Leishmania amazonensis (IC50 9.65 µM). 4-Bromo-N'-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)benzohydrazide (16) exhibited leishmanicidal activity (IC50 12.16 µM). Regarding trypanocide activity, compound 13 was low cytotoxic to LLC-MK2 cells (SI = 95.28). Furthermore, through molecular modeling studies, the cysteine proteases cruzain, rhodesain and CPB2.8 were identified as the potential biological targets.

Asunto(s)

Diseño de Fármacos , Hidrazinas , Leishmania , Naftoquinonas , Tripanocidas , Trypanosoma cruzi , Naftoquinonas/farmacología , Naftoquinonas/química , Naftoquinonas/síntesis química , Trypanosoma cruzi/efectos de los fármacos , Tripanocidas/farmacología , Tripanocidas/síntesis química , Tripanocidas/química , Leishmania/efectos de los fármacos , Hidrazinas/química , Hidrazinas/farmacología , Animales , Antiprotozoarios/farmacología , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Pruebas de Sensibilidad Parasitaria , Concentración 50 Inhibidora , Relación Estructura-Actividad , Cisteína Endopeptidasas

RESUMEN

Two unusual naphthoquinones, named here as pleonotoquinones A (1) and B (2), were isolated along with two known anthraquinones (3 and 4) via chromatographic separations of an ethyl acetate extract of the roots of Pleonotoma jasminifolia. Compounds 1 and 2 are the first examples of quinones bearing a 2-methyloxepine moiety. The compounds were isolated with the aid of mass spectrometry and molecular networking, and their structures were resolved using 1D and 2D NMR and HRESIMS data. The isolated compounds were evaluated for their antiproliferative activity against human cancer cell lines, and compounds 1 and 2 displayed cytotoxicity against human colon cancer HCT116 cells (IC50 = 2.6 µM for compound 1 and IC50 = 4.3 µM for compound 2) and human liver cancer HepG2 cells (IC50 = 1.9 µM for compound 1 and IC50 = 6.4 µM for compound 2).

Asunto(s)

Antineoplásicos Fitogénicos , Ensayos de Selección de Medicamentos Antitumorales , Naftoquinonas , Raíces de Plantas , Humanos , Naftoquinonas/farmacología , Naftoquinonas/química , Naftoquinonas/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Estructura Molecular , Raíces de Plantas/química , Células Hep G2 , Células HCT116 , Boraginaceae/química

RESUMEN

The search for novel anticancer drugs is essential to expand treatment options, overcome drug resistance, reduce toxicity, promote innovation, and tackle the economic impact. The importance of these studies lies in their contribution to advancing cancer research and enhancing patient outcomes in the battle against cancer. Here, we developed new asymmetric hybrids containing two different naphthoquinones linked by a 1,2,3-1H-triazole nucleus, which are potential new drugs for cancer treatment. The antitumor activity of the novel compounds was tested using the breast cancer cell lines MCF-7 and MDA-MB-231, using the non-cancer cell line MCF10A as control. Our results showed that two out of twenty-two substances tested presented potential antitumor activity against the breast cancer cell lines. These potential drugs, named here 12g and 12h were effective in reducing cell viability and promoting cell death of the tumor cell lines, exhibiting minimal effects on the control cell line. The mechanism of action of the novel drugs was assessed revealing that both drugs increased reactive oxygen species production with consequent activation of the AMPK pathway. Therefore, we concluded that 12g and 12h are novel AMPK activators presenting selective antitumor effects.

Asunto(s)

Antineoplásicos , Neoplasias de la Mama , Naftoquinonas , Humanos , Femenino , Células MCF-7 , Especies Reactivas de Oxígeno/metabolismo , Triazoles/farmacología , Naftoquinonas/farmacología , Proteínas Quinasas Activadas por AMP , Proliferación Celular , Apoptosis , Línea Celular Tumoral , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Ensayos de Selección de Medicamentos Antitumorales

RESUMEN

Ipê is a plant of the Bignoniaceae family. Among the compounds extracted from this tree, lapachol is notable because its structural modification allows the production of ß-lapachone, which has anticancer properties. The objective of this work was to test this hypothesis at a cellular level in vitro and assess its potential safety for use. The following tests were performed: MTT cell viability assay, apoptotic index determination, comet assay, and micronucleus test. The results showed that ß-lapachone had a high cytotoxic capacity for all cell lines tested: ACP02 (gastric adenocarcinoma cells), MCF7 (breast carcinoma cells), HCT116 (colon cancer cells) and HEPG2 (hepatocellular carcinoma cells). Regarding genotoxicity, the exposure of cells to sublethal doses of ß-lapachone induced DNA damage (assessed by the comet assay) and nuclear abnormalities, such as nucleoplasmic bridges and nuclear buds (assessed by the micronucleus test). All tested cell lines responded similarly to ß-lapachone, except for ACP02 cells, which were relatively resistant to the cytotoxic effects of the compound in the MTT test. Our results collectively indicate that although ß-lapachone showed antiproliferative activity against cancer cell lines, it also caused harmful effects in these cells, suggesting that the use of ß-lapachone in treating cancer should be carried out with caution.

Asunto(s)

Antineoplásicos , Neoplasias del Colon , Naftoquinonas , Humanos , Apoptosis , Naftoquinonas/farmacología , Antineoplásicos/farmacología , Daño del ADN

RESUMEN

Leishmaniasis is a disease caused by Leishmania spp., affecting millions of people around the world. For decades, its treatment has been based on pentavalent antimonials, which notoriously cause toxic side effects in patients. In this study, epoxy-α-lapachone incorporated into an oil-in-water-type microemulsion (ELAP-ME) and meglumine antimoniate (MA) were assayed in monotherapy and in combination (ELAP-ME/MA) in BALB/c mice infected with Leishmania (Leishmania) amazonensis. In general, there was a reduction in paw lesion size (up to 37% reduction) and decreases of parasite loads in the footpad (∼40%) and lymph nodes (∼31%) of animals treated with ELAP-ME/MA, when compared to the non-treated control groups. Analyses of serum biochemical parameters revealed that the ELAP-ME/MA showed lower renal and hepatic toxicity when compared to MA 2-doses/week monotherapy. These findings indicate that the ELAP-ME/MA combination may be a promising approach for the treatment of cutaneous leishmaniasis.

Asunto(s)

Antiprotozoarios , Leishmania , Leishmaniasis Cutánea , Naftoquinonas , Compuestos Organometálicos , Humanos , Animales , Ratones , Antimoniato de Meglumina/uso terapéutico , Leishmaniasis Cutánea/tratamiento farmacológico , Leishmaniasis Cutánea/parasitología , Meglumina/uso terapéutico , Compuestos Organometálicos/uso terapéutico , Ratones Endogámicos BALB C

RESUMEN

SUMMARY: The objective of this study was to investigate the therapeutic wound healing potential and molecular mechanisms of shikonin as small molecules in vitro. A mouse burn model was used to explore the potential therapeutic effect of shikonin; we traced proliferating cells in vivo to locate the active area of skin cell proliferation. Through the results of conventional pathological staining, we found that shikonin has a good effect on the treatment of burned skin and promoted the normal distribution of skin keratin at the damaged site. At the same time, shikonin also promoted the proliferation of skin cells at the damaged site; importantly, we found a significant increase in the number of fibroblasts at the damaged site treated with shikonin. Most importantly, shikonin promotes fibroblasts to repair skin wounds by regulating the PI3K/AKT signaling pathway. This study shows that shikonin can effectively promote the proliferation of skin cell, and local injection of fibroblasts in burned skin can play a certain therapeutic role.

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El objetivo de este trabajo fue investigar el potencial terapéutico de cicatrización de heridas y los mecanismos moleculares de la shikonina como moléculas pequeñas in vitro. Se utilizó un modelo de quemaduras en ratones para explorar el posible efecto terapéutico de la shikonina; Rastreamos las células en proliferación in vivo para localizar el área activa de proliferación de células de la piel. A través de los resultados de la tinción para patología convencional, encontramos que la shikonina tiene un buen efecto en el tratamiento de la piel quemada y promueve la distribución normal de la queratina de la piel en el sitio dañado. Al mismo tiempo, la shikonina también promovió la proliferación de células de la piel en el sitio dañado. Es importante destacar que encontramos un aumento significativo en la cantidad de fibroblastos en el sitio dañado tratado con shikonina. Lo más importante es que la shikonina promueve la función reparadora de fibroblastos en las heridas de la piel regulando la vía de señalización PI3K/ AKT. Este estudio muestra que la shikonina puede promover eficazmente la proliferación de células de la piel y que la inyección local de fibroblastos en la piel quemada puede desempeñar un cierto papel terapéutico.

Asunto(s)

Animales , Ratones , Cicatrización de Heridas/efectos de los fármacos , Quemaduras/tratamiento farmacológico , Naftoquinonas/administración & dosificación , Piel , Técnicas In Vitro , Naftoquinonas/farmacología , Fosfatidilinositol 3-Quinasas , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Proteínas Proto-Oncogénicas c-akt , Fibroblastos , Ratones Endogámicos C57BL

RESUMEN

Plumbago scandens L. (Plumbaginaceae) occurs in all regions of Brazil. It has been described as toxic to cattle and goats. Caustic lesions in the upper digestive tract characterize poisoning. P. scandens contains a naphthoquinone named plumbagin, which presents high cytotoxic activity. Plumbago auriculata Lam., a widely used ornamental plant, is considered potentially toxic, but there is limited data about its toxicity. This work aimed to validate analytical methodologies for determining the levels of plumbagin in samples of leaves, stems, and rumen content to be used as an auxiliary chemical marker in the laboratory diagnosis of intoxication. One methodology used thin layer chromatography (TLC), and another used high-performance liquid chromatography (HPLC). The presence of palisade grass (Urochloa brizantha (Hochst. ex A.Rich.) R.D.Webster), Guinea grass (Megathyrsus maximus (Jacq.) B.K.Simon & S.W.L.Jacobs), corn silage, and rumen content did not interfere with plumbagin in the two methodologies. The TLC methodology generates qualitative results but is simple to implement and has a low cost. The HPLC methodology showed a limit of detection (LOD) of 0.01 µg/mL and a limit of quantification (LOQ) of 0.05 µg/mL. Leaf and stem samples of P. scandens evaluated showed high levels of plumbagin (0.261 ± 0.087 % and 0.327 ± 0.055 %, respectively). In contrast, leaves of P. auriculata did not show detectable levels of the toxin, and some stem samples showed low levels (up to 0.000114 %). Thus, these methodologies can be used to confirm or rule out the consumption of P. scandens in rumen content from animals suspected of poisoning.

Asunto(s)

Naftoquinonas , Plumbaginaceae , Animales , Bovinos , Cromatografía Líquida de Alta Presión/métodos , Cromatografía en Capa Delgada , Plumbaginaceae/química , Raíces de Plantas/química

RESUMEN

Anxiety-related mental health problems are estimated at 3.6% globally, benzodiazepines (BZDs) are the class of drugs indicated for the treatment of anxiety, including lorazepam and diazepam. However, concerns have been raised about the short- and long-term risks associated with BZDs. Therefore, despite anxiolytic and antidepressant drugs, there is a need to develop more effective pharmacotherapies with fewer side effects than existing drugs. The present work reported the synthesis, anxiolytic activity, mechanism of action in Adult Zebrafish (Danio rerio) and in silico study of a europium metallic complex with Lapachol, [Eu(DBM)3. LAP]. Each animal (n = 6/group) was treated intraperitoneally (i.p.; 20 µL) with the synthesized complex (4, 20 and 40 mg/Kg) and with the vehicle (DMSO 3%; 20 µL), being submitted to the tests of locomotor activity and 96h acute toxicity. The light/dark test was also performed, and the serotonergic mechanism (5-HT) was evaluated through the antagonists of the 5-HTR1, 5-HTR2A/2C and 5-HTR3A/3B receptors. The complex was characterized using spectrometric techniques, and the anxiolytic effect of complex may be involved the neuromodulation of receptors 5-HT3A/3B, since the pre-treatment with pizotifen and cyproheptadine did not block the anxiolytic effect of [Eu(DBM)3. LAP], unlike fluoxetine had its anxiolytic effect reversed. In addition, molecular docking showed interaction between the [Eu(DBM)3. LAP] and 5HT3A receptor with binding energy -7.8 kcal/mol and the ADMET study showed that complex has low toxic risk. It is expected that the beginning of this study will allow the application of the new anxiolytic drugs, given the pharmacological potential of the lapachol complex.Communicated by Ramaswamy H. Sarma.

Asunto(s)

Ansiolíticos , Naftoquinonas , Animales , Ansiolíticos/farmacología , Ansiolíticos/uso terapéutico , Pez Cebra , Europio , Simulación del Acoplamiento Molecular , Benzodiazepinas

RESUMEN

Photodynamic therapy (PDT) has been used for various purposes, including as an antitumor resource in a noninvasive therapy with minimal side effects. Sinningia magnifica (Otto & A. Dietr.) Wiehler is a rupicolous plant found in rock crevices in Brazilian tropical forests. Initial studies indicate the presence of phenolic glycosides and anthraquinones in species of the genus Sinningia (Generiaceae family). It is known that anthraquinones are natural photosensitizers with potential PDT applications. This led us to investigate the potential compounds of S. magnifica for use as a natural photosensitizer against the melanoma (SK-MEL-103) and the prostate cancer (PC-3) cell lines in a bioguided study. Our results showed that singlet oxygen production by the 1,3-DPBF photodegradation assay greatly increased in the presence of crude extract and fractions. The biological activity evaluation showed photodynamic action against melanoma cell line SK-MEL-103 and prostate cell line PC-3. These results suggest the presence of potential photosensitizing substances, as demonstrated in this in vitro antitumor PDT study by the naphthoquinones Dunniol and 7-hydroxy-6-methoxy-α-dunnione for the first time. Naphthoquinones, anthraquinones and phenolic compounds were identified in the crude extract by UHPLC-MS/MS analysis, motivating us to continue with the bioguided phytochemical study aiming to discover more photochemically bioactive substances in Gesneriaceae plants.

Asunto(s)

Melanoma , Naftoquinonas , Fotoquimioterapia , Humanos , Espectrometría de Masas en Tándem , Melanoma/tratamiento farmacológico , Naftoquinonas/farmacología , Naftoquinonas/química , Naftoquinonas/uso terapéutico , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Antraquinonas/farmacología , Antraquinonas/química , Mezclas Complejas

RESUMEN

Quinones are natural products widely distributed in nature, which are involved in stages of several vital biological processes, with mostly having a variety of pharmacological properties. The main groups comprising most of these compounds are benzoquinones, naphthoquinones, anthraquinones, and phenanthraquinones. Quinone isolation has been a focus of study around the world in recent years; for this reason, this study approaches the junction of natural quinones identified by 13 C Nuclear Magnetic Resonance (NMR) spectroscopic analytical techniques. The methodology used to obtain the data collected articles from various databases on quinones from 2000 to 2022. As a result, 137 compounds were selected, among which 70 were characterized for the first time in the period investigated; moreover, the study also discusses the biosynthetic pathways of quinones and the pharmacological activities of the compounds found, giving an overview of the various applications of these compounds.

Asunto(s)

Naftoquinonas , Quinonas , Quinonas/farmacología , Quinonas/química , Benzoquinonas/química , Naftoquinonas/química , Antraquinonas/química , Espectroscopía de Resonancia Magnética

RESUMEN

Cancer is responsible for high mortality rates worldwide, representing a serious health problem. In this sense, melanoma corresponds to the most aggressive type of skin cancer, being the cause of the highest death rates. Therapeutic strategies for the treatment of melanoma remain limited, with problems associated with toxicity, serious side effects, and mechanisms of resistance. The potential of natural products for the prevention and treatment of melanoma has been reported in different studies. Among these compounds, naphthoquinones (1,2-naphthoquinones and 1,4-naphthoquinones) stand out for their diverse pharmacological properties, including their antitumor activity. Thus, this review covers different studies found in the literature on the application of natural naphthoquinones targeting melanoma, providing information regarding the mechanisms of action investigated for these compounds. Finally, we believe that this review provides a comprehensive basis for the use of natural naphthoquinones against melanoma and that it may contribute to the discovery of promising compounds, specifically naphthoquinones, aimed at the treatment of this cancer.

Asunto(s)

Antineoplásicos , Melanoma , Naftoquinonas , Humanos , Melanoma/tratamiento farmacológico , Antineoplásicos/farmacología , Naftoquinonas/farmacología

RESUMEN

The subclass naphthoquinone represents a substance group containing several compounds with important activities against various pathogenic microorganisms. Accordingly, we evaluated O-allyl-lawsone (OAL) antiparasitic and antifungal activity free and encapsulated in 2-hydroxypropyl-ß-cyclodextrin (OAL MKN) against Trypanosoma cruzi and Sporothrix spp. OAL and OAL MKN were synthesized and characterized by physicochemical methods. The IC50 values of OAL against T. cruzi were 2.4 µM and 96.8 µM, considering epimastigotes and trypomastigotes, respectively. At the same time, OAL MKN exhibited a lower IC50 value (0.5 µM) for both trypanosome forms and low toxicity for mammalian cells. Additionally, the encapsulation showed a selectivity index approximately 240 times higher than that of benznidazole. Regarding antifungal activity, OAL and OAL MKN inhibited Sporothrix brasiliensis growth at 16 µM, while Sporothrix schenckii was inhibited at 32 µM. OAL MKN also exhibited higher selectivity toward fungus than mammalian cells. In conclusion, we described the encapsulation of O-allyl-lawsone in 2-hydroxypropyl-ß-cyclodextrin, increasing the antiparasitic activity compared with the free form and reducing the cytotoxicity and increasing the selectivity towardSporothrix yeasts and the T. cruzi trypomastigote form. This study highlights the potential development of this inclusion complex as an antiparasitic and antifungal agent to treat neglected diseases.

Asunto(s)

Enfermedad de Chagas , Naftoquinonas , Trypanosoma cruzi , Animales , 2-Hidroxipropil-beta-Ciclodextrina/farmacología , Antifúngicos/farmacología , Antifúngicos/química , Antifúngicos/uso terapéutico , Antiparasitarios/uso terapéutico , Enfermedad de Chagas/tratamiento farmacológico , Mamíferos , Naftoquinonas/uso terapéutico

RESUMEN

From Eleutherine plicata, naphthoquinones, isoeleutherine, and eleutherol were isolated, and previous studies have reported the antioxidant activity of these metabolites. The present work evaluated the role of oxidative changes in mice infected with Plasmodium berghei and treated with E. plicata extract, fraction, and isolated compounds, as well as to verify possible oxidative changes induced by these treatments. E. plicata extracts were prepared from powder from the bulbs, which were submitted to maceration with ethanol, yielding the extract (EEEp), which was fractionated under reflux, and the dichloromethane fraction (FDMEp) was submitted for further fractionation, leading to the isolation of isoeleutherine, eleutherine, and eleutherol. The antimalarial activity was examined using the suppressive test, evaluating the following parameters of oxidative stress: trolox equivalent antioxidant capacity (TEAC), thiobarbituric acid reactive substances (TBARS), and reduced glutathione (GSH). Furthermore, the molecular docking of naphthoquinones, eleutherol, eleutherine, and isoeleutherine interactions with antioxidant defense enzymes was investigated, which was favorable for the formation of the receptor-ligand complex, according to the re-rank score values. Eleutherine and isoeleutherine are the ones with the lowest binding energy for catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx1), showing themselves as possible targets of these molecules in the involvement of redox balance. Data from the present study showed that treatments with E. plicata stimulated an increase in antioxidant capacity and a reduction in oxidative stress in mice infected with P. berghei, with naphthoquinones being responsible for reducing oxidative changes and disease severity.

Asunto(s)

Antioxidantes , Naftoquinonas , Ratones , Animales , Antioxidantes/farmacología , Antioxidantes/metabolismo , Simulación del Acoplamiento Molecular , Estrés Oxidativo , Naftoquinonas/química , Catalasa/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/química , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Superóxido Dismutasa/metabolismo