RESUMO
Mayaro virus (MAYV) is the causative agent of Mayaro fever, which is characterized mainly by acute fever and long-term severe arthralgia, common manifestations of other arbovirus infections, making the correct diagnosis a challenge. Besides, MAYV infections have been reported in South America, especially in Brazil. However, the lack of vaccines or specific antiviral drugs to control these infections makes the search for new antivirals an urgent need. Herein, we evaluated the antiviral potential of synthetic ß-enaminoesters derivatives against MAYV replication and their pharmacokinetic and toxicological (ADMET) properties using in vitro and in silico strategies. For this purpose, Vero cells were infected with MAYV at an MOI of 0.1, treated with compounds (50 µM) for 24 h, and virus titers were quantified by plaque reduction assays. Compounds 2b (83.33%) and 2d (77.53%) exhibited the highest activity with inhibition rates of 83.33% and 77.53%, respectively. The most active compounds 2b (EC50 = 18.92 µM; SI > 52.85), and 2d (EC50 = 14.52 µM; SI > 68.87) exhibited higher potency and selectivity than the control drug suramin (EC50 = 38.97 µM; SI > 25.66). Then, we investigated the mechanism of action of the most active compounds. None of the compounds showed virucidal activity, neither inhibited virus adsorption, but compound 2b inhibited virus entry (62.64%). Also, compounds 2b and 2d inhibited some processes involved with the release of new virus particles. Finally, in silico results indicated good ADMET parameters of the most active compounds and reinforced their promising profile as drug candidates against MAYV.
Assuntos
Alphavirus , Antivirais , Ésteres , Replicação Viral , Antivirais/farmacologia , Antivirais/química , Chlorocebus aethiops , Animais , Células Vero , Ésteres/farmacologia , Ésteres/química , Alphavirus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Simulação por Computador , Brasil , Infecções por Alphavirus/tratamento farmacológico , Infecções por Alphavirus/virologiaRESUMO
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.
Assuntos
Neoplasias da Mama , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/química , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Células MCF-7 , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Simulação de Acoplamento Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Ésteres/farmacologia , Ésteres/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidoresRESUMO
To combine the activity characteristics of 18ß-glycyrrhetinic acid (18ß-GA) and anthraquinone compounds (rhein and emodin), reduce toxicity, and explore the structure-activity relationship (SAR) of anthraquinones, 18ß-GA-anthraquinone ester compounds were synthesized by one-step organic synthesis. The products were separated and purified by HPLC and characterized by NMR and EI-MS. It was finally determined as di-18ß-GA-3-rhein ester (1, New), GA dimer (2, known), 18ß-GA-3-emodin ester (3, known), and di-18ß-GA-1-emodin ester (4, new). The MIC of three reactants and four products against Escherichia coli and Staphylococcus aureus were detected in vitro. Its developmental toxicity and cardiotoxicity were assessed using zebrafish embryos. The experimental results showed that rhein had the best antibacterial activity against Staphylococcus aureus with MIC50 of 2.4 mM, and it was speculated that -COOH, -OH, and intramolecular hydrogen bonds in anthraquinone compounds would enhance the antibacterial effect, while the presence of-CH3 might weaken the antibacterial activity. Product 1 increased the hatching rate and survival rate of zebrafish embryos and reduced the malformation rate and cardiomyocyte apoptosis. This experiment lays the foundation for further studying the SAR of anthraquinones and providing new drug candidates.
Assuntos
Antraquinonas , Antibacterianos , Escherichia coli , Ácido Glicirretínico , Testes de Sensibilidade Microbiana , Staphylococcus aureus , Peixe-Zebra , Animais , Antraquinonas/farmacologia , Antraquinonas/química , Antraquinonas/síntese química , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Ácido Glicirretínico/farmacologia , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/química , Ácido Glicirretínico/síntese química , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Escherichia coli/efeitos dos fármacos , Embrião não Mamífero/efeitos dos fármacos , Ésteres/química , Ésteres/farmacologia , Ésteres/síntese químicaRESUMO
Resin glycosides are characteristic of plants of the Convolvulaceae family and are well-known purgative ingredients in crude drugs, such as Rhizoma Jalapae, Orizaba Jalapa Tuber, and Pharbitidis Semen, which are used in traditional medicine and derived from plants belonging to this family. Isolated resin glycosides have demonstrated diverse biological activities, including antibacterial, ionophoric, anti-inflammatory, antiviral, and multidrug-resistance-modulating properties, as well as cytotoxicity against cancer cells. These compounds consist of hydroxyl fatty acid oligoglycosides (glycosidic acids), with portions of the saccharide moieties acylated with some organic acids to form the core structure. This study investigated the glycosidic acid components of a crude resin glycoside fraction obtained from a methanolic extract of Ipomoea alba L. seeds (Convolvulaceae). Eleven new glycosidic acid methyl esters and one known methyl ester were isolated from a glycosidic acid fraction treated with trimethylsilyldiazomethane in hexane. Their structures were determined using acidic hydrolysis and electrospray ionization-time of fight mass spectrometry and NMR spectral analyses. These compounds are penta-, tetra-, or triglycosides, with methyl 11S-hydroxytetradecanoate or methyl 11S-hydroxyhexadecanoate as the aglycone. Although D-quinovose and L-rhamnose are common monosaccharide components, the remaining monosaccharides are D-glucose, D-xylose, or D-fucose. The crude resin glycoside fraction showed non-negligible cytotoxicity against HL-60 human promyelocytic leukemia cells.
Assuntos
Glicosídeos , Ipomoea , Extratos Vegetais , Resinas Vegetais , Sementes , Ipomoea/química , Glicosídeos/química , Glicosídeos/farmacologia , Glicosídeos/isolamento & purificação , Resinas Vegetais/química , Humanos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Sementes/química , Estrutura Molecular , Ésteres/química , Ésteres/farmacologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Atopic dermatitis (AD) is a chronic skin condition that is characterized by dysregulated immune responses and a heightened risk of Staphylococcus aureus infections, necessitating the advancement of innovative therapeutic methods. This study explored the potential of (6Z,9Z,12Z,15Z)-(2R,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl octadeca-6,9,12,15-tetraenoate (HSN-S1), a compound derived from the marine alga Hizikia fusiformis, which shows anti-inflammatory, antimicrobial, and immunomodulatory properties. HSN-S1 was isolated and characterized using advanced chromatographic and spectroscopic methods. Its efficacy was evaluated via in vitro assays with keratinocytes, macrophages, and T cells to assess cytokine suppression and its immunomodulatory effects; its antibacterial activity against S. aureus was quantified. The in vivo effectiveness was validated using a 2,4-dinitrochlorobenzene-induced AD mouse model that focused on skin pathology and cytokine modulation. HSN-S1 significantly reduced pro-inflammatory cytokine secretion, altered T-helper cell cytokine profiles, and showed strong antibacterial activity against S. aureus. In vivo, HSN-S1 alleviated AD-like symptoms in mice and reduced skin inflammation, transepidermal water loss, serum immunoglobulin-E levels, and Th2/Th17 cytokine outputs. These findings suggest HSN-S1 to be a promising marine-derived candidate for AD treatment, as it offers a dual-target approach that could overcome the limitations of existing therapies, hence warranting further clinical investigation.
Assuntos
Antibacterianos , Citocinas , Dermatite Atópica , Imunossupressores , Phaeophyceae , Staphylococcus aureus , Dermatite Atópica/tratamento farmacológico , Animais , Camundongos , Phaeophyceae/química , Antibacterianos/farmacologia , Antibacterianos/isolamento & purificação , Staphylococcus aureus/efeitos dos fármacos , Citocinas/metabolismo , Humanos , Imunossupressores/farmacologia , Imunossupressores/isolamento & purificação , Imunossupressores/química , Modelos Animais de Doenças , Ésteres/farmacologia , Ésteres/química , Feminino , Camundongos Endogâmicos BALB C , Organismos Aquáticos , Queratinócitos/efeitos dos fármacosRESUMO
As an oleanolic acid derivative, CDDO-Me lacks selectivity for tumors. Based on the high reactive oxygen species (ROS) level in cancer cells, compound 4 was selected from 17 new CDDO arylboronate ester derivatives. A preliminary study revealed that 4 displayed the highest selectivity for cancer cells. Furthermore, 4 could be transformed to 4H by ROS to increase its covalent binding ability and antiproliferation effect (IC50 of 2.11 vs 0.37 µM) in BGC-823 cells. Interestingly, 4 increased ROS levels to induce apoptosis in BGC-823 cells. Moreover, the LD50 of 4 (91.2 mg/kg) was much greater than that of CDDO-Me (61.7 mg/kg) in ICR mice. A pharmacokinetic study indicated that 4 could be transformed to 4H in vivo. In addition, 4 exhibited a greater tumor inhibition rate (86.2%) than CDDO-Me (51.7%). Overall, the design of 4 provided an effective modification strategy for CDDO to increase the selectivity for cancer cells.
Assuntos
Antineoplásicos , Apoptose , Proliferação de Células , Camundongos Endogâmicos ICR , Ácido Oleanólico , Animais , Humanos , Masculino , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Ácidos Borônicos/química , Ácidos Borônicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Ésteres/química , Ésteres/farmacologia , Ésteres/síntese química , Estrutura Molecular , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , Ácido Oleanólico/farmacocinética , Ácido Oleanólico/síntese química , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Formamidas/química , Formamidas/farmacologia , Etilaminas/química , Etilaminas/farmacologiaRESUMO
The common presence of glycidyl esters (GEs) in refined vegetable oils has been a concern for food safety. The present study aimed to investigate the inhibitory effects of three carotenoids derived from Haematococcus pluvialis microalga on GE formation in both rice oil and a chemical model during heating. The addition of astaxanthin (AS), lutein (LU), and ß-carotene (CA) at 0.6 mg/g in rice oil can reduce GE formation by 65.0%, 57.1%, and 57.5%, respectively, which are significantly higher than those achieved by common antioxidants such as l-ascorbyl palmitate (39.0%), α-tocopherol (18.5%), tert-butyl hydroquinone (42.7%), and quercetin (26.2%). UPLC-Q-TOF-MS/MS analysis showed that two new compounds, that is, propylene glycol monoester and diester of palmitic acid, were formed in the CA-added chemical model, which provided direct experimental evidence for the inhibition of antioxidants including AS, LU, and CA against GE formation not only by indirect antioxidative action but also by direct radical reactions to competitively prevent the formation of cyclic acyloxonium intermediates. Furthermore, it was interestingly found that only AS could react with the GEs. The adduct of AS with GEs, astaxanthin-3-O-propanetriol esters, was preliminarily identified using Q-TOF-MS/MS in the heated AS-GE model, suggesting that reacting with GEs might represent another distinct mechanism of AS to eliminate GEs.
Assuntos
Carotenoides , Ésteres , Temperatura Alta , Ésteres/química , Ésteres/farmacologia , Carotenoides/química , Óleos de Plantas/química , Óleos de Plantas/farmacologia , Xantofilas/química , Xantofilas/farmacologia , Espectrometria de Massas em Tandem , Compostos de Epóxi/química , Modelos Químicos , Antioxidantes/química , Antioxidantes/farmacologia , Luteína/química , Luteína/farmacologia , Clorofíceas/química , Clorófitas/químicaRESUMO
In this paper, we present the synthesis and characterization of two known sulfonyl hydrazides (1 and 2) and their new sulfonyl hydrazone derivatives (9-20), as well as in vitro and in silico investigations of their cytotoxic properties against human lung (A549) and human breast (MCF-7) cancer cell lines. The target compounds (9-20) obtained in high yields were synthesized for the first time by a multi-step reaction, and their structures were confirmed by elemental analysis and various spectral techniques, including FT-IR, 1H-, and 13C-NMR. The antiproliferative profiles of these compounds (1, 2, and 9-20) in this study were determined at concentrations of 200, 100, 50, and 25 µM against selected cancer cell lines for 72 h using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. Except for compounds 1 and 2, other compounds (9-20) demonstrated cytotoxic activity at concentrations lower than 200 µM. The newly synthesized compounds (9-20) demonstrated antiproliferative activities at a micromolar level, with IC50 values in the range of 29.59-176.70 µM for the A549 cell line and 27.70-170.30 µM for the MCF-7 cell line. Among these compounds, compound 15 (IC50 = 29.59 µM against A549 cell line and IC50 = 27.70 µM against MCF-7 cell line) showed the highest cytotoxic activity against these two cancer cell lines compared to the reference drug cisplatin (IC50 = 22.42 µM against A549 cell line and IC50 = 18.01 µM against MCF-7 cell line). From docking simulations, to establish a plausible binding mode of compounds, we noticed that compound 15 demonstrated the highest affinity (-6.8508 kcal/mol) for estrogen receptor-beta (ERbeta) compared to others, suggesting promising ERbeta binding potential. Most compounds followed Lipinski's rule of five, with acceptable logP values. Additionally, all had mixed gastrointestinal absorption and limited blood-brain barrier permeability. Overall, our study proposed new sulfonyl hydrazones as a potential class of anticancer agents.
Assuntos
Antineoplásicos , Proliferação de Células , Desenho de Fármacos , Hidrazonas , Simulação de Acoplamento Molecular , Humanos , Hidrazonas/química , Hidrazonas/farmacologia , Hidrazonas/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Células MCF-7 , Células A549 , Relação Estrutura-Atividade , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Linhagem Celular Tumoral , Ésteres/química , Ésteres/farmacologiaRESUMO
Liver cancer is a complex disease that involves various oncoproteins and the inactivation of tumor suppressor proteins (TSPs). Gankyrin is one such oncoprotein, first identified in human hepatocellular carcinoma, that is known to inactivate multiple TSPs, leading to proliferation and metastasis of tumor cells. Despite this, there has been limited development of small molecule gankyrin binders for the treatment of liver cancer. In this study, we are reporting the structure-based design of gankyrin-binding small molecules which inhibit the proliferation of HuH6 and HepG2 cells while also increasing the levels of certain TSPs, such as Rb and p53. Interestingly the first molecule to exhibit inhibition by 3D structure stabilization is seen. These results suggest a possible mechanism for small-molecule inhibition of gankyrin and demonstrate that gankyrin is a viable therapeutic target for the treatment of liver cancer.
Assuntos
Antineoplásicos , Proliferação de Células , Proteínas Proto-Oncogênicas , Triazóis , Humanos , Triazóis/química , Triazóis/farmacologia , Triazóis/síntese química , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Relação Estrutura-Atividade , Estrutura Molecular , Ensaios de Seleção de Medicamentos Antitumorais , Ácidos Sulfônicos/química , Ácidos Sulfônicos/farmacologia , Ácidos Sulfônicos/antagonistas & inibidores , Linhagem Celular Tumoral , Ésteres/química , Ésteres/farmacologia , Ésteres/síntese química , Complexo de Endopeptidases do Proteassoma/metabolismo , Complexo de Endopeptidases do Proteassoma/química , Relação Dose-Resposta a Droga , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , BenzenossulfonatosRESUMO
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.
Assuntos
Antineoplásicos , Apoptose , Autofagia , Proliferação de Células , Neoplasias de Mama Triplo Negativas , Humanos , Apoptose/efeitos dos fármacos , Feminino , Proliferação de Células/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Linhagem Celular Tumoral , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/uso terapêutico , Compostos Organosselênicos/química , Sobrevivência Celular/efeitos dos fármacos , Ésteres/química , Ésteres/farmacologia , Células MCF-7RESUMO
Betulinic acid is a lupane-type pentacyclic triterpene mostly found in birch bark and thoroughly explored for its wide range of pharmacological activities. Despite its impressive biological potential, its low bioavailability has challenged many researchers to develop different formulations for achieving better in vitro and in vivo effects. We previously reported the synthesis of fatty acid esters of betulinic acid using butyric, stearic, and palmitic acids (But-BA, St-BA, and Pal-BA) and included them in surfaced-modified liposomes (But-BA-Lip, St-BA-Lip, Pal-BA-Lip). In the current study, we evaluated the cytotoxic effects of both fatty acid esters and their respective liposomal formulations against MCF-7, HT-29, and NCI-H460 cell line. The cytotoxic assessment of BA derivatives revealed that both the fatty esters and their liposomal formulations acted as cytotoxic agents in a dose- and time-dependent manner. But-BA-Lip exerted stronger cytotoxic effects than the parent compound, BA and its liposomal formulation, and even stronger effects than 5-FU against HT-29 cells (IC50 of 30.57 µM) and NCI-H460 cells (IC50 of 30.74 µM). BA's fatty esters and their respective liposomal formulations facilitated apoptosis in cancer cells by inducing nuclear morphological changes and increasing caspase-3/-7 activity. The HET-CAM assay proved that none of the tested compounds induced any irritative effect, suggesting that they can be used safely for local applications.
Assuntos
Ácido Betulínico , Neoplasias da Mama , Ésteres , Lipossomos , Triterpenos Pentacíclicos , Triterpenos , Humanos , Lipossomos/química , Triterpenos Pentacíclicos/farmacologia , Ésteres/química , Ésteres/farmacologia , Triterpenos/farmacologia , Triterpenos/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Células HT29 , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Neoplasias do Colo/metabolismo , Apoptose/efeitos dos fármacos , Células MCF-7 , Antineoplásicos/farmacologia , Antineoplásicos/química , Sobrevivência Celular/efeitos dos fármacos , Ácidos Graxos/química , Feminino , Proliferação de Células/efeitos dos fármacosRESUMO
Developing multitargeted ligands as promising therapeutics for Alzheimer's disease (AD) has been considered important. Herein, a novel class of cinnamamide/ester-triazole hybrids with multifaceted effects on AD was developed based on the multitarget-directed ligands strategy. Thirty-seven cinnamamide/ester-triazole hybrids were synthesized, with most exhibiting significant inhibitory activity against Aß-induced toxicity at a single concentration in vitro. The most optimal hybrid compound 4j inhibited copper-induced Aß toxicity in AD cells. its action was superior to that of donepezil and memantine. It also moderately inhibited intracellular AChE activity and presented favorable bioavailability and blood-brain barrier penetration with low toxicity in vivo. Of note, it ameliorated cognitive impairment, neuronal degeneration, and Aß deposition in Aß1-42-injured mice. Mechanistically, the compound regulated APP processing by promoting the ADAM10-associated nonamyloidogenic signaling and inhibiting the BACE1-mediated amyloidogenic pathway. Moreover, it suppressed intracellular AChE activity and tau phosphorylation. Therefore, compound 4j may be a promising multitargeted active molecule against AD.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Cinamatos , Triazóis , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Triazóis/química , Triazóis/farmacologia , Triazóis/síntese química , Cinamatos/química , Cinamatos/farmacologia , Cinamatos/síntese química , Humanos , Camundongos , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Relação Estrutura-Atividade , Estrutura Molecular , Ésteres/química , Ésteres/farmacologia , Ésteres/síntese química , Relação Dose-Resposta a Droga , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Descoberta de Drogas , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/síntese química , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/antagonistas & inibidores , MasculinoRESUMO
The active splicing strategy has witnessed improvement in bioactivity and antifungal spectra in pesticide discovery. Herein, a series of simple-structured molecules (Y1-Y53) containing chloro-substituted benzyl esters were designed using the above strategy. The structure-activity relationship (SAR) analysis demonstrated that the fatty acid fragment-structured esters were more effective than those containing an aromatic acid moiety or naphthenic acid part. Compounds Y36 and Y41, which featured a thiazole-4-acid moiety and trifluoromethyl aliphatic acid part, respectively, exhibited excellent in vivo curative activity (89.4%, 100 mg/L Y36) and in vitro fungicidal activity (EC50 = 0.708 mg/L, Y41) against Botrytis cinerea. Determination of antifungal spectra and analysis of scanning electron microscopy (SEM), membrane permeability, cell peroxidation, ergosterol content, oxalic acid pathways, and enzymatic assays were performed separately here. Compound Y41 is cost effective due to its simple structure and shows promise as a disease control candidate. In addition, Y41 might act on a novel target through a new pathway that disrupts the cell membrane integrity by inducing cell peroxidation.
Assuntos
Botrytis , Desenho de Fármacos , Ésteres , Fungicidas Industriais , Ésteres/química , Ésteres/farmacologia , Relação Estrutura-Atividade , Botrytis/efeitos dos fármacos , Fungicidas Industriais/farmacologia , Fungicidas Industriais/química , Fungicidas Industriais/síntese química , Estrutura Molecular , Doenças das Plantas/microbiologia , Testes de Sensibilidade MicrobianaRESUMO
Cancer represents one of the most significant health challenges currently facing humanity, and plant-derived antitumour drugs represent a prominent class of anticancer medications in clinical practice. Isovaleryl sucrose esters, which are natural constituents, have been identified as having potential antitumour effects. However, the mechanism of action remains unclear. In this study, 12 isovaleryl sucrose ester components, including five new (1-5) and seven known compounds (6-12), were isolated from the roots of Atractylodes japonica. The structures of the compounds were elucidated using 1D and 2D-NMR spectroscopy, complemented by HR-ESI-MS mass spectrometry. The cytotoxic activities of all the compounds against human colon cancer cells (HCT-116) and human lung adenocarcinoma cells (A549) were also evaluated using the CCK8 assay. The results demonstrated that compounds 2, 4, and 6 were moderately inhibitory to HCT-116 cells, with IC50 values of 7.49 ± 0.48, 9.03 ± 0.21, and 13.49 ± 1.45 µM, respectively. Compounds 1 and 6 were moderately inhibitory to A549, with IC50 values of 8.36 ± 0.77 and 7.10 ± 0.52 µM, respectively. Molecular docking revealed that compounds 1-9 exhibited a stronger affinity for FGFR3 and BRAF, with binding energies below -7 kcal/mol. Compound 2 exhibited the lowest binding energy of -10.63 kcal/mol to FGFR3. We screened the compounds with lower binding energies, and the protein-ligand complexes already obtained after molecular docking were subjected to exhaustive molecular dynamics simulation experiments, which simulated the dynamic behaviour of the molecules in close proximity to the actual biological environment, thus providing a deeper understanding of their functions and interaction mechanisms. The present study provides a reference for the development and use of iso-valeryl sucrose esters in the antitumour field.
Assuntos
Atractylodes , Ésteres , Simulação de Acoplamento Molecular , Sacarose , Humanos , Sacarose/química , Sacarose/análogos & derivados , Sacarose/farmacologia , Ésteres/química , Ésteres/farmacologia , Atractylodes/química , Estrutura Molecular , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Células HCT116 , Linhagem Celular Tumoral , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Células A549 , Simulação de Dinâmica Molecular , Proliferação de Células/efeitos dos fármacosRESUMO
Hypoxia-inducing factor-1α (HIF-1α) is overexpressed in variety of tumor patients and plays an important role in the regulation of hypoxia response in tumor cells. Therefore, its inhibitors have become one of the targets for the treatment of a variety of cancers. Two series of panaxadiol (PD) ester derivatives containing pyrazole (18a-j) and pyrrole (19a-n) moiety were synthesized and their HIF-1α inhibitory activities were evaluated. Among all the target compouds, compounds 18c, 19d, and 19n (IC50 = 8.70-10.44 µM) showed better HIF-1α inhibitory activity than PD (IC50 = 13.35 µM). None of these compounds showed cytotoxicity above 100 µM and inhibited HIF-1α transcription in a dose-dependent manner. These compounds showed good antitumor activity and provide lead compounds for further design and activity study of PD ester derivatives.
Assuntos
Ésteres , Ginsenosídeos , Subunidade alfa do Fator 1 Induzível por Hipóxia , Pirazóis , Pirróis , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Pirróis/farmacologia , Pirróis/química , Pirróis/síntese química , Estrutura Molecular , Linhagem Celular Tumoral , Pirazóis/farmacologia , Pirazóis/química , Pirazóis/síntese química , Ésteres/química , Ésteres/farmacologia , Ésteres/síntese química , Ginsenosídeos/farmacologia , Ginsenosídeos/química , Ginsenosídeos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Relação Estrutura-AtividadeRESUMO
Twelve polyoxygenated cyclohex(a/e)ne diterpene esters, named albiflorenes A-L (1-12), were isolated from the whole plants of Kaempferia albiflora, known as "Prao Mang Mum." Their structures and relative stereochemistry were determined by extensive spectroscopic analysis. Furthermore, the comparison of experimental electronic circular dichroism (ECD) curves with the curves predicted by TDDFT was used to determine the absolute configurations. Albiflorenes contain polyoxygenated cyclohexane (or cyclohexene) derivatives, which are linked to either isopimarane or abietane diterpene acid units. The discovery marks the first occurrence of a conjugate between polyoxygenated cyclohexane (or cyclohexene) rings and diterpenoids. Among the isolates, albiflorene C specifically exhibited antibacterial activity against Bacillus cereus with MIC and MBC values of 3.13 and 6.25 µg/mL, respectively.
Assuntos
Antibacterianos , Diterpenos , Ésteres , Testes de Sensibilidade Microbiana , Zingiberaceae , Diterpenos/química , Diterpenos/farmacologia , Diterpenos/isolamento & purificação , Ésteres/química , Ésteres/farmacologia , Zingiberaceae/química , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Bacillus cereus/efeitos dos fármacos , Estrutura Molecular , Dicroísmo CircularRESUMO
Sugar esters display surface-active properties, wetting, emulsifying, and other physicochemical phenomena following their amphipathic nature and recognize distinct biological activity. The development of nutritional pharmaceuticals and other applications remains of great interest. Herein, three novel homologous series of several N-mono-fatty acyl amino acid glucosyl esters were synthesized, and their physicochemical properties and biological activities were evaluated. The design and preparation of these esters were chemically performed via the reaction of glucose with different fatty acyl amino acids as renewable starting materials, with the suggestion that they would acquire functional characteristics superior and competitive to certain conventional surfactants. The synthesized products are characterized using FTIR, 1H-NMR, and 13C-NMR spectroscopy. Further, their physicochemical properties, such as HLB, CMC, Γmax, γCMC, and Amin, were determined. Additionally, their antimicrobial and anticancer efficiency were assessed. The results indicate that the esters' molecular structure, including the acyl chain length and the type of amino acid, significantly influences their properties. The measured HLB ranged from 8.84 to 12.27, suggesting their use as oil/water emulsifiers, wetting, and cleansing agents. All esters demonstrate promising surface-active characteristics, with moderate to high foam production with good stability. Notably, compounds 6-O-(N-dodecanoyl, tetradecanoyl cysteine)-glucopyranose (34, 35), respectively and 6-O-(N-12-hydroxy-9-octadecenoyl cysteine)-glucopyranose (38) display superior foamability. Wetting efficiency increased with decreasing the chain length of the acyl group. The storage results reveal that increasing the fatty acyl hydrophobe length enhances the derived emulsion's stability for up to 63 days. Particularly, including cysteine in these glucosyl esters improves wetting, foaming, and emulsifying potentialities. Furthermore, the esters exhibit antibacterial activity against several tested Gram-positive and Gram-negative bacteria and fungi. On the other hand, they show significant antiproliferative effects on some liver tumor cell lines. For instance, compounds 6-O-(N-12-hydroxy-9-octadecenoylglycine)-glucopyranose (28), 6-O-(N-dodecanoyl, hexadecanoyl, 9-octadecenoyl and 12-hydroxy-9-octadecenoylvaline)- glucopyranose (29, 31, 32 and 33), respectively in addition to the dodecanoyl, hexadecanoyl, 9-octadecenoyl and 12-hydroxy-9-octadecenoyl cysteine glucopyranose (34, 36, 37 and 38), respectively significantly inhibit the examined cancer cells.
Assuntos
Anti-Infecciosos , Antineoplásicos , Tensoativos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Tensoativos/química , Tensoativos/síntese química , Tensoativos/farmacologia , Humanos , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/síntese química , Relação Estrutura-Atividade , Testes de Sensibilidade Microbiana , Ésteres/química , Ésteres/farmacologia , Ésteres/síntese química , Linhagem Celular Tumoral , Aminoácidos/químicaRESUMO
This study introduces boronic ester-based ROS-responsive amphiphilic copolymers for antioxidant drug delivery. Tuning the hydrophobic/hydrophilic balance optimized the size, curcumin encapsulation, ROS-triggered release, cellular uptake, and intracellular ROS scavenging. The lead P1b formulation self-assembled into stable 10 nm micelles enabling rapid ROS-triggered curcumin release and preferential cellular internalization. P1b eliminated over 90% of pathogenic intracellular ROS within 10 minutes, demonstrating a rapid antioxidant therapy.
Assuntos
Ácidos Borônicos , Curcumina , Ésteres , Polímeros , Espécies Reativas de Oxigênio , Espécies Reativas de Oxigênio/metabolismo , Ésteres/química , Ésteres/farmacologia , Humanos , Ácidos Borônicos/química , Curcumina/química , Curcumina/farmacologia , Polímeros/química , Micelas , Interações Hidrofóbicas e Hidrofílicas , Antioxidantes/química , Antioxidantes/farmacologia , Portadores de Fármacos/química , Tensoativos/química , Tensoativos/síntese química , Liberação Controlada de Fármacos , Sistemas de Liberação de Medicamentos , Sobrevivência Celular/efeitos dos fármacos , Estrutura MolecularRESUMO
Mitochondria-targeted antioxidants (MTAs) have been studied quite intensively in recent years as potential therapeutic agents and vectors for the delivery of other active substances to mitochondria and bacteria. Their most studied representatives are MitoQ and SkQ1, with its fluorescent rhodamine analog SkQR1, a decyl ester of rhodamine 19 carrying plastoquinone. In the present work, we observed a pronounced antibacterial action of SkQR1 against Gram-positive bacteria, but virtually no effect on Gram-negative bacteria. The MDR pump AcrAB-TolC, known to expel SkQ1, did not recognize and did not pump out SkQR1 and dodecyl ester of rhodamine 19 (C12R1). Rhodamine 19 butyl (C4R1) and ethyl (C2R1) esters more effectively suppressed the growth of ΔtolC Escherichia coli, but lost their potency with the wild-type E. coli pumping them out. The mechanism of the antibacterial action of SkQR1 may differ from that of SkQ1. The rhodamine derivatives also proved to be effective antibacterial agents against various Gram-positive species, including Staphylococcus aureus and Mycobacterium smegmatis. By using fluorescence correlation spectroscopy and fluorescence microscopy, SkQR1 was shown to accumulate in the bacterial membrane. Thus, the presentation of SkQR1 as a fluorescent analogue of SkQ1 and its use for visualization should be performed with caution.
Assuntos
Antibacterianos , Ésteres , Testes de Sensibilidade Microbiana , Rodaminas , Antibacterianos/farmacologia , Antibacterianos/química , Rodaminas/química , Rodaminas/farmacologia , Ésteres/química , Ésteres/farmacologia , Plastoquinona/análogos & derivados , Plastoquinona/farmacologia , Plastoquinona/química , Bactérias Gram-Positivas/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Corantes Fluorescentes/químicaRESUMO
Isoliquiritigenin (ISL) is a chalcone that has shown great potential in the treatment of cancer. However, its relatively weak activity and low water solubility limit its clinical application. In this study, we designed and synthesized 21 amino acid ester derivatives of ISL and characterized the compounds using 1H NMR and 13C NMR. Among them, compound 9 (IC50 = 14.36 µM) had a better inhibitory effect on human cervical cancer (Hela) than ISL (IC50 = 126.5 µM), and it was superior to the positive drug 5-FU (IC50 = 33.59 µM). The mechanism of the action experiment showed that compound 9 could induce Hela cell apoptosis and autophagy through the PI3K/Akt/mTOR pathway.