RESUMO
Gossypol (Gsp) and antibiotics present in water bodies become organic pollutants that are harmful to human health and the ecological environment. Accurate and effective detection of these pollutants has far-reaching significance in many fields. A new three-dimensional metal-organic framework (MOF), {[Eu3(L)2(HCOO-)(H2O)3]·2H2O·2DMF}n (Eu-MOF), was synthesized from 3,5-bis(2,4-dicarboxylphenyl)nitrobenzene (H4L) ligand and Eu3+ via the solvothermal method in this paper. The Eu-MOF demonstrates strong red fluorescence and can remain stable in different pH solutions. The MOF fluorescence probe could detect organic pollutants through the "shut-off" effect, with a fast response speed and a low detection limit [Gsp, nitrofurantoin (NFT), and nitrofurazone (NFZ) for 0.43, 0.38, and 0.41 µM, respectively]. During the testing process, Eu-MOF exhibited good selectivity and recoverability. Furthermore, the mechanism of fluorescence quenching was investigated, and the recoveries were also good in real samples. This paper introduced a deep learning model to recognize the fluorescence images, a portable intelligent logic detector designed for real-time detection of Gsp by logic gate strategy, and an anticounterfeiting mark prepared based on inkjet printing. Importantly, this work provides a new way of thinking for the detection of organic pollutants in water with high sensitivity and practicality by combining the fluorescence probe with machine learning and logical judgment.
Assuntos
Antibacterianos , Európio , Corantes Fluorescentes , Gossipol , Estruturas Metalorgânicas , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Európio/química , Antibacterianos/análise , Antibacterianos/química , Gossipol/análise , Gossipol/química , Poluentes Químicos da Água/análise , Nitrofuranos/análise , Espectrometria de Fluorescência , Estrutura Molecular , Limite de DetecçãoRESUMO
The folate metabolism enzyme ALDH1L1 catalyzed 10-formyltetrahydrofolate to tetrahydrofolate and CO2. Non-small cell lung cancer cells (NSCLC) strongly express ALDH1L1. Gossypol binds to an allosteric site and disrupts the folate metabolism by preventing NADP+ binding. The Cryo-EM structures of tetrameric C-terminal aldehyde dehydrogenase human ALDH1L1 complex with gossypol were examined. Gossypol-bound ALDH1L1 interfered with NADP+ by shifting the allosteric site of the structural conformation, producing a closed-form NADP+ binding site. In addition, the inhibition activity of ALDH1L1 was targeted with gossypol in NSCLC. The gossypol treatment had anti-cancer effects on NSCLC by blocking NADPH and ATP production. These findings emphasize the structure characterizing ALDH1L1 with gossypol.
Assuntos
Gossipol , Humanos , Gossipol/química , Gossipol/farmacologia , Gossipol/metabolismo , NADP/metabolismo , NADP/química , Modelos Moleculares , Microscopia Crioeletrônica , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Aldeído Oxirredutases/metabolismo , Aldeído Oxirredutases/química , Ligação Proteica , Sítios de Ligação , Sítio Alostérico , Conformação Proteica , Linhagem Celular Tumoral , Oxirredutases atuantes sobre Doadores de Grupo CH-NHRESUMO
The development of simple and rapid analytical tools for gossypol (GSP) is important to the food industry and medical field. Here, we report a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) method for the detection of GSP by using a reactive matrix 4-hydrazinoquinazoline (4-HQ). The two aldehyde groups of GSP react with the 4-HQ and therefore improve the detection sensitivity and selectivity of GSP. Moreover, GSP forms homogeneous crystals with the 4-HQ matrix, allowing the quantification of the GSP by the proposed method. With the optimized experimental conditions, GSP could be detected at concentrations as low as 0.1 µM and quantified in a wide linear range (1-500 µM). After a brief extraction with an organic solvent, the GSP contents in cottonseeds and cottonseed kernels from different provinces of China were determined successfully. The spiked recovery of GSP in cottonseed/cottonseed kernel samples was obtained as 97.88-105.80%, showing the reliability of the assay for GSP determination in real samples.
Assuntos
Gossipol , Limite de Detecção , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Gossipol/análise , Gossipol/química , Gossypium/química , Reprodutibilidade dos TestesRESUMO
Axial chirality of biaryls can generate varied bioactivities. Gossypol is a binaphthyl compound made by cotton plants. Of its two axially chiral isomers, (-)-gossypol is the bioactive form in mammals and has antispermatogenic activity, and its accumulation in cotton seeds poses health concerns. Here we identified two extracellular dirigent proteins (DIRs) from Gossypium hirsutum, GhDIR5 and GhDIR6, which impart the hemigossypol oxidative coupling into (-)- and (+)-gossypol, respectively. To reduce cotton seed toxicity, we disrupted GhDIR5 by genome editing, which eliminated (-)-gossypol but had no effects on other phytoalexins, including (+)-gossypol, that provide pest resistance. Reciprocal mutagenesis identified three residues responsible for enantioselectivity. The (-)-gossypol-forming DIRs emerged later than their enantiocomplementary counterparts, from tandem gene duplications that occurred shortly after the cotton genus diverged. Our study offers insight into how plants control enantiomeric ratios and how to selectively modify the chemical spectra of cotton plants and thereby improve crop quality.
Assuntos
Gossipol , Animais , Gossipol/toxicidade , Gossipol/análise , Gossipol/química , Edição de Genes , Gossypium/genética , Gossypium/metabolismo , Sementes/metabolismo , Mamíferos/genéticaRESUMO
BACKGROUND: Cottonseed oil is one of the most widely consumed cooking oils because of its high nutritional benefits and relatively low price. The present study evaluated the effects of tetramethoxy gossypol (TMG), a rarely reported degradation product of free gossypol produced in crudely extracted cottonseed oil, on the metabolic responses of liver, heart, spleen, kidney and lung tissues in rats using proton nuclear magnetic resonance (1 H NMR) spectroscopy combined with chemometric and bioinformatics techniques. RESULTS: Endogenous low-molecular-weight metabolites in rat liver, heart, spleen, kidney and lung tissues were profiled by 1 H NMR spectroscopy. The unsupervised principal components analysis and the supervised orthogonal partial least squares discriminant analysis revealed that the metabolic profiles in liver samples were greatly changed after TMG administration. Twenty significantly changed liver metabolites were screened out and further evaluated by receiver operating characteristic curve analysis, which were closely related to amino acid, glutathione, energy and lipid metabolism. CONCLUSION: Concerning the potential chronic exposure to TMG in cottonseed oil and other cottonseed products, the cumulative effects of dietary TMG on tissues, especially the liver, should be noted when improving the quality control standard of cottonseed oil. © 2022 Society of Chemical Industry.
Assuntos
Óleo de Sementes de Algodão , Gossipol , Animais , Óleo de Sementes de Algodão/análise , Óleo de Sementes de Algodão/química , Óleo de Sementes de Algodão/farmacologia , Dieta , Gossipol/análise , Gossipol/química , Gossipol/farmacologia , Fígado , Espectroscopia de Ressonância Magnética , RatosRESUMO
Covering up to 2022Gossypol is a polyphenolic compound isolated from cottonseed. There are two optical enantiomers of gossypol, (-)-gossypol and (+)-gossypol. Gossypol exists as three different tautomers, aldehyde, ketone and lactol. Gossypol is toxic and provides a protective mechanism for cotton plants against pests. Gossypol was used as a male contraceptive in China in the 1970s. It was eventually abandoned due to noticeable side effects, disruption of potassium uptake and incomplete reversibility. Gossypol has gained considerable research interest due to its attractive biological activities, especially antitumor and antivirus. Gossypol derivatives are prepared by a structural modification to reduce toxicity and improve their therapeutic effect. This review depicts the bioactivity and regulation mechanisms of gossypol and its derivatives as drug lead compounds, with emphasis on its antitumor mechanism. The design and synthesis of pharmacologically active derivatives based on the structure of gossypol, such as gossypol Schiff bases, apogossypol, gossypolone, are thoroughly discussed. This review aims to serve as a reference for gossypol-based drug discovery and drug design.
Assuntos
Gossipol , Desenho de Fármacos , Descoberta de Drogas , Gossipol/química , Gossipol/farmacologia , Humanos , Masculino , Bases de Schiff/química , EstereoisomerismoRESUMO
Common "glanded" (Gd) cottonseeds contain the toxic compound gossypol that restricts human consumption of the derived products. The "glandless" (Gl) cottonseeds of a new cotton variety, in contrast, show a trace gossypol content, indicating the great potential of cottonseed for agro-food applications. This work comparatively evaluated the chemical composition and thermogravimetric behaviors of the two types of cottonseed kernels. In contrast to the high gossypol content (3.75 g kg-1) observed in Gd kernels, the gossypol level detected in Gl kernels was only 0.06 g kg-1, meeting the FDA's criteria as human food. While the gossypol gland dots in Gd kernels were visually observed, scanning electron microcopy was not able to distinguish the microstructural difference between ground Gd and Gl samples. Chemical analysis and Fourier transform infrared (FTIR) spectroscopy showed that Gl kernels and Gd kernels had similar chemical components and mineral contents, but the former was slightly higher in protein, starch, and phosphorus contents. Thermogravimetric (TG) processes of both kernels and their residues after hexane and ethanol extraction were based on three stages of drying, de-volatilization, and char formation. TG-FTIR analysis revealed apparent spectral differences between Gd and Gl samples, as well as between raw and extracted cottonseed kernel samples, indicating that some components in Gd kernels were more susceptible to thermal decomposition than Gl kernels. The TG and TG-FTIR observations suggested that the Gl kernels could be heat treated (e.g., frying and roasting) at an optimal temperature of 140-150 °C for food applications. On the other hand, optimal pyrolysis temperatures would be much higher (350-500 °C) for Gd cottonseed and its defatted residues for non-food bio-oil and biochar production. The findings from this research enhance the potential utilization of Gd and Gl cottonseed kernels for food applications.
Assuntos
Gossypium/química , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/química , Sementes/química , Gossipol/análise , Gossipol/química , Humanos , Extratos Vegetais/análise , Extratos Vegetais/química , Sementes/ultraestrutura , Análise Espectral , TermogravimetriaRESUMO
The effects of anti-inflammatory drug gossypol on osteoarthritis (OA) treatment were discussed in this paper. After identified using toluidine blue and immunofluorescence staining of type II collagen, chondrocytes from OA patients were treated with interleukin-1ß (IL-1ß), gossypol, and overexpressed connexin43 (CX43). In treated chondrocytes, according to MTT assay and flow cytometry, gossypol increased viability and reduced apoptosis of IL-1ß induced chondrocytes. Enzyme linked immunosorbent assay (ELISA) suggested that gossypol downregulated inflammatory tumor necrosis factor (TNF)-α level. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot confirmed that gossypol downregulated CX43, nuclear factor-kappa B (NF-κB) p65, TNF-α, toll like receptor 4 (TLR4), myeloid differentiation primary response gene 88 (MyD88) and interleukin-6 (IL-6) expressions. Besides, overexpressed CX43 reversed the effects of gossypol on viability, apoptosis, and expressions of factors related to TLR4/MyD88/NF-κB pathway of IL-1ß-induced chondrocytes. In conclusion, gossypol ameliorates IL-1ß-induced apoptosis and inflammation in chondrocytes by suppressing TLR4/MyD88/NF-κB pathway via downregulating CX43.
Assuntos
Apoptose , Condrócitos/patologia , Conexina 43/metabolismo , Gossipol/farmacologia , Inflamação/patologia , Interleucina-1beta/toxicidade , Fator 88 de Diferenciação Mieloide/metabolismo , Receptor 4 Toll-Like/metabolismo , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Regulação para Baixo/efeitos dos fármacos , Gossipol/química , Humanos , Interleucina-6/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Vascular endothelial growth factor (VEGF) plays an important role in chronic inflammation associated with several diseases. Many plant extracts have nutritional and healthy benefits by down-regulating VEGF expression, but there was no report on VEGF regulation by cottonseed extracts in any biological system. The objective was to investigate cell viability and VEGF expression regulated by gossypol and ethanol extracts using lipopolysaccharides (LPS) as a control. MTT, qPCR and immunoblotting techniques were used to monitor cell viability, VEGF mRNA and protein levels in mouse RAW264.7 macrophages. Gossypol dramatically reduced macrophage viability but cottonseed extracts and LPS exhibited minor effect on cell viability. VEGFb mRNA levels were approximately 40 fold of VEGFa in the macrophages. Gossypol increased VEGFa and VEGFb mRNA levels up to 27 and 4 fold, respectively, and increased VEGF protein. LPS increased VEGFa mRNA by sixfold but decreased VEGFb mRNA. LPS increased VEGF protein in 2-4 h but decreased in 8-24 h. Glanded seed extracts showed some stimulating effects on VEGF mRNA levels. Glandless seed coat extract showed increased VEGFb mRNA levels but its kernel extract reduced VEGF mRNA levels. This study demonstrated that gossypol and ethanol extracts differentially regulated cell viability and VEGF expression in mouse macrophages.
Assuntos
Gossypium/química , Gossipol/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Extratos Vegetais/farmacologia , Sementes/química , Fator A de Crescimento do Endotélio Vascular/genética , Sequência de Aminoácidos , Animais , Sobrevivência Celular/efeitos dos fármacos , Óleo de Sementes de Algodão , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Gossipol/química , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Extratos Vegetais/química , RNA Mensageiro/genética , Fator A de Crescimento do Endotélio Vascular/química , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Series of imidazo[1,2-a]pyridines designed from gossypol modification based on Groebke-Blackburn-Bienaymé reaction were discovered as potent Bcl-2 inhibitors. Compound 4 was found to display good anti-proliferative activities for 7 human cancer cell lines (0.33-1.7 µM) among them, which were better than separate gossypol and imidazopyridine moiety compounds. It was capable of suppressing antiapoptotic proteins Bcl-2 and Bcl-XL demonstrated by mechanism studies, and possible binding model was also illustrated by molecular modelling.
Assuntos
Antineoplásicos/farmacologia , Gossipol/química , Imidazóis/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Piridinas/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidazóis/química , Imidazóis/isolamento & purificação , Modelos Moleculares , Estrutura Molecular , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Piridinas/química , Piridinas/isolamento & purificação , Relação Estrutura-AtividadeRESUMO
Plant polyphenol gossypol has anticancer activities. This may increase cottonseed value by using gossypol as a health intervention agent. It is necessary to understand its molecular mechanisms before human consumption. The aim was to uncover the effects of gossypol on cell viability and gene expression in cancer cells. In this study, human colon cancer cells (COLO 225) were treated with gossypol. MTT assay showed significant inhibitory effect under high concentration and longtime treatment. We analyzed the expression of 55 genes at the mRNA level in the cells; many of them are regulated by gossypol or ZFP36/TTP in cancer cells. BCL2 mRNA was the most stable among the 55 mRNAs analyzed in human colon cancer cells. GAPDH and RPL32 mRNAs were not good qPCR references for the colon cancer cells. Gossypol decreased the mRNA levels of DGAT, GLUT, TTP, IL families and a number of previously reported genes. In particular, gossypol suppressed the expression of genes coding for CLAUDIN1, ELK1, FAS, GAPDH, IL2, IL8 and ZFAND5 mRNAs, but enhanced the expression of the gene coding for GLUT3 mRNA. The results showed that gossypol inhibited cell survival with decreased expression of a number of genes in the colon cancer cells.
Assuntos
Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Gossipol/farmacologia , Biomarcadores , Biomarcadores Tumorais , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Neoplasias do Colo/genética , Óleo de Sementes de Algodão/química , Relação Dose-Resposta a Droga , Regulação para Baixo , Genes Reporter , Gossipol/química , Humanos , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologiaRESUMO
To further study the structure-activity relationship of gossypol, hemigossypol (1) and its derivatives (2-23) were successfully designed via structure simplification and chemically synthesized. The anti-tobacco mosaic virus (TMV), fungicidal, and insecticidal activities of them were tested systematically. Most of these derivatives exhibited excellent anti-TMV activity. Furthermore, these compounds also exhibited broad-spectrum fungicidal activities against 14 kinds of phytopathogenic fungi. In particular, hemigossypol acid lactone (7) was stable in the air. In terms of biological activity, it not only showed anti-TMV activity (inhibitory rates of 70.3, 65.4 and 72.4% at 500 µg/mL for inactivation, curative, and protection activity in vivo, respectively) comparable to ningnanmycin but also exhibited higher insecticidal activity against mosquito larvae (60%/0.25 mg/kg) than the commercial species rotenone. None of hemigossypol and the tested derivatives showed antitumor activities.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antivirais/síntese química , Antivirais/farmacologia , Fungicidas Industriais/síntese química , Fungicidas Industriais/farmacologia , Inseticidas/síntese química , Inseticidas/farmacologia , Animais , Antineoplásicos/química , Antivirais/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Culicidae/efeitos dos fármacos , Culicidae/crescimento & desenvolvimento , Desenho de Fármacos , Fungos/efeitos dos fármacos , Fungos/crescimento & desenvolvimento , Fungicidas Industriais/química , Gossipol/química , Gossipol/farmacologia , Humanos , Inseticidas/química , Doenças das Plantas/microbiologia , Doenças das Plantas/virologia , Relação Estrutura-Atividade , Vírus do Mosaico do Tabaco/efeitos dos fármacosRESUMO
Human aspartate/asparagine-ß-hydroxylase (AspH) is a 2-oxoglutarate (2OG) dependent oxygenase that catalyses the hydroxylation of Asp/Asn-residues of epidermal growth factor-like domains (EGFDs). AspH is reported to be upregulated on the cell surface of invasive cancer cells in a manner distinguishing healthy from cancer cells. We report studies on the effect of small-molecule active pharmaceutical ingredients (APIs) of human cancer therapeutics on the catalytic activity of AspH using a high-throughput mass spectrometry (MS)-based inhibition assay. Human B-cell lymphoma-2 (Bcl-2)-protein inhibitors, including the (R)-enantiomer of the natural product gossypol, were observed to efficiently inhibit AspH, as does the antitumor antibiotic bleomycin A2. The results may help in the design of AspH inhibitors with the potential of increased selectivity compared to the previously identified Fe(II)-chelating or 2OG-competitive inhibitors. With regard to the clinical use of bleomycin A2 and of the Bcl-2 inhibitor venetoclax, the results suggest that possible side-effects mediated through the inhibition of AspH and other 2OG oxygenases should be considered.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Bleomicina/farmacologia , Inibidores Enzimáticos/farmacologia , Gossipol/farmacologia , Oxigenases de Função Mista/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Antibióticos Antineoplásicos/química , Bleomicina/química , Relação Dose-Resposta a Droga , Composição de Medicamentos , Inibidores Enzimáticos/química , Gossipol/química , Humanos , Oxigenases de Função Mista/isolamento & purificação , Oxigenases de Função Mista/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-AtividadeRESUMO
In this work, two new chitosan-Schiff base derivatives (HCS-GSP and LCS-GSP) were synthesized by the condensation reaction of high molecular weight chitosan (HCS) and low molecular weight chitosan (LCS) with (-)-gossypol (GSP), respectively. For this purpose, racemic gossypol was isolated from cotton seeds and it was further enantiomerically purified by diastereomeric resolution technique using l-tryptophan methyl ester hydrochloride. Then, chitosan polymers were derivatized with (-)-gossypol by the condensation reaction. The isolated and synthesized coumpounds were characterized by physical measurements and spectroscopic methods (elemental analysis C,H,N, Uv-vis, FT-IR, 1H&13C NMR and TG/DTG/DTA). The antioxidant activity of high molecular weight chitosan (HCS), low molecular weight chitosan (LCS) and their gossypol derivatives was evaluated as radical scavengers against 1,1-diphenyl-2-picrylhydrazyl radicals (DPPH). The results showed that both of the chitosan-gossypol derivatives (HCS-GSP and LCS-GSP) had a better ability to scavenging DPPH radical (IC50, 12 µg/mL and 16 µg/mL, respectively) than its unmodified chitosan.
Assuntos
Antioxidantes/farmacologia , Compostos de Bifenilo/antagonistas & inibidores , Quitosana/farmacologia , Gossipol/farmacologia , Picratos/antagonistas & inibidores , Antioxidantes/síntese química , Antioxidantes/química , Quitosana/química , Gossipol/química , Conformação Molecular , Bases de Schiff/química , Bases de Schiff/farmacologiaRESUMO
Cullin-RING E3 ligase (CRL) is the largest family of E3 ubiquitin ligase, responsible for ubiquitylation of â¼20% of cellular proteins. CRL plays an important role in many biological processes, particularly in cancers due to abnormal activation. CRL activation requires neddylation, an enzymatic cascade transferring small ubiquitin-like protein NEDD8 to a conserved lysine residue on cullin proteins. Recent studies have validated that neddylation is an attractive anticancer target. In this study, we report the establishment of an Alpha-Screen-based high throughput screen (HTS) assay for in vitro CUL5 neddylation, and screened a library of 17,000 compounds including FDA approved drugs, natural products and synthetic drug-like small-molecule compounds. Gossypol, a natural compound derived from cotton seed, was identified as an inhibitor of cullin neddylation. Biochemical studies showed that gossypol blocked neddylation of both CUL5 and CUL1 through direct binding to SAG-CUL5 or RBX1-CUL1 complex, and CUL5-H572 plays a key role for gossypol binding. On cellular level, gossypol inhibited cullin neddylation in a variety of cancer cell lines and selectively caused accumulation of NOXA and MCL1, the substrates of CUL5 and CUL1, respectively, in multiple cancer cell lines. Combination of gossypol with specific MCL1 inhibitor synergistically suppress growth of human cancer cells. Our study revealed a previously unknown anti-cancer mechanism of gossypol with potential to develop a new class of neddylation inhibitors.
Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Transporte/metabolismo , Proteínas Culina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Gossipol/farmacologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas Supressoras de Tumor/metabolismo , Linhagem Celular Tumoral , Anticoncepcionais Masculinos , Proteínas Culina/genética , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Gossipol/química , Ensaios de Triagem em Larga Escala , Humanos , Modelos Biológicos , Modelos Moleculares , Estrutura Molecular , Complexos Multiproteicos , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Tumor-targeted drug delivery is highly important for improving chemotherapy, as it reduces the dose of cytotoxic agents and minimizes the death of healthy tissues. Towards this goal, a conjugate was synthesized of gossypol and a MCF-7 cancer cell specific CPP (cell penetrating peptide), thus providing a selective drug delivery system. Utilizing the aldehyde moiety of gossypol, the tumor homing CPP RLYMRYYSPTTRRYG was attached through a semi-labile imine linker, which was cleaved in a traceless fashion under aqueous conditions and had a half-life of approximately 10â hours. The conjugate killed MCF-7 cells to a significantly greater extent than HeLa cells or healthy fibroblasts.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Peptídeos Penetradores de Células/química , Gossipol/química , Gossipol/farmacologia , Aldeídos/química , Sequência de Aminoácidos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Fibroblastos/citologia , Células HeLa , Humanos , Iminas/química , Células MCF-7 , Tiazolidinas/químicaRESUMO
Zika virus (ZIKV) infection during pregnancy leads to severe congenital Zika syndrome, which includes microcephaly and other neurological malformations. No therapeutic agents have, so far, been approved for the treatment of ZIKV infection in humans; as such, there is a need for a continuous effort to develop effective and safe antiviral drugs to treat ZIKV-caused diseases. After screening a natural product library, we have herein identified four natural products with anti-ZIKV activity in Vero E6 cells, including gossypol, curcumin, digitonin, and conessine. Except for curcumin, the other three natural products have not been reported before to have anti-ZIKV activity. Among them, gossypol exhibited the strongest inhibitory activity against almost all 10 ZIKV strains tested, including six recent epidemic human strains. The mechanistic study indicated that gossypol could neutralize ZIKV infection by targeting the envelope protein domain III (EDIII) of ZIKV. In contrast, the other natural products inhibited ZIKV infection by targeting the host cell or cell-associated entry and replication stages of ZIKV. A combination of gossypol with any of the three natural products identified in this study, as well as with bortezomib, a previously reported anti-ZIKV compound, exhibited significant combinatorial inhibitory effects against three ZIKV human strains tested. Importantly, gossypol also demonstrated marked potency against all four serotypes of dengue virus (DENV) human strains in vitro. Taken together, this study indicates the potential for further development of these natural products, particularly gossypol, as the lead compound or broad-spectrum inhibitors against ZIKV and other flaviviruses, such as DENV.
Assuntos
Antivirais/farmacologia , Produtos Biológicos/farmacologia , Zika virus/efeitos dos fármacos , Alcaloides/química , Alcaloides/farmacologia , Animais , Antivirais/química , Produtos Biológicos/química , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Curcumina/química , Curcumina/farmacologia , Vírus da Dengue/efeitos dos fármacos , Digitonina/química , Digitonina/farmacologia , Sinergismo Farmacológico , Gossipol/química , Gossipol/farmacologia , Humanos , Estrutura Molecular , Células Vero , Infecção por Zika virus/virologiaRESUMO
We have recently developed a one-pot process for simultaneous extraction and chemical modification (SECheM) on Cienfuegosia digitata, a Mauritanian Malvaceae called locally "Izide". On the basis of this innovative methodology that consisted of using ground plant roots as starting material in gossypol Schiff base semisynthesis, we now report how this concept can be used to access enantiomerically pure Schiff base atropisomer derivatives of gossypol in only two steps. This study has been envisioned since enantiomerically pure Schiff base atropisomer derivatives of gossypol are generally more potent biologically when compared to racemic gossypol Schiff bases.
Assuntos
Gossipol/síntese química , Plantas/química , Bases de Schiff/química , Gossipol/química , Análise Espectral/métodos , EstereoisomerismoRESUMO
To improve the tumor synergistic therapeutic effects of carrier-free dual-drug delivery systems and realize ultralow dose administration, we developed a tumor targeting and high-efficiency synergistic chemotherapy system (HA-Gn@DPGn NPs) based on polyvinyl alcohol (PVA) reinforced gossypolone (Gn) and doxorubicin (DOX) π-π stacking nanoparticles (DPGn NPs), in which PVA filled the gaps between Gn and DOX and bridged Gn and DOX tightly. Hyaluronic acid modifier hyaluronic acid-gossypolone (HA-Gn) was covered on the surface of DPGn NPs to form HA-Gn@DPGn NPs that procured active targeting properties. This system presented a spherical shape with a uniform hydrodynamic size of 87 ± 6.8 nm, a high drug loading of 80.31%, and high stability. FTIR and UV spectra demonstrated that HA-Gn was covered on the surface of the system and showed significant π-π stacking properties. A considerably low combination index of Gn and DOX (0.1862) was determined at an ultra-low dose of DOX under a Gn : DOX ratio of 50 : 1. HA-Gn@DPGn NPs also demonstrated excellent tumor synergistic therapeutic efficacy (TIR > 87%) at an ultralow dose of DOX and Gn. This system demonstrates high tumor comprehensive synergistic therapeutic efficacy at an ultralow drug dose with multiple favorable therapeutic characteristics, including negligible side effects, tumor targeting ability and thermal-responsive drug release, and thus has considerable potential for tumor synergistic therapy.
Assuntos
Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Gossipol/análogos & derivados , Nanopartículas/química , Álcool de Polivinil/química , Células 3T3 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Gossipol/química , Gossipol/farmacologia , Humanos , Ácido Hialurônico/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Microemulsions (MEs) have gained increasing interest as carriers of hydrophobic bioactives in the last decades. However, it is still difficult to control the uptake and the release of bioactives directly extracted from plants. In this study, modified ME nanodroplets (nano-sized self-assembled liquids, NSSLs) were employed as extraction medium of gossypol, a toxic component of cottonseed. Loading was performed using both pure gossypol, and gossypol obtained by extraction from cottonseed. We achieved two goals: i) remove gossypol from cottonseed to obtain cotton-oil free of gossypol; and ii) extract gossypol directly into a nano-delivery vehicle for biomedical purposes. Structural and dynamical information on the unloaded and gossypol-loaded NSSL systems were obtained by self-diffusion nuclear magnetic resonance, SD-NMR, and spin-probe electron paramagnetic resonance (EPR) studies. The results showed that NSSL formed fluid water-in-oil (W/O) nano domains at the lowest water contents; a more viscous bicontinuous structure at comparable oil and water contents, and, finally, oil-in-water (O/W, micellar-like) at the higher concentration of water. These micellar-like structures were more fluid at the external hydrated surface, as demonstrated by SD-NMR, while the lipidic region tested by EPR revealed an increasing packing. In all these structures, gossypol mainly localized in the lipophilic region close to the water interface. Overall, SD-NMR and EPR provided complementary information, helping to clarify the structural properties of NSSLs formed at different water contents and their ability to incorporate gossypol also directly from cottonseed-NSSL mixtures.