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1.
Nanotechnology ; 35(33)2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38701760

RESUMO

For the first time, this study shows the nanoarchitectonic process to obtain an acetogenin-enriched nanosystem (AuNPs-Ac) using an aqueous extract fromAnnona cherimolaMill (ACM) composed of gold nanoparticles embedded in an organic matrix that acts as stabilizing agent and presents anti-inflammatory activity and cytotoxical effect against HepG2 cell line, promoting apoptosis. The synthesis of AuNPs-Ac was confirmed by x-ray diffraction analysis, showing metallic gold as the only phase, and the scanning transmission microscope showed an organic cap covering the AuNPs-Ac. Fourier-transformed infrared suggests that the organic cap comprises a combination of different annonaceous acetogenins, alkaloids, and phenols by the presence of bands corresponding to aromatic rings and hydroxyl groups. High-Performance Liquid Chromatography has demonstrated the presence of annonacin, a potent acetogenin, in the extract of ACM. Anin vitroanti-inflammatory activity of the extract of ACM and the AuNPs-Ac was performed using the albumin denaturation method, showing a nonlinear response, which is better than sodium diclofenac salt in a wide range of concentrations that goes from 200 to 400µg ml-1with both samples. The viability assay was studied using trypan blue, treating IMR90 and HepG2 at different concentrations of AuNPs-Ac. The results defined a median lethal dose of 800µg ml-1against HepG2 through apoptosis according to the ratio of caspase-cleaved 9/alpha-tubulin evaluated. It was also demonstrated that the nanosystem presents a higher cytotoxic effect on the HepG2 cell line than in IMR90, suggesting a targeted mechanism. In addition, the nanosystem performs better than using only the extract of ACM in the anti-inflammatory or antiproliferative test, attributed to their higher surface area.


Assuntos
Acetogeninas , Anti-Inflamatórios , Apoptose , Ouro , Nanopartículas Metálicas , Extratos Vegetais , Humanos , Acetogeninas/farmacologia , Acetogeninas/química , Células Hep G2 , Apoptose/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Nanopartículas Metálicas/química , Ouro/química , Ouro/farmacologia , Sobrevivência Celular/efeitos dos fármacos
2.
Drug Deliv ; 31(1): 2324716, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38555735

RESUMO

Annonaceous acetogenins (ACGs) have potent anti-tumor activity, and the problems of their low solubility, hemolysis, and in vivo delivery have been solved by encapsulation into nanoparticles. However, the high toxicity still limits their application in clinic. In this paper, the co-delivery strategy was tried to enhance the in vivo anti-tumor efficacy and reduce the toxic effects of ACGs. Ginsenoside Rh2, a naturally derived biologically active compound, which was reported to have synergistic effect with paclitaxel, was selected to co-deliver with ACGs. And due to its similarity with cholesterol in chemical structure, the co-loading liposomes, (ACGs + Rh2)-Lipo, were successfully constructed using Rh2 instead of cholesterol as the membrane material. The obtained (ACGs + Rh2)-Lipo and ACGs-Lipo had similar mean particle size (about 80 nm), similar encapsulation efficiency (EE, about 97%) and good stability. The MTS assay indicated that (ACGs + Rh2)-Lipo had stronger toxicity in vitro. In the in vivo study, in contrast to ACGs-Lipo, (ACGs + Rh2)-Lipo demonstrated an improved tumor targetability (3.3-fold in relative tumor targeting index) and significantly enhanced the antitumor efficacy (tumor inhibition rate, 72.9 ± 5.4% vs. 60.5 ± 5.4%, p < .05). The body weight change, liver index, and spleen index of tumor-bearing mice showed that Rh2 can attenuate the side effects of ACGs themselves. In conclusion, (ACGs + Rh2)-Lipo not only alleviated the toxicity of ACGs to the organism, but also enhanced their anti-tumor activity, which is expected to break through their bottleneck.


Assuntos
Acetogeninas , Ginsenosídeos , Glioma , Camundongos , Animais , Acetogeninas/farmacologia , Acetogeninas/química , Lipossomos , Glioma/tratamento farmacológico , Colesterol
3.
Mar Drugs ; 22(2)2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38393023

RESUMO

Mycalin A (MA) is a polybrominated C-15 acetogenin isolated from the marine sponge Mycale rotalis. Since this substance displays a strong antiproliferative bioactivity towards some tumour cells, we have now directed our studies towards the elucidation of the MA interactome through functional proteomic approaches, (DARTS and t-LIP-MS). DARTS experiments were performed on Hela cell lysates with the purpose of identifying MA main target protein(s); t-LiP-MS was then applied for an in-depth investigation of the MA-target protein interaction. Both these techniques exploit limited proteolysis coupled with MS analysis. To corroborate LiP data, molecular docking studies were performed on the complexes. Finally, biological and SPR analysis were conducted to explore the effect of the binding. Mortalin (GRP75) was identified as the MA's main interactor. This protein belongs to the Hsp70 family and has garnered significant attention due to its involvement in certain forms of cancer. Specifically, its overexpression in cancer cells appears to hinder the pro-apoptotic function of p53, one of its client proteins, because it becomes sequestered in the cytoplasm. Our research, therefore, has been focused on the possibility that MA might prevent this sequestration, promoting the re-localization of p53 to the nucleus and facilitating the apoptosis of tumor cells.


Assuntos
Acetogeninas , Proteínas de Choque Térmico HSP70 , Poríferos , Animais , Humanos , Acetogeninas/farmacologia , Poríferos/metabolismo , Simulação de Acoplamento Molecular , Células HeLa , Proteômica , Proteína Supressora de Tumor p53/metabolismo
4.
J Nat Prod ; 87(1): 14-27, 2024 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-38233978

RESUMO

Sorafenib was first approved as the standard treatment for advanced hepatocellular carcinoma (HCC). Despite providing an advantage in terms of patient survival, sorafenib has shown poor clinical efficacy and severe side effects after long-term treatment. Thus, combination treatment is a potential way to increase the effectiveness and reduce the dose-limiting toxicity of sorafenib. Extracts of the seeds of Annona montana have shown synergistic antitumor activity with sorafenib, and seven annonaceous acetogenins, including three new acetogenins, muricin P (2), muricin Q (3), and muricin R (4), were isolated from the extracts by bioguided fractionation and showed synergy with sorafenib. The structures of these compounds were determined using spectroscopic and chemical methods. Annonacin (1) and muricin P (2), which reduced intracellular ATP levels and promoted apoptosis, exhibited synergistic cytotoxicity with sorafenib in vitro. In vivo, annonacin (1) displayed synergistic antitumor activity by promoting tumor cell apoptosis. Moreover, the potential mechanism of annonacin (1) was predicted by transcriptomic analysis, which suggested that SLC33A1 is a potential target in HCC. Annonacin (1) might be a novel candidate for combination therapy with sorafenib against advanced HCC.


Assuntos
Antineoplásicos Fitogênicos , Carcinoma Hepatocelular , Furanos , Lactonas , Neoplasias Hepáticas , Humanos , Acetogeninas/farmacologia , Acetogeninas/química , Sorafenibe/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Estrutura Molecular , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Neoplasias Hepáticas/tratamento farmacológico , Linhagem Celular Tumoral , Apoptose
5.
J Nat Prod ; 87(2): 207-216, 2024 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-38237151

RESUMO

Four new adjacent bis-tetrahydrofuran acetogenins, bullacin C (7), uvarirufin (9), and uvariasolins III (12) and IV (13), along with 11 known acetogenins, were isolated from the stem of Uvaria rufa. Their structures were elucidated based on spectroscopic data analysis, including 1D and 2D NMR, HRESIMS, and MALDI-MS/MS of the lithium adducts. Absolute configurations were assigned using Mosher ester analysis and ECD measurements. Uvarirufin (9) possesses a unique C-39 skeleton among acetogenins. Most tested acetogenins exhibited cytotoxicity against human cancer cell lines (HCT 116, 22Rv1, MDA-MB-435, OVCAR3). Squamocin (8) and uvarirufin (9) were found to be the most potent, with an IC50 value of 1.2 µM for both in HCT 116 colon cancer cells. Additionally, a new application of Dragendorff's reagent is proposed herein for the TLC detection of acetogenins.


Assuntos
Antineoplásicos , Neoplasias Ovarianas , Uvaria , Feminino , Humanos , Acetogeninas/farmacologia , Acetogeninas/química , Apoptose , Linhagem Celular Tumoral , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Espectrometria de Massas em Tandem , Uvaria/química
6.
J Ethnopharmacol ; 322: 117598, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38113989

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Multi-Drug Resistance (MDR), mediated by P-glycoprotein (P-gp) is one of the barriers to successful chemotherapy in colon cancer patients. Annona muricata L. (A.muricata), commonly known as soursop/Graviola, is a medicinal plant that has been traditionally used in treating diverse diseases including cancer. Phytochemicals of A.muricata (Annonaceous Acetogenins-AGEs) have been well-reported for their anti-cancer effects on various cancers. AIM OF THE STUDY: The study aimed to examine the effect of AGEs in reversing MDR in colorectal cancer cells. METHODS: Based on molecular docking and molecular dynamic simulation, the stability of annonacin upon P-gp was investigated. Further in vitro studies were carried in oxaliplatin-resistant human colon cancer cells (SW480R) to study the biological effect of annonacin, in reversing drug resistance in these cells. RESULTS: Molecular docking and simulation studies have indicated that annonacin stably interacted at the drug binding site of P-gp. In vitro analysis showed that annonacin was able to significantly reduce the expression of P-gp by 2.56 folds. It also induced apoptosis in the drug-resistant colon cancer cells. Moreover, the intracellular accumulation of P-gp substrate (calcein-AM) was observed to increase in resistant cells upon treatment with annonacin. CONCLUSION: Our findings suggest that annonacin could inhibit the efflux of chemotherapeutic drugs mediated by P-gp and thereby help in reversing MDR in colon cancer cells. Further in vivo studies are required to decipher the underlying mechanism of annonacin in treating MDR cancers.


Assuntos
Annona , Neoplasias do Colo , Furanos , Lactonas , Humanos , Transportadores de Cassetes de Ligação de ATP/metabolismo , Annona/química , Acetogeninas/farmacologia , Simulação de Acoplamento Molecular , Resistência a Múltiplos Medicamentos , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Neoplasias do Colo/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos
7.
Molecules ; 28(19)2023 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-37836749

RESUMO

The aim of this study was to evaluate, for the first time, the antiproliferative, apoptotic and diminishing effects of the anchored growth-independent capacity of an ethanol macerate extract from the Annona cherimola seed (EMCHS) in the human gastric cancer cell line SNU-1. The cells treated with EMCHS (20 µg/mL) significantly reduced the capacity to form clones of the tumor cell. Moreover, 50 µg/mL of EMCHS extract induced apoptosis, as was shown by the Annexin-V assay. UHPLC-MS/MS analysis detected two acetogenins (Annonacinone and Annonacin) in the EMCHS, which could be largely responsible for its selective antiproliferative effect. The identification of fatty acids by GC-FID showed the presence of eight fatty acids, among which was, oleic acid, which has recognized activity as an adjuvant in antitumor treatments. Taken together, our results indicate that the EMCHS seems promising for use as a natural therapy against gastric cancer disease.


Assuntos
Annona , Carcinoma , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Espectrometria de Massas em Tandem , Extratos Vegetais/farmacologia , Linhagem Celular , Apoptose , Sementes , Acetogeninas/farmacologia , Ácidos Graxos/farmacologia , Linhagem Celular Tumoral
8.
Molecules ; 28(15)2023 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-37570713

RESUMO

Annona muricate is a tropical plant that is well-known for its edible fruit of therapeutic interest. LCMS/MS analyses were applied to identify phytoconstituents of the ethanolic extract of the whole fruits and the aqueous extract of the edible fruit part, in addition to the investigation of their anticancer properties against Ehrlich ascites carcinoma (EAC) in male albino mice. LCMS/MS analyses resulted in the identification of 388 components, representing a wide array of classes of compounds, including acetogenins as the major constituents, alkaloids, flavonoids, and phenolics. Among them, four compounds were tentatively characterized as new compounds (1-4), including an acid derivative, protocatechuic-coumaroyl-quinic acid (1), and three flavonoid derivatives, dihydromyricetin galloyl hexoside (2), apigenin gallate (3), and dihydromyricetin hexouronic acid hexoside (4). Induction with EAC cells resulted in abnormalities in the gene expression of pro-apoptotic genes (Bax and caspase-3) and anti-apoptotic gene (Bcl-2) in the tumor mass. Moreover, microscopic, histopathological, and immune-histochemical examinations of the tumor mass and liver tissues exhibited extensive growth of malignant Ehrlich carcinoma cells and marked hydropic degeneration of hepatocytes and infiltration by tumor cells to liver tissue with marked inflammatory reaction. These abnormalities were markedly ameliorated aftertreatment of EAC mice with A. muricata extracts.


Assuntos
Annona , Camundongos , Animais , Annona/química , Acetogeninas/química , Extratos Vegetais/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/metabolismo
9.
J Pharm Pharmacol ; 75(10): 1357-1365, 2023 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-37440207

RESUMO

OBJECTIVES: Annona muricata, also known as graviola, is traditionally used for the treatment of a range of disorders including cancer. Interest in A. muricata use has increased in recent years. This study investigated the quality and safety of a selection of commercially available A. muricata leaf products. METHODS: Seven commercially available products were purchased via online shopping sites. Each product was assessed for quality indicators including weight variation, quantification of the bioactive constituent annonacin, presence of annonaceous acetogenins and contaminants. The samples were evaluated by thin-layer chromatography, high-performance liquid chromatography, liquid chromatography-mass spectroscopy, low-resolution mass spectrometry and nuclear magnetic resonance spectroscopy. Microbial analysis was carried out in accordance with the British Pharmacopoeia. Heavy metals were analysed by inductive coupled plasma mass spectrometry. KEY FINDINGS: Of the seven products analysed, one product contained less than half of the content stated on the label. The labelled dosage recommendation varied between products. There was a high variation in annonacin concentration (1.05-3.09 mg/g) and the presence of annonaceous acetogenins. One of the products was found to have a total aerobic microbial count above the United States Pharmacopoeia limit. CONCLUSIONS: The variation in the indicators of quality and safety of commercially available A. muricata leaf products tested have implications for clinicians and people living with cancer who use these herbal products.


Assuntos
Annona , Neoplasias , Humanos , Acetogeninas/análise , Acetogeninas/química , Annona/química , Folhas de Planta/química , Extratos Vegetais/análise
10.
Mar Drugs ; 21(6)2023 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-37367643

RESUMO

Studies estimate that nearly 2 million new cases of gastric cancer will occur worldwide during the next two decades, which will increase mortality associated with cancer and the demand for new treatments. Marine algae of the Laurencia genus have secondary metabolites known for their cytotoxic action, such as terpenes and acetogenins. The species Laurencia obtusa has demonstrated cytotoxicity against many types of tumors in previous analyses. In this study, we determined the structure of terpenes, acetogenins, and one fatty acid of Laurencia using mass spectrometry (ESI-FT-ICR/MS). In vitro cytotoxicity assays were performed with adenocarcinoma gastric cells (AGS) to select the most cytotoxic fraction of the crude extract of L. obtusa. The Hex:AcOEt fraction was the most cytotoxic, with IC50 9.23 µg/mL. The selectivity index of 15.56 shows that the Hex:AcOEt fraction is selective to cancer cells. Compounds obtained from L. obtusa were tested by the analysis of crystallographic complexes. Molecular docking calculations on the active site of the HIF-2α protein showed the highest affinity for sesquiterpene chermesiterpenoid B, identified from HEX:AcOEt fraction, reaching a score of 65.9. The results indicate that L. obtusa presents potential compounds to be used in the treatment of neoplasms, such as gastric adenocarcinoma.


Assuntos
Antineoplásicos , Laurencia , Sesquiterpenos , Laurencia/química , Acetogeninas/química , Simulação de Acoplamento Molecular , Terpenos/metabolismo , Sesquiterpenos/farmacologia , Sesquiterpenos/química , Antineoplásicos/farmacologia , Antineoplásicos/metabolismo
11.
Sci Rep ; 13(1): 10254, 2023 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-37355735

RESUMO

Natural products are a promising source of new compounds with a wide spectrum of pharmacological properties, including antiprotozoal activities. Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is one of several neglected tropical diseases with reduced options for treatment, which presents limitations such as toxicity and ineffectiveness in the chronic stage of the disease. Aiming to investigate the Brazilian flora for the discovery of new anti-T. cruzi compounds, the MeOH extract from Porcelia macrocarpa R.E. Fries (Annonaceae) fruit peels displayed potent activity against trypomastigotes and intracellular amastigotes and was subjected to bioactivity-guided fractionation. Using different chromatographic steps, a fraction composed of a mixture of four new chemically related acetogenins was obtained. The compounds were characterized as (2S*,3R*,4R*)-3-hydroxy-4-methyl-2-(n-octadeca-13',17'-dien-11'-inil)butanolide (1), (2S*,3R*,4R*)-3-hydroxy-4-methyl-2-(n-eicosa-13',19'-dien-11'-inil)butanolide (2), (2S*,3R*,4R*)-3-hydroxy-4-methyl-2-(n-octadec-13'-en-11'-inil)butanolide (3), and (2S*,3R*,4R*)-3-hydroxy-4-methyl-2-(n-eicosa-13'-en-11'-inil)butanolide (4) by NMR analysis and UHPLC/ESI-HRMS data. The mixture of compounds 1-4, displayed an EC50 of 4.9 and 2.5 µg/mL against trypomastigote and amastigote forms of T. cruzi, respectively, similar to the standard drug benznidazole (EC50 of 4.8 and 1.4 µg/mL). Additionally, the mixture of compounds 1-4 displayed no mammalian toxicity for murine fibroblasts (CC50 > 200 µg/mL), resulting in a SI > 40.8 and > 83.3 against trypomastigotes and amastigotes, respectively. Based on these results, the mechanism of action of this bioactive fraction was investigated. After a short-time incubation with the trypomastigotes, no alterations in the cell membrane permeability were observed. However, it was verified a decrease in the intracellular calcium of the parasites, without significant pH variations of the acidocalcisomes. The intracellular damages were followed by an upregulation of the reactive oxygen species and ATP, but no depolarization effects were observed in the mitochondrial membrane potential. These data suggest that the mixture of compounds 1-4 caused an irreversible oxidative stress in the parasites, leading to death. If adequately studied, these acetogenins can open new insights for the discovery of new routes of death in T. cruzi.


Assuntos
Annonaceae , Doença de Chagas , Tripanossomicidas , Trypanosoma cruzi , Animais , Camundongos , Acetogeninas/farmacologia , Acetogeninas/uso terapêutico , Cálcio/metabolismo , Doença de Chagas/tratamento farmacológico , Tripanossomicidas/metabolismo
12.
Molecules ; 28(9)2023 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-37175219

RESUMO

Glioblastoma (GBM) is an incurable primary brain tumor with a poor prognosis. Resection, radiation therapy, and temozolomide (TMZ) are insufficient to increase survival, making the treatment limited. Thus, the search for more effective and specific treatments is essential, making plants a promising source for elucidating new anti-glioblastoma compounds. Accordingly, this study investigated the effects of four fractions of hexane and ethyl acetate extract of Annona coriacea Mart., enriched with acetogenins, against GBM cell lines. All four fractions were selectively cytotoxic to GBM cells when compared to TMZ. Moreover, A. coriacea fractions delayed cell migration; reduced cytoplasmic projections, the metalloproteinase 2 (MMP-2) activity; and induced morphological changes characteristic of necroptosis, possibly correlated with the increase in receptor-interacting protein kinase 1 and 3 (RIP-1 and RIP-3), apoptosis-inducing factor (AIF), and the non-activation of cleaved caspase 8. The present findings reinforce that fractions of A. coriacea Mart. should be considered for more studies focusing treatment of GBM.


Assuntos
Annona , Neoplasias Encefálicas , Glioblastoma , Humanos , Metaloproteinase 2 da Matriz , Acetogeninas/farmacologia , Necroptose , Glioblastoma/metabolismo , Temozolomida/farmacologia , Linhagem Celular Tumoral , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Resistencia a Medicamentos Antineoplásicos , Apoptose
13.
Molecules ; 28(7)2023 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-37049648

RESUMO

The high potency of the tetrahydrofuran-containing acetogenins (THF-ACGs) against a broad range of human cancer cell lines has stimulated interest in structurally simpler mimetics. In this context, we have previously reported THF-ACG mimetics in which the THF and butenolide moieties of a mono-THF-ACG were replaced with carbohydrate and thiophene residues, respectively. In the present study, towards the targeting of these carbohydrate analogues to prostate cancer (PCa), we synthesized prodrugs in which a parent thiophene or butenolide congener was conjugated through a self-immolative linker to 2-[3-(1,3-dicarboxypropyl)ureido] pentanedioic acid (DUPA), a highly specific ligand for prostate-specific membrane antigen (PSMA), which is overexpressed on prostate tumors. Both prodrugs were found to be more active against receptor positive LNCaP than receptor-negative PC-3 cells, with 2.5 and 12 times greater selectivity for the more potent thiophene analog and the less active butenolide congener, respectively. This selectivity for LNCaP over PC-3 contrasted with the behavior of the parent drugs, which showed similar or significantly higher activity for PC-3 compared to LNCaP. These data support the notion that higher activity of these DUPA-derived prodrugs against LNCaP cells is connected to their binding to PSMA and suggest that the conjugation of PSMA ligands to this family of cytotoxic agents may be effective for targeting them to PCa.


Assuntos
Pró-Fármacos , Neoplasias da Próstata , Masculino , Humanos , Acetogeninas/farmacologia , Antígenos de Superfície/metabolismo , Neoplasias da Próstata/patologia , Furanos/farmacologia , Carboidratos , Tiofenos , Linhagem Celular Tumoral
14.
Int J Mol Sci ; 24(3)2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36768615

RESUMO

Annonaceae is a large family composed of more than 119 genera and more than 2500 species that are distributed in both tropical and subtropical areas. The Annona genus is a member of Annonaceae family, which encompasses about 175 species, most of which are native to Brazil and tropical America. This plant is commonly found on tropical and subtropical continents. Annona atemoya is a commercially important hybrid of A. squamosa and A. cherimola. Phytochemical investigations of A. atemoya leaves, fruit, and seeds have been conducted in limited studies. The purpose of this study was to investigate the constituents of the leaves, fruit pulp, and seeds of A. atemoya because few studies have reported their constituents. Annonaceous acetogenins were identified in the leaves and pulp of A. atemoya for the first time. Twenty compounds were identified: sixteen were acetogenins and four were alkaloids. Additionally, two compounds were isolated, and their structures were confirmed by spectroscopic analysis and compared with the results of previous studies. The concentration of acetogenins in the pulp was very low compared with that in the leaves, whereas the seeds were found to contain the highest concentrations and greatest diversity of compounds.


Assuntos
Alcaloides , Annona , Acetogeninas/química , Annona/química , Alcaloides/análise , Extratos Vegetais/química , Sementes/química
15.
Nutrients ; 15(2)2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36678273

RESUMO

Graviola (Annunona muricata L.), a plant growing in tropical regions, has many names and a range of ethnomedicinal uses. The leaves are used to treat insomnia, diabetes, cystitis, and headaches, the crushed seeds have anthelmintic properties, and the fruits are used in the preparation of ice creams, candy, syrups, shakes, and other beverages. The key active components are believed to be annonaceous acetogenins, with more than 100 such compounds having been isolated from A. muricata. The plant is also a source of a range of phenolic compounds, essential oils, alkaloids, flavonol triglycosides, and megastigmanes, together with various minerals, including Mg, Fe, Cu, K, and Ca. Its key phenolic compounds are rutin, kaempferol, and quercetin. This paper provides an overview of the current state of knowledge about the antioxidant properties of various graviola organs and their major constituents, based on a review of various electronic databases. However, few findings have been obtained from clinical trials, and few in vitro and animal studies suggest that graviola preparations have antioxidant properties; as such, the antioxidant potential of graviola, and its safety, remain unclear.


Assuntos
Annona , Anti-Infecciosos , Antineoplásicos Fitogênicos , Animais , Antioxidantes/farmacologia , Acetogeninas , Extratos Vegetais/farmacologia
16.
J Biomol Struct Dyn ; 41(3): 821-832, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-34907862

RESUMO

Multi drug resistance (MDR) in tumor might be caused leading to the overexpression of transporters, such as ATP-binding cassette sub-family B member 1 (ABCB1). A combination of non-toxic and potent ABC inhibitors along with conventional anti-cancer drugs is needed to reverse MDR in tumors. A variety of phytochemicals have been previously shown to reverse MDR. Annonaceous acetogenins (AAs) with C35/C37 long-chain fatty acids were reported for their anti-tumor activity, however, their effect on reversing MDR is not yet investigated. We aimed to investigate some selective AAs against the B1 subtype of ABC transporter using computational studies. Various modules of Maestro software were utilized for our in-silico analysis. Few well-characterized AAs were screened for their drug-likeness properties and tested for binding affinity at ATP and drug binding sites of ABCB1 through molecular docking. The stability of the ligand-protein complex (lowest docking score) was then determined by a molecular dynamic (MD) simulation study. Out of 24 AAs, Annonacin A (-8.10 kcal/mol) and Annohexocin (-10.49 kcal/mol) docked with a greater binding affinity at the ATP binding site than the first-generation inhibitor of ABCB1 (Verapamil: -3.86 kcal/mol). MD simulation of Annonacin A: ABCB1 complex for 100 ns also indicated that Annonacin A would stably bind to the ATP binding site. We report that Annonacin A binds at a greater affinity with ABCB1 and might act as a potential drug lead to reverse MDR in tumor cells. Communicated by Ramaswamy H. Sarma.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Acetogeninas/farmacologia , Simulação de Dinâmica Molecular , Simulação de Acoplamento Molecular , Resistencia a Medicamentos Antineoplásicos , Resistência a Múltiplos Medicamentos , Neoplasias/tratamento farmacológico , Trifosfato de Adenosina , Nucleotídeos/metabolismo , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/uso terapêutico
17.
J Asian Nat Prod Res ; 25(7): 704-710, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36200370

RESUMO

Determining the structures of new natural products from marine species not only enriches our understanding of the diverse chemistry of these species, but can also lead to the discovery of compounds with novel and/or important biological activities. Herein, we describe the isolation of isomaneonene C (1), a new halogenated C15 acetogenin, and three known compounds, α-snyderol (2), cis-maneonene D (3), and isomaneonene B (4), from the organic extract obtained from the red alga Laurencia cf. mariannensis collected from Iheya Island, Okinawa, Japan. The structures of these secondary metabolites were elucidated spectroscopically. All compounds were inactive at 30 µg/disc against methicillin-resistant Staphylococcus aureus (MRSA) in combination treatment with a ß-lactam drug, meropenem.


Assuntos
Laurencia , Staphylococcus aureus Resistente à Meticilina , Laurencia/química , Estrutura Molecular , Acetogeninas/farmacologia , Acetogeninas/química
18.
Molecules ; 27(23)2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36500310

RESUMO

The Annonaceae are an old family of flowering plants belonging to the order Magnoliales, distributed mainly in tropical regions. Numerous Annonaceae species find ethnobotanical use for curing a broad range of diseases, among them cancer and infections by diverse pathogens. Hence, bioactive natural products from Annonaceae have received considerable interest in drug development. Beyond cytotoxic acetogenins, unique aporphine-derived polycyclic aromatic alkaloids are characteristic constituents of Annonaceae. Among them are unique tri- and tetracyclic aromatic alkaloids like azafluorenones, diazafluoranthenes, azaanthracenes, and azaoxoaporphines. The complex substitution pattern of these alkaloids represents a major challenge in structure elucidation of isolated natural products. Based on a broad spectrum of alkaloids available from our previous work, we present a GC-MS protocol for the identification of over 20 polycyclic aromatic alkaloids from Annonaceae. This collection of data will contribute to the future identification of the metabolite patterns of extracts from Annonaceae as an important source of novel bioactive secondary metabolites.


Assuntos
Alcaloides , Annonaceae , Produtos Biológicos , Annonaceae/química , Cromatografia Gasosa-Espectrometria de Massas , Alcaloides/química , Acetogeninas
19.
Chem Pharm Bull (Tokyo) ; 70(11): 823-826, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36328525

RESUMO

Here, we synthesized three acetogenin analogs containing pyrimidine moieties linked by amine bonds, which represent the skeleton structure of pyrimidifen, a mitochondrial complex I-inhibiting insecticide. Replacing the pyrimidine moiety linked by the amine bond remarkably enhanced growth-inhibitory activity of the analogs against several human cancer cell lines. Moreover, these analogs selectively and potently inhibited the growth of these human cancer cell lines regardless of the pyrimidine substituents. Furthermore, COMPARE analyses suggested that these analogs inhibited cancer growth by inhibiting mitochondrial complex I. Our study provides insights into the design of acetogenin analogs as novel antitumor agents.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Acetogeninas , Aminas/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Pirimidinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Relação Estrutura-Atividade , Proliferação de Células , Estrutura Molecular
20.
Carbohydr Res ; 521: 108671, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36113243

RESUMO

The THF containing acetogenin 4-deoxyannonmontacin (4-DAN) has attracted interest for its potent cytotoxicity against a broad range of human tumor cell lines, and relatively simple structure. Herein is described the synthesis and cytotoxicity of C-10 epimers of 4-DAN and analogues thereof comprising carbohydrate and thiophene substitutes for the THF and butenolide moieties respectively. The key synthetic ploy was the union of THF and butenolide segments or their substitutes, via an alkene cross metathesis. The different analogues showed cytotoxicity in the low micromolar to nanomolar range against the human prostate cancer cell lines LNCaP and PC3. A relatively simple mannose-linked thiophene analog was found to be similar in activity to 4-DAN.


Assuntos
Antineoplásicos , Neoplasias da Próstata , 4-Butirolactona/análogos & derivados , Acetogeninas/farmacologia , Alcenos/química , Antineoplásicos/química , Carboidratos , Linhagem Celular Tumoral , Humanos , Masculino , Manose , Neoplasias da Próstata/tratamento farmacológico , Tiofenos , Tricotecenos
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