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1.
Molecules ; 27(11)2022 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-35684400

RESUMO

In 1789, the Annonaceae family was catalogued by de Jussieu. It encompasses tropical and subtropical plants which are widespread in distribution across various continents such as Asia, South and Central America, Australia and Africa. The genus of Annona is one of 120 genera of the Annonaceae family and contains more than 119 species of trees and shrubs. Most species are found in tropical America, where over 105 species have been identified. Due to its edible fruits and medicinal properties, Annona is the most studied genus of Annonaceae family. To date, only a limited number of these species have economic value, including A. squamosa L. (sugar apple), A. cherimola Mill. (Cherimoya), A. muricata L. (guanabana or soursop), A. atemoya Mabb. (atemoya), a hybrid between A. cherimola and A. squamosa, A. reticulata L. (custard apple), A. glabra L. (pond-apple) and A. macroprophyllata Donn. Sm. (ilama). Phytochemically, several classes of secondary metabolites, including acetogenins, essential oils, alkaloids, terpenoids and flavonoids. The pharmacological activities of Annona species leaves and seeds include antibacterial, anticancer, antidiabetic and anti-inflammatory properties.


Assuntos
Alcaloides , Annona , Annonaceae , Acetogeninas/farmacologia , Alcaloides/análise , Annona/química , Frutas/química
2.
J Am Soc Mass Spectrom ; 33(4): 627-634, 2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-35344372

RESUMO

Annonaceous acetogenins are natural products held responsible for atypical Parkinsonism due to chronic consumption in traditional medicine or as food, leading to the development of analytical strategies for their complete chemical characterization in complex mixtures. Characterization by tandem mass spectrometry (MS/MS) of acetogenins using collision-induced dissociation from lithium adducts provides additional structural information compared to protonated or sodiated species such as ketone location on the acetogenin backbone. However, very low intensity diagnostic ions together with the lack of extensive structural information regarding position of OH and THF substituents limit this approach. Copper adducts led to diagnostic fragment ions that allow us to identify the position of oxygen rings and hydroxyl substituents. Fragmentation rules were established on the basis of acetogenin standards allowing the identification of 45 over the 77 analogues observed in an extract of Annona muricata by LC-MS/MS using postcolumn infusion of copper sulfate (CuSO4) solution. Molecular networks that were generated thanks to specific fragmentations obtained with copper led to the distinction of THF ring position or to the identification of hydroxylated lactone, for instance.


Assuntos
Acetogeninas , Annona , Acetogeninas/análise , Acetogeninas/química , Annona/química , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida , Cobre , Lítio , Espectrometria de Massas em Tandem
3.
Molecules ; 27(6)2022 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-35335229

RESUMO

The chemical diversity of the approximately 1,200 natural products isolated from red algae of the genus Laurencia, in combination with the wide range of their biological activities, have placed species of Laurencia in the spotlight of marine chemists' attention for over 60 years. The chemical investigation of the organic (CH2Cl2/MeOH) extracts of Laurencia microcladia and Laurencia obtusa, both collected off the coasts of Tinos island in the Aegean Sea, resulted in the isolation of 32 secondary metabolites, including 23 C15 acetogenins (1-23), 7 sesquiterpenes (24-30) and 2 diterpenes (31 and 32). Among them, six new C15 acetogenins, namely 10-acetyl-sagonenyne (2), cis-sagonenyne (3), trans-thuwalenyne C (4), tinosallene A (11), tinosallene B (12) and obtusallene XI (17), were identified and their structures were elucidated by extensive analysis of their spectroscopic data. Compounds 1-3, 5-11, 13 and 15-32 were evaluated for their antibacterial activity against Staphylococcus aureus and Escherichia coli.


Assuntos
Produtos Biológicos , Laurencia , Rodófitas , Sesquiterpenos , Acetogeninas/química , Produtos Biológicos/química , Laurencia/química , Rodófitas/química , Sesquiterpenos/química
4.
Molecules ; 27(3)2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-35164158

RESUMO

As part of our continuous studies involving the prospection of natural products from Brazilian flora aiming at the discovery of prototypes for the development of new antiparasitic drugs, the present study describes the isolation of two natural acetylene acetogenins, (2S,3R,4R)-3-hydroxy-4-methyl-2-(n-eicos-11'-yn-19'-enyl)butanolide (1) and (2S,3R,4R)-3-hydroxy-4-methyl-2-(n-eicos-11'-ynyl)butanolide (2), from the seeds of Porcelia macrocarpa (Warm.) R.E. Fries (Annonaceae). Using an ex-vivo assay, compound 1 showed an IC50 value of 29.9 µM against the intracellular amastigote forms of Leishmania (L.) infantum, whereas compound 2 was inactive. These results suggested that the terminal double bond plays an important role in the activity. This effect was also observed for the semisynthetic acetylated (1a and 2a) and eliminated (1b and 2b) derivatives, since only compounds containing a double bond at C-19 displayed activity, resulting in IC50 values of 43.3 µM (1a) and 23.1 µM (1b). In order to evaluate the effect of the triple bond in the antileishmanial potential, the mixture of compounds 1 + 2 was subjected to catalytic hydrogenation to afford a compound 3 containing a saturated side chain. The antiparasitic assays performed with compound 3, acetylated (3a), and eliminated (3b) derivatives confirmed the lack of activity. Furthermore, an in-silico study using the SwissADME online platform was performed to bioactive compounds 1, 1a, and 1b in order to investigate their physicochemical parameters, pharmacokinetics, and drug-likeness. Despite the reduced effect against amastigote forms of the parasite to the purified compounds, different mixtures of compounds 1 + 2, 1a + 2a, and 1b + 2b were prepared and exhibited IC50 values ranging from 7.9 to 38.4 µM, with no toxicity for NCTC mammalian cells (CC50 > 200 µM). Selectivity indexes to these mixtures ranged from >5.2 to >25.3. The obtained results indicate that seeds of Porcelia macrocarpa are a promising source of interesting prototypes for further modifications aiming at the discovery of new antileishmanial drugs.


Assuntos
Acetogeninas/farmacologia , Acetileno/farmacologia , Annonaceae/química , Antiprotozoários/farmacologia , Leishmania/efeitos dos fármacos , Acetogeninas/química , Acetileno/análogos & derivados , Antiprotozoários/química , Humanos , Leishmaniose/tratamento farmacológico , Sementes/química
5.
Colloids Surf B Biointerfaces ; 213: 112426, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35219964

RESUMO

ACGs (annonaceous acetogenins) possess excellent antitumor activity, but their serious accompanying toxicity has prevented their application in the clinic. To address this problem, we therefore constructed an intratumoral drug delivery system integrating chemotherapy and photothermal therapy. The PEGylation of polydopamine nanoparticles (PDA-PEG NPs) possessed an excellent biocompatibility with size of 70.96 ± 2.55 nm, thus can be used as good photothermal materials in the body. Moreover, PDA-PEG NPs can kill half of cancer cells under NIR (near-infrared) laser irradiation, and the survival rate of 4T1 cells is only 1% when ACG NPs and PDA-PEG NPs are combined. In vivo distribution studies showed that the 0.1 mg/kg ACGs NPs + PDA-PEG NPs + NIR group had the highest tumor inhibition rate, which was significantly superior to that of the 0.1 mg/kg ACGs NPs intratumoral injection group (82.65% vs. 59.08%). Altogether, the combination of PDA-PEG NPs + NIR with chemotherapy drugs may provide a feasible and effective strategy for the treatment of superficial tumors.


Assuntos
Neoplasias da Mama , Nanopartículas , Acetogeninas/farmacologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Feminino , Humanos , Injeções Intralesionais , Fototerapia
6.
Molecules ; 27(4)2022 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-35208993

RESUMO

Soursop (Annona muricata Lin.) is a plant belonging to the Annonaceae family that has been widely used globally as a traditional medicine for many diseases. In this review, we discuss the traditional use, chemical content, and pharmacological activities of A.muricata. From 49 research articles that were obtained from 1981 to 2021, A.muricata's activities were shown to include anticancer (25%), antiulcer (17%), antidiabetic (14%), antiprotozoal (10%), antidiarrhea (8%), antibacterial (8%), antiviral (8%), antihypertensive (6%), and wound healing (4%). Several biological activities and the general mechanisms underlying the effects of A.muricata have been tested both in vitro and in vivo. A.muricata contains chemicals such as acetogenins (annomuricins and annonacin), alkaloids (coreximine and reticuline), flavonoids (quercetin), and vitamins, which are predicted to be responsible for the biological activity of A.muricata.


Assuntos
Acetogeninas/uso terapêutico , Annona/química , Furanos/uso terapêutico , Lactonas/uso terapêutico , Extratos Vegetais/química , Folhas de Planta/química , Acetogeninas/química , Furanos/química , Humanos , Lactonas/química
7.
J Biol Chem ; 298(3): 101602, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35063503

RESUMO

Mitochondrial complex I (NADH:ubiquinone oxidoreductase), a crucial enzyme in energy metabolism, captures the redox potential energy from NADH oxidation/ubiquinone reduction to create the proton motive force used to drive ATP synthesis in oxidative phosphorylation. High-resolution single-particle electron cryo-EM analyses have provided detailed structural knowledge of the catalytic machinery of complex I, but not of the molecular principles of its energy transduction mechanism. Although ubiquinone is considered to bind in a long channel at the interface of the membrane-embedded and hydrophilic domains, with channel residues likely involved in coupling substrate reduction to proton translocation, no structures with the channel fully occupied have yet been described. Here, we report the structure (determined by cryo-EM) of mouse complex I with a tight-binding natural product acetogenin inhibitor, which resembles the native substrate, bound along the full length of the expected ubiquinone-binding channel. Our structure reveals the mode of acetogenin binding and the molecular basis for structure-activity relationships within the acetogenin family. It also shows that acetogenins are such potent inhibitors because they are highly hydrophobic molecules that contain two specific hydrophilic moieties spaced to lock into two hydrophilic regions of the otherwise hydrophobic channel. The central hydrophilic section of the channel does not favor binding of the isoprenoid chain when the native substrate is fully bound but stabilizes the ubiquinone/ubiquinol headgroup as it transits to/from the active site. Therefore, the amphipathic nature of the channel supports both tight binding of the amphipathic inhibitor and rapid exchange of the ubiquinone/ubiquinol substrate and product.


Assuntos
Acetogeninas , Complexo I de Transporte de Elétrons , Acetogeninas/antagonistas & inibidores , Acetogeninas/metabolismo , Acetogeninas/farmacologia , Animais , Microscopia Crioeletrônica , Complexo I de Transporte de Elétrons/metabolismo , Camundongos , NAD/metabolismo , Oxirredução , Relação Estrutura-Atividade , Ubiquinona/metabolismo
8.
Nat Prod Res ; 36(3): 765-771, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32772561

RESUMO

Araticum is an edible and appreciable fruit of Annona coriacea, which is popularly known as a traditional herb in the Brazilian cerrado. A phytochemical study from the leaves of A. coriacea showed that HPLC-ESI-Q-Orbitrap® provided through PRM experiments (MS2) is an efficient method for the fast and accurate analysis of a complex mixture of annonaceous acetogenins, with the identification of sylvaticin and gigantetrocin-A type acetogenins for the first time. In addition, the crude leaf extract and acetogenin-rich fractions were assayed against Streptococcus mutans, S. mitis, S. sanguinis and S. salivarius strains, which are usually related to oral infections.


Assuntos
Acetogeninas , Annona , Acetogeninas/farmacologia , Antibacterianos/farmacologia , Cromatografia Líquida de Alta Pressão , Frutas
9.
Chem Pharm Bull (Tokyo) ; 69(10): 1029-1033, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34602571

RESUMO

In a previous study, we found that the thiophene carboxamide solamin analog, which is a mono-tetrahydrofuran annonaceous acetogenin, showed potent antitumor activity through the inhibition of mitochondrial complex I. In this study, we synthesized analogs with short alkyl chains instead of the n-dodecyl group in the tail part. We evaluated their growth inhibitory activities against human cancer cell lines. We found that the alkyl chain in the tail part plays an essential role in their activity.


Assuntos
Acetogeninas/farmacologia , Antineoplásicos/farmacologia , Acetogeninas/síntese química , Acetogeninas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Conformação Molecular , Relação Estrutura-Atividade
10.
J Biomed Nanotechnol ; 17(10): 2062-2070, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34706806

RESUMO

Annonaceous acetogenins (ACGs) have attracted much attention because of excellent antitumor activity. However, the lack of selectivity and the accompanying serious toxicity have eventually prevented ACGs from entering clinical application. To decrease the side effects of ACGs, the cytotoxicity of ACGs on 10 types of tumor cell lines was investigated by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) test to identify one that was very sensitive to ACGs. Meanwhile, ACGs nanoparticles (ACGs-NPs) were prepared using poloxamer 188 (P188) as an excipient so as to solve the problem of poor solubility and the in vivo delivery of ACGs. ACG-NPs were 163.9±2.5 nm in diameter, negatively charged, and spherical with a high drug loading content (DLC) of 44.9±1.2%. MTS assays demonstrated that ACGs had strong cytotoxicity against JEG-3, HeLa, SiHa, MCF-7, A375, A2058, A875, U-118MG, LN- 229, and A431 cells, among which JEG-3 cell line was extremely sensitive to ACGs with a 50% inhibitory concentration (IC50) value of 0.26 ng/mL, a very encouraging discovery. ACGs-NPs demonstrated very good dose-dependent antitumor efficacy in a broad range of 45?1200 µg/kg on JEG-3 tumor-bearing mice. At a very low dose (1200 µg/kg), ACGs-NPs achieved a high tumor inhibition rate (TIR) of 77.6% through oral administration, displaying a significant advantage over paclitaxel (PTX) injections that are currently used as first-line anti-choriocarcinoma drugs. In the acute toxicity study, the half lethal dose (LD50) of ACGs-NPs was 135.5 mg/kg, which was over 100 times as of the effective antitumor dose, indicating good safety of ACGs-NPs. ACGs-NPs show promise as a new type of and potent anti-choriocarcinoma drug in the future.


Assuntos
Coriocarcinoma , Nanopartículas , Acetogeninas/farmacologia , Animais , Linhagem Celular Tumoral , Células HeLa , Humanos , Camundongos , Paclitaxel
11.
PLoS One ; 16(7): e0250394, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34237060

RESUMO

Plant species from Annonaceae are commonly used in traditional medicine to treat various cancer types. This study aimed to investigate the antiproliferative potential of an alkaloid and acetogenin-rich fraction from the fruit peel of Annona crassiflora in HepG2 cells. A liquid-liquid fractionation was carried out on the ethanol extract of A. crassiflora fruit peel in order to obtain an alkaloid and acetogenin-rich fraction (AF-Ac). Cytotoxicity, proliferation and migration were evaluated in the HepG2 cells, as well as the proliferating cell nuclear antigen (PCNA), vinculin and epidermal growth factor receptor (EGFR) expression. In addition, intracellular Ca2+ was determined using Fluo4-AM and fluorescence microscopy. First, 9 aporphine alkaloids and 4 acetogenins that had not yet been identified in the fruit peel of A. crassiflora were found in AF-Ac. The treatment with 50 µg/mL AF-Ac reduced HepG2 cell viability, proliferation and migration (p < 0.001), which is in accordance with the reduced expression of PCNA and EGFR levels (p < 0.05). Furthermore, AF-Ac increased intracellular Ca2+ in the HepG2 cells, mobilizing intracellular calcium stores, which might be involved in the anti-migration and anti-proliferation capacities of AF-Ac. Our results support the growth-inhibitory potential of AF-Ac on HepG2 cells and suggest that this effect is triggered, at least in part, by PCNA and EGFR modulation and mobilization of intracellular Ca2+. This study showed biological activities not yet described for A. crassiflora fruit peel, which provide new possibilities for further in vivo studies to assess the antitumoral potential of A. crassiflora, especially its fruit peel.


Assuntos
Acetogeninas/análise , Alcaloides/análise , Annona/química , Frutas/química , Neoplasias Hepáticas/patologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Hep G2 , Humanos
12.
Molecules ; 26(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34069113

RESUMO

Annona cherimola Mill., or the custard apple, is one of the species belonging to the Annonaceae family, is widely used in traditional medicine, and has been reported to be a valuable source of bioactive compounds. A unique class of secondary metabolites derived from this family are Annonaceous acetogenins, lipophilic polyketides considered to be amongst the most potent antitumor compounds. This review provides an overview of the chemical diversity, isolation procedures, bioactivity, modes of application and synthetic derivatives of acetogenins from A. cherimola Mill.


Assuntos
Acetogeninas/química , Acetogeninas/uso terapêutico , Annona/química , Acetogeninas/isolamento & purificação , Acetogeninas/farmacologia , Anticarcinógenos/farmacologia , Carboidratos/química , Micelas , Polímeros/química
13.
Curr Drug Discov Technol ; 18(6): e010921191171, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33563198

RESUMO

BACKGROUND: Anti-apoptotic protein BCL-XL plays a vital role in tumorigenesis and cancer chemotherapy resistance, resulting in a good target for cancer treatment. Understanding the function of BCL-XL has driven the progression of a new class of cancer drugs that can mimic its natural inhibitors, BH3-only proteins, to trigger apoptosis. This mimicking is initiated through acetogenins due to their excellent biological properties. Acetogenins, which can be isolated from Annonaceae plants, have a unique structure along with several oxygenated functionalities. OBJECTIVE: Based on their biological capability, various acetogenins were studied in the present study and compared alongside ABT-737 on molecular docking. METHODS: The docking simulation of acetogenins was performed using AutoDock Vina software. RESULTS: Our findings have shown eleven acetogenins-BCL-XL protein complex, namely, muricin B (2), muricin F (4), muricin H (6), muricin I (7), xylomaticin (9), annomontacin (12), annonacin (14), squamocin (15), squamostatin A (16), bullatacin (20) and annoreticulin (21) exhibited strong binding affinities lower than - 10.4 kcalmol-1 as compared to ABT-373-BCL-XL complex. Six hydrogen bonds along with hydrophobic interaction were detected on the complex of BCL-XL with muricin B (2), muricin G (5), corossolone (11), and isoannonacin-10-one A (18). CONCLUSION: These findings indicated that some acetogenins could represent a new potential BCLXL inhibitor that could mimic the BH3-only protein for the induction of apoptosis in cancer chemotherapy.


Assuntos
Acetogeninas , Antineoplásicos , Acetogeninas/farmacologia , Antineoplásicos/farmacologia , Apoptose , Proteínas Reguladoras de Apoptose/farmacologia , Simulação de Acoplamento Molecular
14.
Protein Pept Lett ; 28(3): 304-314, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32938339

RESUMO

BACKGROUND: In individuals with ovarian cancer, an increase in the circulating level of the epidermal growth factor (EGF) is readily apparent. Ovarian cancer cells exhibit signaling pathway of the epidermal growth factor (EGFR) and respond to the EGF. Annona muricata (AM) has been shown to decrease ovarian cell proliferation however, role of AM in regulating EGF actions is not yet to be reported. OBJECTIVE: In this study, we proposed that the fractionated compound acetogenin can inhibit the activation of EGFR-regulated signaling cascades such as MAPK7 / PI3K-Akt / mTOR / STAT upon EGF stimulation. METHODS: Ethanolic extract was prepared for the whole AM plant and Thin Layer Chromatography (TLC) was performed to characterize the secondary metabolites and each fraction was assessed using kedde reagent for the presence of acetogenin. The effects of acetogenins were then tested on the survival of PA-1 ovarian cancer cells under basal and EGF stimulated conditions. To delineate the role of acetogenin in EGFR signaling cascades, the in silico docking studies were conducted. RESULTS: The fraction of acetogenin decreased the viability of EGF induced PA-1 ovarian cancer cells that indicating the EGF inhibitory effects of acetogenin. The docking studies specifically illustrated that when the acetogenin binding with tyrosine kinase (TK) and regulatory unit (RU) which subsequently resulted in a reduction in EGF induced the survival of PA-1 ovarian cancer cells. DISCUSSION: The vital regulatory role of acetogenin reported in this study indicate significant anticancer activities of acetogenin from AM. The in silico study of the acetogenin function predicted that it binds specifically to Asp837 (phosphor-acceptor site) of EGFR, essential for phosphorylation of substrates in the TK domain and RU which promote downstream signaling. CONCLUSION: Acetogenin isolated from AM effectively inhibited the survival of PA-1 ovarian cancer cells through impaired EGF signaling.


Assuntos
Acetogeninas/farmacologia , Annona/química , Fator de Crescimento Epidérmico/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Acetogeninas/química , Acetogeninas/isolamento & purificação , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia
15.
Drug Des Devel Ther ; 14: 4993-5004, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33235438

RESUMO

BACKGROUND: Annonaceous acetogenins (ACGs) are secondary metabolites produced by the Annonaceae family and display potent anticancer activity against various cancer cell lines. Squamocin and bullatacin are two examples of ACGs that show promising antitumor activity; however, preclinical data are not sufficient partly due to their being highly lipophilic and poorly soluble in water. These compounds also display high toxicity to normal cells. Due to these disadvantageous properties, the therapeutic potential of squamocin and bullatacin as antitumor agents has not been fully evaluated. METHODS: In order to enhance their water solubility and potentially improve their cancer targeting, squamocin and bullatacin were conjugated to a glucose or galactose to yield glycosylated derivatives by direct glycosylation or the Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reaction (the click reaction). The synthesized compounds were evaluated for their anticancer property against HeLa, A549 and HepG2 cancer cell lines using MTT assay. RESULTS: Nine glycosyl derivatives were synthesized and structurally characterized. Most of them show comparable in vitro cytotoxicity against HeLa, A549 and HepG2 cancer cell lines as their parent compounds squamocin and bullatacin. It appears that the type of sugar residue (glucose or galactose), the position at which the sugar residue is attached, and whether or not a linking spacer is present do not affect the potency of these derivatives much. The solubility of galactosylated squamocin 13 in phosphate buffer saline (PBS, pH = 7) is greatly improved (1.37 mg/mL) in comparison to squamocin (not detected in PBS). CONCLUSION: The conjugation of a glucose or galactose to squamocin and bullatacin yields glycosyl derivatives with similar level of anticancer activity in tested cell lines. Further studies are needed to demonstrate whether or not these compounds show reduced toxicity to normal cells and their therapeutic potential as antitumor agents.


Assuntos
Acetogeninas/farmacologia , Annonaceae/química , Antineoplásicos Fitogênicos/farmacologia , Glicoconjugados/farmacologia , Acetogeninas/química , Acetogeninas/isolamento & purificação , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Glicoconjugados/síntese química , Glicoconjugados/química , Humanos , Estrutura Molecular , Solubilidade , Células Tumorais Cultivadas
16.
Molecules ; 25(20)2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33096836

RESUMO

Annonaceous acetogenins (ACGs) are lipophilic polyketides isolated exclusively from Annonaceae. They are considered to be amongst the most potent antitumor compounds. Nevertheless, their applications are limited by their poor solubility. The isolation of ACGs from Annona cherimola leaves, an agricultural waste, has not been reported to date. Molvizarin (1) cherimolin-1 (2), motrilin (3), annonacin (4) and annonisin (5) are isolated for the first time from A. cherimola deciduous leaves. Annonacin was found to be four- and two-times more potent in tumoral cells (HeLa, 23.6% live cells; IGROV-1, 40.8% live cells for 24 h) than in HEK-293 at 50 µM (24 h, 87.2% live cells). Supramolecular polymer micelles (SMPMs) were synthesized to encapsulate the major ACG isolated, annonacin, in order to improve its solubility in aqueous media. The bioavailability of this compound was increased by a factor of 13 in a simulated human digestive system when compared with free annonacin and an encapsulation efficiency of 35% was achieved. In addition, the cytotoxic activity of SMPMs that hosted annonacin (100 µM, 24 h, 5.8% live cells) was increased compared with free annonacin in water (100 µM, 24 h, 92% live cells). These results highlight the use of by-products of A. cherimola, and their pure compounds, as a promising source of anticancer agents. The use of SMPMs as nanocarriers of ACGs could be an alternative for their application in food field as nutraceutical to enhance the administration and efficacy.


Assuntos
Acetogeninas/farmacologia , Annona/química , Antineoplásicos Fitogênicos/farmacologia , Nanopartículas/química , Folhas de Planta/química , Acetogeninas/química , Acetogeninas/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Disponibilidade Biológica , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/química , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Estrutura Molecular
17.
Redox Rep ; 25(1): 80-86, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32878595

RESUMO

ABSTRACT Objectives: This work investigated the effect of acetogenin-rich fraction of Annona muricata leaves (AFAL) on antioxidant status and some markers of benign prostatic hyperplasia (BPH) in rats. Methods: BPH was experimentally induced in the rats by subcutaneous injection of testosterone propionate (TP, 3 mg/kg) for 28 consecutive days. The rats were administered orally different doses of AFAL (100 and 200 mg/kg) for 7 days. Prostate-specific antigen (PSA), prostate weight, relative prostate weight, prostate protein content and oxidative stress indices of the rats were evaluated. Results: It was observed that 200 mg/kg AFAL significantly reduced the PSA level, mean prostate weights and mean relative prostate weights of the test rats compared to the TP group, and the values were not significantly different from the normal control and group treated with a standard drug. The plant extract also significantly enhanced the antioxidant capacity of the test rats which were evidently compromised in the group that received the exogenous hormone alone. Histopathology of the prostate showed a marked recovery for the test rats after treatment with AFAL. Conclusion: Oral administration of acetogenin-rich fraction of Annona muricata leaves ameliorated TP-induced BPH in rats and significantly enhanced the antioxidant capacity of the rats.


Assuntos
Acetogeninas/farmacologia , Annona/química , Antioxidantes/metabolismo , Hiperplasia Prostática/tratamento farmacológico , Acetogeninas/química , Animais , Masculino , Camundongos Endogâmicos , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Próstata/patologia , Antígeno Prostático Específico/sangue , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Ratos Wistar , Propionato de Testosterona/toxicidade , Testes de Toxicidade Aguda
18.
Chem Asian J ; 15(22): 3660-3681, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-32975357

RESUMO

In this review, we have abstracted the various syntheses of acetogenins where the start point has been muricatacin. The latter can best be synthesized in either enantiomer form by the Sharpless method in three steps and can be admired as a gateway molecule for a quick assembly of many higher acetogenins. Muricatacin with orthogonally differentiated hydroxy groups and the available lactone carbonyl for chain elongation/modification can enable the concise synthesis of higher acetogenins. Many closely related synthetic intermediates possible from muricatacin are also abstracted here. The review should give impetus for future synthetic endeavours where the start point could be muricatacin and at least to the new molecules that are yet to be synthesized.


Assuntos
Acetogeninas/síntese química , Furanos/química , Acetogeninas/química , Estrutura Molecular , Estereoisomerismo
19.
Chem Biodivers ; 17(11): e2000484, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32960490

RESUMO

Our search for candidates for photosynthesis inhibitors is allowing us to report the effect of two acetogenins identified in Annona coriacea Mart. leaves, ACG-A and ACG-B, a non-adjacent bis-THF and a mono-THF types, respectively. This is an important class of natural products which presents biological properties such as anticancer, neurotoxic, larvicidal and insecticidal. However, this is only the second report associated to its herbicidal activity. Their mechanisms of action on the light reactions of the photosynthesis were elucidated by polarographic techniques. Compounds inhibited the noncyclic electron transport on basal, phosphorylating, and uncoupled conditions from H2 O to methyl viologen (MV); therefore, they act as Hill reaction inhibitors. Studies on fluorescence of chlorophyll a (ChL a) indicated that they inhibited the acceptor side of PSII between P680 and PQ-pool, exactly as the commercial herbicide DCMU does.


Assuntos
Acetogeninas/química , Annona/química , Acetogeninas/isolamento & purificação , Acetogeninas/metabolismo , Acetogeninas/farmacologia , Annona/metabolismo , Clorofila A/química , Cloroplastos/metabolismo , Transporte de Elétrons/efeitos dos fármacos , Luz , Fotossíntese/efeitos dos fármacos , Fotossíntese/efeitos da radiação , Complexo de Proteína do Fotossistema II/antagonistas & inibidores , Complexo de Proteína do Fotossistema II/metabolismo , Folhas de Planta/química , Folhas de Planta/metabolismo , Spinacia oleracea/metabolismo
20.
Mar Drugs ; 18(8)2020 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-32751383

RESUMO

Mycalin A, a polybrominated C15 acetogenin isolated from the encrusting sponge Mycale rotalis, displays an antiproliferative activity on human melanoma (A375) and cervical adenocarcinoma (HeLa) cells and induces cell death by an apoptotic mechanism. Various analogues and degraded derivatives of the natural substance have been prepared. A modification of the left-hand part of the molecule generates the most active substances. A structurally simplified lactone derivative of mycalin A, lacking the C1-C3 side chain, is the most active among the synthesized compounds exhibiting a strong cytotoxicity on both A375 and HeLa cells but not but not on human dermal fibroblast (HDF) used as healthy cells. Further evidence on a recently discovered chlorochromateperiodate-catalyzed process, used to oxidise mycalin A, have been collected.


Assuntos
Acetogeninas/farmacologia , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico , Acetogeninas/química , Acetogeninas/isolamento & purificação , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Relação Dose-Resposta a Droga , Feminino , Células HeLa , Humanos , Concentração Inibidora 50 , Células MCF-7 , Melanoma/patologia , Estrutura Molecular , Poríferos/química , Neoplasias Cutâneas/patologia , Relação Estrutura-Atividade , Neoplasias do Colo do Útero/patologia
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