Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
Mais filtros

Base de dados
País como assunto
Tipo de documento
Intervalo de ano de publicação
1.
J Am Chem Soc ; 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38918178

RESUMO

Metals are important cofactors in the metabolic processes of cyanobacteria, including photosynthesis, cellular respiration, DNA replication, and the biosynthesis of primary and secondary metabolites. In adaptation to the marine environment, cyanobacteria use metallophores to acquire trace metals when necessary as well as to reduce potential toxicity from excessive metal concentrations. Leptochelins A-C were identified as structurally novel metallophores from three geographically dispersed cyanobacteria of the genus Leptothoe. Determination of the complex structures of these metabolites presented numerous challenges, but they were ultimately solved using integrated data from NMR, mass spectrometry and deductions from the biosynthetic gene cluster. The leptochelins are comprised of halogenated linear NRPS-PKS hybrid products with multiple heterocycles that have potential for hexadentate and tetradentate coordination with metal ions. The genomes of the three leptochelin producers were sequenced, and retrobiosynthetic analysis revealed one candidate biosynthetic gene cluster (BGC) consistent with the structure of leptochelin. The putative BGC is highly homologous in all three Leptothoe strains, and all possess genetic signatures associated with metallophores. Postcolumn infusion of metals using an LC-MS metabolomics workflow performed with leptochelins A and B revealed promiscuous binding of iron, copper, cobalt, and zinc, with greatest preference for copper. Iron depletion and copper toxicity experiments support the hypothesis that leptochelin metallophores may play key ecological roles in iron acquisition and in copper detoxification. In addition, the leptochelins possess significant cytotoxicity against several cancer cell lines.

2.
Mar Drugs ; 19(12)2021 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-34940674

RESUMO

Lipids are one of the primary metabolites of microalgae and cyanobacteria, which enrich their utility in the pharmaceutical, feed, cosmetic, and chemistry sectors. This work describes the isolation, structural elucidation, and the antibiotic and antibiofilm activities of diverse lipids produced by different microalgae and cyanobacteria strains from two European collections (ACOI and LEGE-CC). Three microalgae strains and one cyanobacteria strain were selected for their antibacterial and/or antibiofilm activity after the screening of about 600 strains carried out under the NoMorFilm European project. The total organic extracts were firstly fractionated using solid phase extraction methods, and the minimum inhibitory concentration and minimal biofilm inhibitory concentration against an array of human pathogens were determined. The isolation was carried out by bioassay-guided HPLC-DAD purification, and the structure of the isolated molecules responsible for the observed activities was determined by HPLC-HRESIMS and NMR methods. Sulfoquinovosyldiacylglycerol, monogalactosylmonoacylglycerol, sulfoquinovosylmonoacylglycerol, α-linolenic acid, hexadeca-4,7,10,13-tetraenoic acid (HDTA), palmitoleic acid, and lysophosphatidylcholine were found among the different active sub-fractions selected. In conclusion, cyanobacteria and microalgae produce a great variety of lipids with antibiotic and antibiofilm activity against the most important pathogens causing severe infections in humans. The use of these lipids in clinical treatments alone or in combination with antibiotics may provide an alternative to the current treatments.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Cianobactérias , Lipídeos/farmacologia , Microalgas , Animais , Antibacterianos/química , Organismos Aquáticos , Lipídeos/química , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos
3.
J Nat Prod ; 83(6): 1885-1890, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32479093

RESUMO

Four natural lactylates of chlorinated fatty acids, chlorosphaerolactylates A-D (1-4), were isolated from the methanolic extract of the cyanobacterium Sphaerospermopsis sp. LEGE 00249 through a combination of bioassay-guided and MS-guided approaches. Compounds 1-4 are esters of (mono-, di-, or tri)chlorinated lauric acid and lactic acid, whose structures were assigned on the basis of spectrometric and spectroscopic methods inclusive of 1D and 2D NMR experiments. High-resolution mass-spectrometry data sets also demonstrated the existence of other minor components that were identified as chlorosphaero(bis)lactylate analogues. The chlorosphaerolactylates were tested for potential antibacterial, antifungal, and antibiofilm properties using bacterial and fungal clinical isolates. Compounds 1-4 showed a weak inhibitory effect on the growth of Staphylococcus aureus S54F9 and Candida parapsilosis SMI416, as well as on the biofilm formation of coagulase-negative Staphylococcus hominis FI31.


Assuntos
Anti-Infecciosos/química , Cianobactérias/química , Ácidos Graxos/química , Antibacterianos/farmacologia , Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/farmacologia , Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Candida/efeitos dos fármacos , Ácidos Graxos/isolamento & purificação , Ácidos Graxos/farmacologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Testes de Sensibilidade Microbiana , Estrutura Molecular , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus hominis/efeitos dos fármacos
4.
Chem Biodivers ; 15(7): e1800076, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29790299

RESUMO

Apocarotenoids are widely distributed among living organisms (bacteria, fungi, algae, plants and even animals) and have been associated with several signaling functions. These compounds are generated by the activity of carotenoid cleavage dioxygenases (CCDs), whose diversity greatly contributes to the large number of apocarotenoids that have been described so far. It is nevertheless expected that a considerable diversity of these molecules is yet to be discovered. In this work, we describe the isolation and structural elucidation of the apocarotenoid 4-oxo-ß-apo-13-carotenone from the cultured freshwater cyanobacterium Anabaena cylindrica PCC 7122, corresponding to the first report of this compound from natural sources.


Assuntos
Anabaena/química , Carotenoides/química , Estrutura Molecular
5.
J Nat Prod ; 80(5): 1411-1420, 2017 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-28421773

RESUMO

Macrocyclic monoacyl lathyrane derivatives bearing a benzoyl moiety were previously found to be strong ABCB1 modulators. To explore the effects of different substituents of the aromatic moiety, 14 new compounds (1.1-1.7, 1.10, and 2.1-2.4) were prepared from jolkinol D (1), obtained from Euphorbia piscatoria, and from jolkinodiol (2), its hydrolysis derivative. Compounds 1.8 and 1.9, having aliphatic moieties, were also obtained. The reversal of ABCB1-mediated MDR was evaluated through functional and chemosensitivity assays on the human ABCB1-gene-transfected L5178Y mouse T-lymphoma cell line. Structure-activity relationships showed that addition of electron-donating groups to the aromatic moiety improved the activity. The effects on the ATPase activity of the strongest modulator (1.3) and the inactive jolkinol D (1) were also investigated and compared. Moreover, in the chemosensitivity assay, most of the compounds interacted synergistically with doxorubicin. Compounds 1.1-1.10 and 2.1-2.4 were further assessed for their collateral sensitivity effect against the human cancer cells: EPG85-257 (gastric) and EPP85-181 (pancreatic), and the matching drug-selected cells EPG85-257RDB, EPG85-257RNOV, EPP85-181RDB, and EPP85-181RNOV. The most promising ones (1.8 and 1.10) along with compound 3, previously selected, were investigated as apoptosis inducers. The compounds were able to induce apoptosis through caspase-3 activation, with significant differences being observed between the parental and resistant cells.


Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Euphorbia/química , Linfoma de Células T/tratamento farmacológico , Compostos Macrocíclicos/isolamento & purificação , Compostos Macrocíclicos/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Antineoplásicos Fitogênicos/química , Caspase 3/química , Linhagem Celular Tumoral , Diterpenos/química , Doxorrubicina/química , Humanos , Linfoma de Células T/química , Compostos Macrocíclicos/química , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade
6.
J Nat Prod ; 78(11): 2684-90, 2015 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-26561962

RESUMO

Euphowelwitschines A (1) and B (2), isolated from a methanolic extract of Euphorbia welwitschii, exhibit a rare combination of structural features in having a 5/8/8 fused-ring system and a 12,15-ether bridge. Moreover, the isolation of the additional new compounds welwitschene (3) and epoxywelwitschene (4) has provided insights into the biogenetic pathway of 12,17-cyclojatrophanes. The structures of 1-4 were determined by spectroscopic methods inclusive of 1D and 2D NMR experiments and X-ray crystallography for compounds 1 and 2. Preliminary information on the selective antiproliferative activity of compounds 1-4 is also described.


Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Diterpenos/isolamento & purificação , Euphorbia/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Cristalografia por Raios X , Diterpenos/química , Diterpenos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Portugal
7.
Bioorg Med Chem ; 22(14): 3696-702, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24864039

RESUMO

Herein, collateral sensitivity effect was exploited as a strategy to select effective compounds to overcome multidrug resistance in cancer. Thus, eleven macrocyclic diterpenes, namely jolkinol D (1), isolated from Euphorbia piscatoria, and its derivatives (2-11) were evaluated for their activity on three different Human cancer entities: gastric (EPG85-257), pancreatic (EPP85-181) and colon (HT-29) each with a variant selected for resistance to mitoxantrone (EPG85-257RN; EPP85-181RN; HT-29RN) and one to daunorubicin (EPG85-257RD; EPP85-181RD; HT-29RD). Jolkinol D (1) and most of its derivatives (2-11) exhibited significant collateral sensitivity effect towards the cell lines EPG85-257RN (associated with P-glycoprotein overexpression) and HT-29RD (altered topoisomerase II expression). The benzoyl derivative, jolkinoate L (8) demonstrated ability to target different cellular contexts with concomitant high antiproliferative activity. These compounds were previously assessed as P-glycoprotein modulators, at non-cytotoxic doses, on MDR1-mouse lymphoma cells. A regression analysis between the antiproliferative activity presented herein and the previously assessed P-glycoprotein modulatory effect showed a strong relation between the compounds that presented both high P-glycoprotein modulation and cytotoxicity.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Diterpenos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos Macrocíclicos/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Diterpenos/química , Diterpenos/isolamento & purificação , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Euphorbia/química , Células HT29 , Humanos , Compostos Macrocíclicos/química , Compostos Macrocíclicos/isolamento & purificação , Camundongos , Conformação Molecular , Fenótipo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
8.
Bioorg Med Chem ; 22(22): 6392-400, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25438763

RESUMO

Aiming to optimize macrocyclic lathyrane-type diterpenes as effective Pgp modulators, the phytochemical study of the methanolic extract of Euphorbia boetica aerial parts was carried out. Two new macrocyclic 6,17-epoxylathyrane-type diterpenes, named epoxyboetiranes A (1) and B (2), along with three known analogues (3-5) were isolated. Epoxyboetirane A (1), a triacetate isolated in large amounts, was hydrolyzed to give epoxylathyrol (6). In order to study the effect of the substitution pattern of the macrocyclic scaffold on MDR reversal, 6 was acylated with aroyl, phenylacetyl, cinnamoyl and alkanoyl chlorides/anhydrides, yielding eight new esters, epoxyboetiranes C-J (7-14). The ability of compounds 1-14 as P-glycoprotein (Pgp, ABCB1) modulators was evaluated through combination of transport and chemosensitivity assays, using L5178Y mouse T lymphoma cell line transfected with the human MDR1 gene. In the transport assay, excepting 1, 3 and 6, the compounds, at non-cytotoxic concentrations, displayed strong MDR reversing activity in a dose-dependent mode, exhibiting all the new acyl derivatives (7-14) a many fold increase in the activity when compared with 1. Apart from 11 and 12, all compounds exhibited remarkable synergistic effects in combination with doxorubicin. An ATPase assay, using membrane vesicles from mammalian cells overexpressing Pgp, was also performed with two representatives of the modulators (4 and 5). The results suggest that both compounds compete with substrates for the Pgp drug-binding sites.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Diterpenos/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Euphorbia/química , Euphorbia/metabolismo , Humanos , Camundongos , Componentes Aéreos da Planta/química , Componentes Aéreos da Planta/metabolismo , Rodaminas/química , Rodaminas/metabolismo
9.
Planta Med ; 80(18): 1739-45, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25371982

RESUMO

Four new diterpenes were isolated from the methanolic extract of Euphorbia piscatoria, two ent-abietanes (1, 2) and two lathyrane-type macrocyclic diterpenes (3, 4), along with three known diterpenes (5-7). Their structures were characterized by spectroscopic methods, mainly 1D and 2D NMR ((1)H, (13)C, DEPT, COSY, HMBC, HMQC, and NOESY) experiments. Compound 2, with an unusual structure, might be considered intermediate in the biosynthesis of ent-abietane α,ß-unsaturated lactones, commonly found in Euphorbia species. Therefore, a possible biogenetic pathway is proposed. The MDR reversal potential of macrocyclic diterpenes 3-5 was evaluated through a drug combination assay, using the L5178Y mouse T lymphoma cell line transfected with the human MDR1 gene. Compounds 3-5 were able to enhance, synergistically, the antiproliferative activity of doxorubicin (combination indexes < 0.5). Moreover, compounds 1-6 were also assessed for their antiproliferative activity on human MDR cancer cell models, namely gastric, pancreatic, and colon. Weak antiproliferative activity was observed for compounds 1 (IC50 = 66.02 ± 7.10 µM) and 4 (IC50 = 39.51 ± 3.82 µM) on the MDR gastric cell line.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Diterpenos/química , Diterpenos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Euphorbia/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Diterpenos/administração & dosagem , Doxorrubicina/administração & dosagem , Ensaios de Seleção de Medicamentos Antitumorais , Linfoma , Espectroscopia de Ressonância Magnética , Camundongos , Estrutura Molecular
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa