RESUMO
The antiproliferative activity of a set of seven natural Amaryllidaceae alkaloids and 32 derivatives against four cancer cell lines (A2780, SW1573, T47-D and WiDr) was determined. The best antiproliferative activities were achieved with alkaloids derived from pancracine (2), haemanthamine (6) and haemantidine (7). For each skeleton, some structure-activity relationships were outlined.
Assuntos
Alcaloides/química , Alcaloides/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Alcaloides/síntese química , Antineoplásicos Fitogênicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Liliaceae/química , Relação Estrutura-AtividadeRESUMO
The new prenylated phloroglucinol α-pyrones 1-3 and the new dibenzofuran 4, together with the known 23-methyl-6-O-demethylauricepyrone (5), achyrofuran (6), and 5,7-dihydroxy-3,8-dimethoxyflavone (gnaphaliin A), were isolated from the aerial parts of Achyrocline satureioides. Their structures were determined by 1D and 2D NMR spectroscopic studies, while the absolute configuration of the sole stereogenic center of 1 was established by vibrational circular dichroism measurements in comparison to density functional theory calculated data. The same (S) absolute configuration of the α-methylbutyryl chain attached to the phloroglucinol nucleus was assumed for compounds 2-6 based on biogenetic considerations. Derivatives 7-16 were prepared from 1 and 5, and the antimicrobial activities of the isolated metabolites and some of the semisynthetic derivatives against a selected panel of Gram-positive and Gram-negative bacteria, as well as a set of yeast molds, were determined.
Assuntos
Achyrocline/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Floroglucinol/isolamento & purificação , Floroglucinol/farmacologia , Pironas/isolamento & purificação , Pironas/farmacologia , Antibacterianos/química , Argentina , Flavonoides/química , Flavonoides/isolamento & purificação , Furanos/química , Furanos/isolamento & purificação , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Floroglucinol/química , Pironas/químicaRESUMO
Nine new ß-dihydroagarofurans (1-9) and four new sesquiterpene pyridine alkaloids (10-13) were isolated from the leaves of Maytenus spinosa. Their structures were determined mainly by 1D- and 2D-NMR spectroscopic studies. The absolute configuration of compound 6 was established using CD spectroscopy. Several derivatives (14-20) were prepared from the sesquiterpene 13. Most of the sesquiterpenoids were tested for anti-HIV activity, but only compound 1 was found to be active.
Assuntos
Alcaloides/isolamento & purificação , Fármacos Anti-HIV/isolamento & purificação , Maytenus/química , Plantas Medicinais/química , Piridinas/isolamento & purificação , Sesquiterpenos/isolamento & purificação , Alcaloides/química , Alcaloides/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Argentina , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Folhas de Planta/química , Piridinas/química , Piridinas/farmacologia , Sesquiterpenos/química , Sesquiterpenos/farmacologiaRESUMO
A set of twenty one lupane derivatives (2-22) was prepared from the natural triterpenoid calenduladiol (1) by transformations on the hydroxyl groups at C-3 and C-16, and also on the isopropenyl moiety. The derivatives were tested for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and some structure-activity relationships were outlined with the aid of enzyme kinetic studies and docking modelization. The most active compound resulted to be 3,16,30-trioxolup-20(29)-ene (22), with an IC50 value of 21.5µM for butyrylcholinesterase, which revealed a selective inhibitor profile towards this enzyme.
Assuntos
Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Triterpenos/farmacologia , Animais , Butirilcolinesterase/sangue , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Enguias , Cavalos , Cinética , Modelos Moleculares , Conformação Molecular , Relação Estrutura-Atividade , Triterpenos/síntese química , Triterpenos/químicaRESUMO
A series of arylnaphthalimides were designed and synthesized to overcome the dose-limiting cytotoxicity of N-acetylated metabolites arising from amonafide, the prototypical antitumour naphthalimide whose biomedical properties have been related to its ability to intercalate the DNA and poison the enzyme Topoisomerase II. Thus, these arylnaphthalimides were first evaluated for their antiproliferative activity against two tumour cell lines and for their antitopoisomerase II in vitro activities, together with their ability to intercalate the DNA in vitro and also through docking modelization. Then, the well-known DNA damage response in Saccharomyces cerevisiae was employed to critically evaluate whether these novel compounds can damage the DNA in vivo. By performing all these assays we conclude that the 5-arylsubstituted naphthalimides not only keep but also improve amonafide's biological activities.
Assuntos
Antineoplásicos/síntese química , DNA Topoisomerases Tipo II/química , DNA/metabolismo , Substâncias Intercalantes/síntese química , Naftalimidas/química , Antineoplásicos/química , Antineoplásicos/toxicidade , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA/química , Dano ao DNA/efeitos dos fármacos , DNA Topoisomerases Tipo II/metabolismo , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Substâncias Intercalantes/química , Substâncias Intercalantes/toxicidade , Células MCF-7 , Simulação de Acoplamento Molecular , Naftalimidas/síntese química , Naftalimidas/toxicidade , Estrutura Terciária de Proteína , Saccharomyces cerevisiae/genéticaRESUMO
A series of dihydropyran and dihydropyridin embelin derivatives were synthesized through a novel and straightforward one-pot protocol based on a three-component reaction with embelin, aldehydes, and cyclic enaminones as synthetic imputs. The type of substituent on the nitrogen atom of the ß-enaminone is key to obtain nitrogenated or oxygenated rings. The obtained compounds were active against Gram-positive bacteria, including multiresistant Staphylococcus aureus clinical isolates.
Assuntos
Antibacterianos/síntese química , Benzoquinonas/síntese química , Di-Hidropiridinas/síntese química , Piranos/síntese química , Antibacterianos/química , Benzoquinonas/química , Di-Hidropiridinas/química , Estrutura Molecular , Piranos/química , EstereoisomerismoRESUMO
Sixteen dihydro-ß-agarofuran sesquiterpenes were isolated from the aerial parts of Schaefferia argentinensis Speg. Their structures were determined by a combination of 1D and 2D NMR and MS techniques. The in vitro antiproliferative activity of the major sesquiterpenes was examined in T47D, MCF7, and MDA-MB231 human cancer cell lines, but was found to be marginal.
Assuntos
Celastraceae/química , Componentes Aéreos da Planta/química , Sesquiterpenos/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Células MCF-7 , Espectroscopia de Ressonância Magnética , Espectrometria de Massas/métodos , Estrutura Molecular , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologiaRESUMO
A set of twenty one lycorenine derivatives has been prepared from the alkaloid hippeastrine (1). The modifications performed on hippeastrine included some functional group transformations, structural simplification and preparation of dimers. All alkaloids were tested as potential antimalarial agents, being the hippeastrine dimers the most active compounds.
Assuntos
Alcaloides de Amaryllidaceae/farmacologia , Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Alcaloides de Amaryllidaceae/síntese química , Alcaloides de Amaryllidaceae/química , Antimaláricos/síntese química , Antimaláricos/química , Dimerização , Humanos , Concentração Inibidora 50 , Modelos Químicos , Estrutura Molecular , Parasitemia/parasitologia , Parasitemia/prevenção & controle , Testes de Sensibilidade Parasitária , Relação Estrutura-AtividadeRESUMO
Fatty acids are of great nutritional, therapeutic, and physiological importance, especially the polyunsaturated n-3 fatty acids, possessing larger carbon chains and abundant double bonds or their immediate precursors. A few higher plant species are able to accumulate these compounds, like those belonging to the Echium genus. Here, the novel E. acanthocarpum hairy root system, which is able to accumulate many fatty acids, including stearidonic and α-linolenic acids, was optimized for a better production. The application of abiotic stress resulted in larger yields of stearidonic and α-linolenic acids, 60 and 35%, respectively, with a decrease in linoleic acid, when grown in a nutrient medium consisting of B5 basal salts, sucrose or glucose, and, more importantly, at a temperature of 15°C. The application of osmotic stress employing sorbitol showed no positive influence on the fatty acid yields; furthermore, the combination of a lower culture temperature and glucose did not show a cumulative boosting effect on the yield, although this carbon source was similarly attractive. The abiotic stress also influenced the lipid profile of the cultures, significantly increasing the phosphatidylglycerol fraction but not the total lipid neither their biomass, proving the appropriateness of applying various abiotic stress in this culture to achieve larger yields.
RESUMO
Currently, there is a pressing need for novel antibacterial agents against drug-resistant bacteria, especially those which have been common in our communities and hospitals, such as methicillin-resistant Staphylococcus aureus (MRSA). The South American plant Achyrocline satureioides ("Marcela") has been widely used in traditional medicine for a number of diseases, including infections. Several crude extracts from this plant have shown good antimicrobial activities in vitro. In the search for the active principle(s) that confers these antimicrobial activities, we have processed the dichloromethane extract from the aerial parts of the plant. One of the isolated compounds showed extraordinary antibacterial activities against a set of clinically relevant Gram-positive strains that widely differ in their antibiogram profiles. This compound was identified as achyrofuran on the basis of its spectroscopic and physical data. We determined the MIC to be around 0.1 µM (0.07 µg/ml) for the reference methicillin-resistant and vancomycin-intermediate S. aureus strain NRS402. Moreover, nanomolar concentrations of achyrofuran killed 10(6) bacteria within 12 h. Based on the presence of the 2,2'-biphenol core, we further studied whether achyrofuran killed bacteria through a mechanism of action similar to that reported for the naturally occurring antibiotic MC21-A. Indeed, we found that achyrofuran was not bacteriolytic by itself although it greatly compromised membrane impermeability as determined by increased SYTOX Green uptake.
Assuntos
Achyrocline/química , Antibacterianos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Furanos/farmacologia , Resistência a Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Resistência a Vancomicina/efeitos dos fármacos , Antibacterianos/isolamento & purificação , Argentina , Relação Dose-Resposta a Droga , Furanos/isolamento & purificação , Componentes Aéreos da Planta/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologiaRESUMO
Thirty one derivatives were prepared from the natural alkaloids haemanthamine (1), haemanthidine (2) and 11-hydroxyvittatine (3). They were evaluated for their in vitro antimalarial activity against chloroquine-sensitive strains of Plasmodium falciparum and some structure-activity relationships were outlined. For haemanthamine derivatives having a methoxy group at C-3, the presence of a free hydroxyl group at C-11 is important for the activity. The double bond at C-1-C-2 plays also an important role to achieve good inhibitory activity. Compound 35 with two nicotinate groups at C-3 and at C-11 was the most active compound with a IC(50) = 0.8 ± 0.06 µM.
Assuntos
Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/farmacologia , Antimaláricos/síntese química , Antimaláricos/farmacologia , Fenantridinas/química , Fenantridinas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Alcaloides de Amaryllidaceae/síntese química , Antimaláricos/química , Relação Dose-Resposta a Droga , Conformação Molecular , Testes de Sensibilidade Parasitária , Fenantridinas/síntese química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Lupane triterpenoids 2 and 5-12 and oleanene derivatives 13 and 14 were prepared from lupeol (1), betulin (3), and germanicol (4). They were tested for anti-HIV activity, and some structure-activity relationships were outlined. The 20-(S) absolute configuration of epoxylupenone (8) was assessed by comparison of the observed and DFT-calculated vibrational circular dichroism spectra. The CompareVOA algorithm was employed to support the C-20 configuration assignment. The 20,29 double bond in lupenone (2) and 3-epilupeol (15) was stereoselectively epoxidized to produce 20-(S)-8 and 20-(S)-16, respectively, an assignment in agreement with their X-ray diffraction structures.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Triterpenos/síntese química , Triterpenos/farmacologia , Fármacos Anti-HIV/química , Dicroísmo Circular , Cristalografia por Raios X , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Triterpenos/químicaRESUMO
Three withanolides were isolated from the aerial parts of Jaborosa reflexa Phil. Jaborosa cabrerae Barboza yielded five sativolide withanolides (including jaborosalactones R, S, 38, and 39) and two trechonolide withanolides epimeric at C-23 (trechonolide A and jaborosalactone 32). In addition, five derivatives were obtained by chemical derivatization of jaborosalactone 38, and all compounds were fully characterized by 1D and 2D NMR spectroscopic studies. The in vitro antiproliferative activities of the major natural withanolides and the semisynthetic derivatives were examined against HBL-100, HeLa, SW1573, T-47D, and WiDr human solid tumor cancer cell lines. Some chemotaxonomic considerations are discussed.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Solanaceae/química , Vitanolídeos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Biomarcadores/química , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Espectroscopia de Ressonância Magnética/métodos , Estrutura Molecular , Componentes Aéreos da Planta/química , Solanaceae/classificação , Relação Estrutura-Atividade , Vitanolídeos/química , Vitanolídeos/isolamento & purificaçãoRESUMO
Four new dihydroagarofurans (1-4) were isolated from the root bark of Plenckia integerrima. The structures of 1-4 were determined by means of 1D and 2D NMR techniques, and circular dichroism (CD) was used to determine the absolute configuration of compound 1.
Assuntos
Fármacos Anti-HIV/química , Celastraceae/química , Extratos Vegetais/química , Sesquiterpenos/química , Fármacos Anti-HIV/isolamento & purificação , Fármacos Anti-HIV/farmacologia , Sobrevivência Celular , Dicroísmo Circular , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Casca de Planta/química , Raízes de Plantas/química , Plantas Medicinais/química , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , EstereoisomerismoRESUMO
Three new benzodihydrofurans (1-3) and seven known aromatic compounds (4-10) were isolated from the roots of Cyperus teneriffae. Vibrational circular dichroism spectroscopy was used to define the absolute configuration of 1.
Assuntos
Benzofuranos/isolamento & purificação , Cyperus/química , Benzofuranos/química , Dicroísmo Circular , Estrutura Molecular , Raízes de Plantas/químicaRESUMO
BACKGROUND: The therapeutic and health promoting role of highly unsaturated fatty acids (HUFAs) from fish, i.e. eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) are well known. These same benefits may however be shared by some of their precursors, the polyunsaturated fatty acids (PUFAs), such as stearidonic acid (SDA, 18:4 n-3). In order to obtain alternative sources for the large-scale production of PUFAs, new searches are being conducted focusing on higher plants oils which can contain these n-3 and n-6 C18 precursors, i.e. SDA and GLA (18:3n-6, γ-linolenic acid). RESULTS: The establishment of the novel Echium acanthocarpum hairy root cultures represents a powerful tool in order to research the accumulation and metabolism of fatty acids (FAs) in a plant particularly rich in GLA and SDA. Furthermore, this study constitutes the first example of a Boraginaceae species hairy root induction and establishment for FA studies and production. The dominant PUFAs, 18:2n-6 (LA, linoleic acid) and 18:3n-6 (GLA), accounted for about 50% of total FAs obtained, while the n-3 PUFAs, 18:3n-3 (ALA, α-linolenic acid) and 18:4n-3 (SDA), represented approximately 5% of the total. Production of FAs did not parallel hairy root growth, and the optimal productivity was always associated with the highest biomass density during the culture period. Assuming a compromise between FA production and hairy root biomass, it was determined that sampling times 4 and 5 gave the most useful FA yields. Total lipid amounts were in general comparable between the different hairy root lines (29.75 and 60.95 mg/g DW), with the major lipid classes being triacylglycerols. The FAs were chiefly stored in the hairy roots with very minute amounts being released into the liquid nutrient medium. CONCLUSIONS: The novel results presented here show the utility and high potential of E. acanthocarpum hairy roots. They are capable of biosynthesizing and accumulating a large range of polyunsaturated FAs, including the target GLA and SDA fatty acids in appreciable quantities.
Assuntos
Echium/metabolismo , Ácidos Graxos Insaturados/análise , Técnicas de Cultura de Tecidos/métodos , Análise de Variância , Ácidos Graxos Insaturados/biossíntese , Ácidos Graxos Insaturados/isolamento & purificação , Ácidos Graxos Insaturados/metabolismo , Raízes de Plantas/metabolismo , Análise de Componente PrincipalRESUMO
A series of kaurene derivatives (1-63) were prepared and evaluated for anti-inflammatory activity. Thirteen of the tested compounds were able to inhibit NO production with an IC(50) between 2 and 10 µM. Compounds 11, 12, 14 and 23 showed low percentage of cell viability, whereas compounds 9, 10, 17, 28, 37, 48, 55, 61 and 62 were non-cytotoxic at the concentration up to 25 µM. Some structure-activity relationships were outlined. Compounds 28, 55 and 62, were selected as representative compounds and they potently inhibited the protein expression of NOS-2. We also determined that inhibition of NF-κB activation might be the mechanism involved in anti-inflammatory effects of these kaurene derivatives. As expected, cytokines IL-6, IL-1α, TNF-α and IFN-γ were downregulated in the presence of compound 28, 55 and 62 after stimulation with LPS. These results indicate that kaurene derivatives might be used for the design of new anti-inflammatory agents.
Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Diterpenos do Tipo Caurano/síntese química , Diterpenos do Tipo Caurano/farmacologia , Animais , Anti-Inflamatórios/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Diterpenos do Tipo Caurano/química , Regulação da Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Camundongos , NF-kappa B/antagonistas & inibidores , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismoRESUMO
The electronic properties of a new set of cytotoxic 2-amino-naphtho[2,3-b]furan-4,9-dione derivatives (1-8) are evaluated. The electron delocalization of these compounds is described by means of their redox potentials and solvatochromic properties. The large solvatochromism of their intramolecular electron transfer band is analyzed using the linear solvation energy relationship method. In addition, this method determined the importance of the molecular environment, quantifying the interactions that compounds (1-8) establish with their surrounding media, with the capacity of acting as hydrogen-bond acceptors (HBA) and hydrogen-bond donors (HBD) and the dipolarity/polarizability being the most significant ones. As a result, a relationship between the electronic and the cytotoxic properties of these compounds is proposed.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Elétrons , Naftoquinonas/química , Naftoquinonas/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Eletroquímica , Transporte de Elétrons , Humanos , Modelos Moleculares , Conformação Molecular , Naftoquinonas/síntese química , Solventes/químicaRESUMO
Seven new triterpenoids (1-7) and 36 known compounds were isolated from the root bark of Maytenus retusa. Their structures were determined by 1D and 2D spectroscopic studies. Several compounds were evaluated for their cytotoxicity against the human tumor cell lines HL-60 and MCF-7. Some of them were cytotoxic, with IC(50) values ranging between 0.2 and 4.7 µM.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Maytenus/química , Plantas Medicinais/química , Triterpenos/isolamento & purificação , Triterpenos/farmacologia , Antineoplásicos Fitogênicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Humanos , Concentração Inibidora 50 , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Casca de Planta/química , Triterpenos/químicaRESUMO
Twenty seven lycorine derivatives were prepared and evaluated for their in vitro antimalarial activity against chloroquine-sensitive strains of Plasmodium falciparum. The best antiplasmodial activities were achieved with lycorine derivatives that present free hydroxyl groups at C-1 and C-2 or esterified as acetates or isobutyrates. The double bond C-2-C-3 is also important for the activity. Concerning to the antiplasmodial activity of the secolycorines, the higher values were obtained with the replacement of the methylenedioxy moiety by hydroxyl or acetate groups and with methyl substituent attached to the nitrogen atom.