RESUMO
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
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
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
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 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
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
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
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
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
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
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
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.
Assuntos
Alcaloides de Amaryllidaceae/química , Antimaláricos/síntese química , Fenantridinas/química , Alcaloides de Amaryllidaceae/síntese química , Alcaloides de Amaryllidaceae/farmacologia , Antimaláricos/química , Antimaláricos/farmacologia , Fenantridinas/síntese química , Fenantridinas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Thirty one ent-kaurane derivatives were prepared from kaurenoic acid (1), grandiflorenic acid (16), 15alpha-acetoxy-kaurenoic acid (26) and 16alpha-hydroxy-kaurenoic acid (31). They were tested for their ability to inhibit cell viability in the mouse leukemic macrophagic RAW 264.7 cell line. The most effective compounds were 12, 20, 21, and 23. These were selected for further evaluation in other human cancer cell lines such as Hela, HepG2, and HT-29. Similar effects were obtained although RAW 264.7 cells were more sensitive. In addition, these compounds were significantly less cytotoxic in non-transformed cells. The apoptotic potential of the most active compounds was investigated and they were able to induce apoptosis with compound 12 being the best inducer. The caspase-3, -8 and -9 activities were measured. The results obtained showed that compounds 12, 21, and 23 induce apoptosis via the activation of caspase-8, whereas compound 20 induces apoptosis via caspase-9. Immunoblot analysis of the expression of p53, Bax, Bcl-2, Bcl-xl, and IAPs in RAW 264.7 cells was also carried out. When cells were exposed to 5 microM of the different compounds, expression levels of p53 and Bax increased whereas levels of antiapoptotic proteins such as Bc1-2, Bc1-x1, and IAPs decreased. In conclusion, kaurane derivatives (12, 20, 21, and 23) induce apoptosis via both the mitochondrial and membrane death receptor pathways, involving the Bcl-2 family proteins. Taken together these results provide a role of kaurane derivatives as apoptotic inducers in tumor cells.
Assuntos
Apoptose/efeitos dos fármacos , Diterpenos do Tipo Caurano/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Expressão Gênica/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Camundongos , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , Relação Estrutura-AtividadeRESUMO
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
In this study, the in vitro activities of a natural sesquiterpene, alpha-cyperotundone, isolated from the root bark of Maytenus retusa and a cobalt(II)-complex of a natural occurring prenyl hydroxynaphthoquinone (lapachol) were evaluated against the trophozoite stage of Acanthamoeba castellanii Neff using a previously developed colorimetric 96-well microtiter plate assay, based on the oxido-reduction of Alamar Blue(R). The obtained activities showed that these two compounds were able to inhibit the in vitro growth of the amoebae at relatively low concentrations. Further identification of the molecular targets of these products and their effects on acanthamoebae should be determined to evaluate their possible therapeutic use.
Assuntos
Acanthamoeba castellanii/efeitos dos fármacos , Antiprotozoários/farmacologia , Cobalto/farmacologia , Naftoquinonas/farmacologia , Sesquiterpenos/farmacologia , Acanthamoeba castellanii/crescimento & desenvolvimento , Celastraceae/química , Cobalto/metabolismo , Humanos , Naftoquinonas/metabolismo , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Sesquiterpenos/químicaRESUMO
A new cDNA encoding hyoscyamine 6beta-hydroxylase (H6H, EC 1.14.11.11), a bifunctional enzyme catalyzing the last two steps in the biosynthesis of scopolamine, was isolated from Atropa baetica roots (GenBank accession no. EF442802). The full cDNA sequence showed an ORF of 1035bp, coding for a protein with 344 amino acid residues. Sequence analyses at the nucleotide level showed that this ORF shares high identity with other H6H from different plant species, such as Anisodus tanguticus and Hyoscyamus niger with 90% identity, and an almost total identity with A. belladonna (98%). Tissue expression analyses showed that the gene transcript was tissue dependent, appearing exclusively in roots, thus being the only biosynthetic site for the production of scopolamine. Furthermore, Southern hybridization experiments revealed that this gene was not part of a multigene family as appears in low copy number. Phylogenetic tree analysis indicated that A. baetica H6H had a very close relationship with A. belladonna and to a lesser extent with H. niger.
Assuntos
Atropa/genética , Oxigenases de Função Mista/genética , Atropa/enzimologia , Sequência de Bases , DNA Complementar , Perfilação da Expressão Gênica , Oxigenases de Função Mista/isolamento & purificação , Dados de Sequência Molecular , Filogenia , Proteínas de Plantas/classificação , Raízes de Plantas/enzimologia , Raízes de Plantas/genética , Escopolamina/biossíntese , Análise de Sequência de DNA , Transcrição GênicaRESUMO
Five new triterpenes (1-5) and one new lignan (6) were isolated from the aerial parts of Maytenus apurimacensis. Their structures were determined on the basis of spectroscopic studies, including homonuclear and heteronuclear correlation NMR experiments (COSY, ROESY, HSQC, and HMBC).
Assuntos
Lignanas/isolamento & purificação , Maytenus/química , Triterpenos/isolamento & purificação , Lignanas/química , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Peru , Folhas de Planta/química , Triterpenos/químicaRESUMO
Four new alkaloids (1-4) have been isolated from a methanolic extract of bulbs of Pancratium canariense, together with 12 known alkaloids (5-16). The structures of the new alkaloids were determined by extensive 1D and 2D NMR spectroscopic studies and X-ray diffraction.
Assuntos
Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/isolamento & purificação , Liliaceae/química , Plantas Medicinais/química , Cristalografia por Raios X , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , EspanhaRESUMO
Two new sesquiterpenes (1-2) and one new lupane triterpene (3) have been isolated from the roots of Maytenus apurimacensis. The novel beta-dihydroagarofurans are the first sesquiterpenes with a basic polyhydroxy skeleton of 15-deoxyalatol and 4,15-dideoxyalatol that show high MDR reversing activity in the protozoan parasite Leishmania tropica.