RESUMO
Two dihydroflavonol glycosides, engeletin and astilbin, were isolated from an EtOAc extract of the leaves of Stelechocarpus cauliflorus R.E. Fr. (Annonaceae). The inhibitory activity of engeletin against a recombinant human aldose reductase (IC50 value=1.16 microM) was twice that of quercetin as a positive control (2.48 microM), and 23 times greater than that of astilbin (26.7 microM). Engeletin inhibited the enzyme uncompetitively. Astilbin was about as potent as the positive control, quercetin, in its inhibition of advanced glycation end-products formation. These flavonoids displayed therapeutic potential in the prevention and treatment of diabetic complications.
Assuntos
Aldeído Redutase/antagonistas & inibidores , Annonaceae/química , Produtos Finais de Glicação Avançada/antagonistas & inibidores , Extratos Vegetais/farmacologia , Folhas de Planta/química , Flavonóis/química , Flavonóis/farmacologia , Glicosídeos/química , Glicosídeos/farmacologia , Estrutura Molecular , Extratos Vegetais/químicaRESUMO
The pharmacological properties of geissoschizine methyl ether, isolated from Uncaria sinensis Oliv., were analyzed in vitro and in vivo using mice central serotonin neurons. In the in vitro experiment, geissoschizine methyl ether inhibited [3H]8-hydroxy-2-(di-n-propylamino)tetralin) ([3H]8-OH-DPAT) (K(i)=0.8 microM), [3H]mesulergine (K(i)=0.9 microM) and [3H]ketanserin (K(i)=1.4 microM), but had less affinity toward [3H]prazosin (K(i) > 10 microM) and [3H]spiperone (K(i) >15 microM) binding to mouse brain membranes. The in vivo studies showed that geissoschizine methyl ether dose-dependently reduced 5-hydroxy-L-tryptophan (I-5-HTP) plus clorgyline-induced head twitch response without inhibiting the I-5-HTP plus clorgyline and 8-OH-DPAT-induced head weaving. On the other hand, geissoschizine methyl ether also decreased the rectal temperature of mice (hypothermic response) in a dose-dependent manner. These results suggest that geissoschizine methyl ether possesses mixed 5-HT(1A) receptor agonist/5-HT(2A/2C) receptor antagonist activities and inhibits the head twitch response by blocking the 5-HT(2A) receptors, and possibly, at least in part, by stimulating the 5-HT(1A) receptors in the central nervous system.
Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Indóis/farmacologia , 5-Hidroxitriptofano/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Ligação Competitiva/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Alcaloides Indólicos , Masculino , Membranas/efeitos dos fármacos , Membranas/metabolismo , Camundongos , Atividade Motora/efeitos dos fármacos , Ensaio Radioligante , Reto/fisiologia , TrítioRESUMO
The leaves of Aglaia edulis afforded a new bisamide, aglaiduline, and two new sulfur-containing bisamides, aglaithioduline and aglaidithioduline. Their structures were established from spectroscopic studies. The sulfur-containing amides exhibited slight antiviral activity against herpes simplex virus types 1 and 2.
Assuntos
Amidas/química , Amidas/farmacologia , Plantas Medicinais/química , Amidas/isolamento & purificação , Antivirais/química , Antivirais/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Folhas de Planta/química , Sulfetos/química , Sulfetos/isolamento & purificação , Sulfetos/farmacologia , ÁrvoresRESUMO
Extracts from the aerial parts of Sanicula europaea L. were investigated for their anti-HIV activity, and the 50% ethanolic extract was shown to exhibit the highest activity. A new triterpene saponin glycoside, 21 beta-(angeloyloxy)-3-O-[beta-D-arabinopyranosyl(1-->4)-beta- D-glucopyranosyl (1-->3)-beta-D-glucuronopyranosyl propyl ester]-3 beta,15,16,22 alpha,28 beta-pentahydroxy-delta(12)-oleanene, saniculoside N (1), in addition to the known phenolic acids, rosmarinic acid (2), and caffeic acid (3) were isolated as major components. Rosmarinic acid was established as the principal active substance.
Assuntos
Fármacos Anti-HIV/isolamento & purificação , HIV-1/efeitos dos fármacos , Ácido Oleanólico/análogos & derivados , Plantas Medicinais/química , Saponinas/isolamento & purificação , Triterpenos/isolamento & purificação , Fármacos Anti-HIV/farmacologia , HIV-1/enzimologia , Hidrólise , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Conformação Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Saponinas/farmacologia , Triterpenos/farmacologiaRESUMO
Eleven biflavonoids, including amentoflavone (1), agathisflavone (2), robustaflavone (3), hinokiflavone (4), volkensiflavone (5), morelloflavone (7), rhusflavanone (9), succedaneaflavanone (10), GB-1a (11), GB-1a 7"-O-beta-glucoside (13), and GB-2a (14) isolated from Rhus succedanea and Garcinia multiflora, as well as their methyl ethers, volkensiflavone hexamethyl ether (6), morelloflavone heptamethyl ether (8), and GB-1a hexamethyl ether (12), were evaluated for their anti-HIV-1 RT activity. The results indicated that compounds 3 and 4 demonstrated similar activity against HIV-1 reverse transcriptase (RT), with IC50 values of 65 microM. Compounds 1, 2, 7, 11, and 14 were moderately active against HIV-1 RT, with IC50 values of 119 microM, 100 microM, 116 microM, 236 microM, and 170 microM, respectively. Morelloflavone (7) also demonstrated significant antiviral activity against HIV-1 (strain LAV-1) in phytohemagglutinin-stimulated primary human peripheral blood mononuclear cells at an EC50 value of 6.9 microM and a selectivity index value of approximately 10. The other biflavonoids were either weakly active, inactive, or not selective against HIV-1 in human lymphocytes.
Assuntos
Fármacos Anti-HIV/farmacologia , Flavonoides/farmacologia , Plantas Medicinais/química , Plantas Tóxicas , Toxicodendron/química , Fármacos Anti-HIV/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Flavonoides/isolamento & purificação , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Replicação Viral/efeitos dos fármacosRESUMO
Soulattrolide (1), a coumarin isolated from Calophyllum teysmannii latex, was found to be a potent inhibitor of HIV-1 reverse transcriptase (RT) with an IC50 of 0.34 microM. Inhibition was remarkably specific, with no appreciable activity being observed toward HIV-2 RT, AMV RT, RNA polymerase, or DNA polymerases alpha or beta.
Assuntos
Cumarínicos/isolamento & purificação , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/enzimologia , Plantas Medicinais/química , Inibidores da Transcriptase Reversa/farmacologia , Cumarínicos/farmacologia , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Humanos , Indicadores e Reagentes , Látex/química , Inibidores da Síntese de Ácido Nucleico , Inibidores da Transcriptase Reversa/isolamento & purificação , Ribonuclease H/antagonistas & inibidoresRESUMO
Baccatin III, which is used as a precursor for the semisynthesis of taxol, showed cytotoxic activity against a variety of cancer cell lines in culture, with ED50 values ranging from approximately 8 to 50 microM. Although the potency of this response is much lower than that mediated by taxol, it was interesting to note that any significant cytotoxic response could be mediated by this compound. Thus, it was considered of potential value to investigate the mechanism of cytotoxic action. Consistent with an antimitotic mode of action, baccatin III induced cultured cells to accumulate in the G2 + M phases of the cell cycle. However, unlike taxol, which potentiates the polymerization of tubulin, baccatin III mediated an antimitotic response through inhibition of the polymerization reaction, similar to colchicine, podophyllotoxin, or vinblastine. Accordingly, baccatin III was unable to reduce the extent of Ca(2+)-induced depolymerization, a hallmark of the biological response mediated by taxol. To further explore the mode of antimitotic activity facilitated by baccatin III, competitive interactions with the colchicine, podophyllotoxin, and vinblastine binding sites of tubulin were investigated. Baccatin III displaced the binding of radiolabeled colchicine or radiolabeled podophyllotoxin, but did not displaced the binding of radiolabeled vinblastine. Greater affinity with the colchicine binding site was observed and the kinetics of inhibition were shown to be mixed. The side chain of taxol, which differentiates the molecule from baccatin III and is known to be of requisite importance for the unique activity mediated by taxol, is not by itself active in any of these processes. Thus, the baccatin III nucleus of taxol may lead to an interaction with tubulin through traditional binding sites. Facilitated by this interaction, the intact molecule of taxol may thereby be permitted to potentiate tubulin polymerization and block cells in the mitotic phase of the cell cycle.
Assuntos
Alcaloides/toxicidade , Taxoides , Animais , Antineoplásicos/toxicidade , Sítios de Ligação , Ciclo Celular/efeitos dos fármacos , Colchicina/metabolismo , Humanos , Camundongos , Microtúbulos/efeitos dos fármacos , Paclitaxel/química , Podofilotoxina/metabolismo , Polímeros , Ligação Proteica/efeitos dos fármacos , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Células Tumorais Cultivadas , Vimblastina/metabolismoRESUMO
An A ring-secocycloartene triterpenoid, nigranoic acid (3,4-secocycloarta-4(28),24-(Z)-diene-3,-26-dioic acid, (1) was isolated from the stems of Schisandra sphaerandra, a Chinese traditional medicinal plant. Its structure elucidation and unambiguous NMR spectral assignment were achieved by the combination of 1D- and 2D-NMR techniques with the aid of computer modeling. Nigranoic acid showed activity in several anti-HIV reverse transcriptase and polymerase assays.
Assuntos
Plantas Medicinais/química , DNA Polimerase Dirigida por RNA/metabolismo , Inibidores da Transcriptase Reversa/isolamento & purificação , Inibidores da Transcriptase Reversa/farmacologia , Triterpenos/isolamento & purificação , China , Transcriptase Reversa do HIV , Humanos , Espectroscopia de Ressonância Magnética , Inibidores da Síntese de Ácido Nucleico , Triterpenos/farmacologiaRESUMO
The anti-HIV agent (+/-)-calanolide A (1) has been synthesized in a five-step approach starting with phloroglucinol [-->5-->6-->11-->18-->(+/-)-1], which includes Pechmann reaction, Friedel-Crafts acylation, chromenylation with 4,4-dimethoxy-2-methylbutan-2-ol, cyclization, and Luche reduction. Cyclization of chromene 11 to chromanone 18 was achieved by employing either acetaldehyde diethyl acetal or paraldehyde in the presence of trifluoroacetic acid and pyridine or PPTS. Luche reduction of chromanone 18 at lower temperature preferably yielded (+/-)-1. Reduction of chromone 12, synthesized by Kostanecki-Robinson reaction from chromene 11, failed to afford (+/-)-1. The synthetic (+/-)-1 has been chromatographically resolved into its optically active forms, (+)- and (-)-1. The anti-HIV activities for synthetic (+/-)-1, as well as resultant (+)- and (-)-1, have been determined. Only (+)-1 accounted for anti-HIV activity, which was similar to the data reported for the natural product, and (-)-1 was inactive.
Assuntos
Antivirais/síntese química , Cumarínicos/síntese química , HIV/efeitos dos fármacos , Antivirais/farmacologia , Cromatografia Líquida de Alta Pressão , Cumarínicos/análise , Cumarínicos/farmacologia , Transcriptase Reversa do HIV , Inibidores da Síntese de Ácido Nucleico , Piranocumarinas , DNA Polimerase Dirigida por RNA , EstereoisomerismoRESUMO
From Hymenocallis littoralis, one new alkaloid, named littoraline, together with 13 known lycorine alkaloids and one lignan, were isolated. The structure and NMR assignments of this new alkaloid were determined by 1D and 2D NMR techniques. Littoraline showed inhibitory activity of HIV reverse transcriptase, and lycorine and haemanthamine showed potent in vitro cytotoxicity.
Assuntos
Alcaloides/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Inibidores da Transcriptase Reversa/isolamento & purificação , Alcaloides/química , Alcaloides/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Transcriptase Reversa do HIV , HIV-1/enzimologia , Humanos , Espectroscopia de Ressonância Magnética , DNA Polimerase Dirigida por RNA/metabolismo , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Células Tumorais CultivadasRESUMO
Swertifrancheside [1], a new flavonone-xanthone glucoside isolated from Swertia franchetiana, 1 beta-hydroxyaleuritolic acid 3-p-hydroxybenzoate [2], a triterpene isolated from the roots of Maprounea africana, and protolichesterinic acid [3], an aliphatic alpha-methylene-gamma-lactone isolated from the lichen Cetraria islandica, were found to be potent inhibitors of the DNA polymerase activity of human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT), with 50% inhibitory doses (IC50 values) of 43, 3.7, and 24 microM, respectively. They were not cytotoxic with cultured mammalian cells. The kinetic mechanisms by which compounds 1-3 inhibited HIV-1 RT were studied as was their potential to inhibit other nucleic acid polymerases. Swertifrancheside [1] bound to DNA and was shown to be a competitive inhibitor with respect to template-primer, but a mixed-type competitive inhibitor with respect to TTP. On the other hand, 1 beta-hydroxyaleuritolic acid 3-p-hydroxybenzoate [2] and protolichesterinic acid [3] were mixed-type competitive inhibitors with respect to template-primer and noncompetitive inhibitors with respect to TTP. Therefore, the mechanism of action of 1 beta-hydroxyaleuritolic acid 3-p-hydroxybenzoate [2] and protolichesterinic acid [3] as HIV-1 RT inhibitors involves nonspecific binding to the enzyme at nonsubstrate binding sites, whereas swertifrancheside [1] inhibits enzyme activity by binding to the template-primer.
Assuntos
4-Butirolactona/análogos & derivados , Flavonoides/farmacologia , Plantas Medicinais/química , Triterpenos/isolamento & purificação , Xantenos/farmacologia , Xantonas , 4-Butirolactona/química , 4-Butirolactona/isolamento & purificação , 4-Butirolactona/farmacologia , Cromatografia Líquida de Alta Pressão , DNA/metabolismo , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Humanos , Cinética , Inibidores da Síntese de Ácido Nucleico , Inibidores da Transcriptase Reversa , Soroalbumina Bovina/farmacologia , Moldes Genéticos , Triterpenos/química , Triterpenos/farmacologia , Zidovudina/farmacologiaRESUMO
The Turkish species Euphorbia myrsinites has yielded four new tetracyclic diterpene tetraesters from a cytotoxic acetone extract, in addition to the known cycloartane-type triterpenoids and betulin. The new compounds and their hydrolysis product have been extensively characterized by high field spectroscopic techniques, and were shown to be four new tetraesters of the parent alcohol, myrsinol.
Assuntos
Antivirais/química , Diterpenos/química , Plantas Medicinais , Inibidores da Transcriptase Reversa , Antivirais/isolamento & purificação , Antivirais/farmacologia , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Ésteres/química , Ésteres/isolamento & purificação , Transcriptase Reversa do HIV , HIV-1/enzimologia , Espectroscopia de Ressonância Magnética , Conformação Molecular , Estrutura Molecular , TurquiaAssuntos
Benzoatos/isolamento & purificação , HIV-1/enzimologia , Plantas Medicinais/química , DNA Polimerase Dirigida por RNA , Triterpenos/isolamento & purificação , Benzoatos/farmacologia , Transcriptase Reversa do HIV , HIV-2/enzimologia , Inibidores da Transcriptase Reversa , Relação Estrutura-Atividade , Tanzânia , Triterpenos/farmacologiaRESUMO
By means of activity-directed chromatographic fractionation using cultured astrocytoma (ASK) cells, six dibenzocyclo-octadiene lignans were isolated from Steganotaenia araliacea stem bark. In addition to the most abundant analogue, steganangin [1], two other known compounds, steganacin [3] and steganolide A [6], and three new compounds, episteganangin [2], steganoate A [4], and steganoate B [5], were obtained. Episteganangin [2] was chemically correlated with the known ketone steganone [7]. All of these compounds demonstrated cytotoxic activity when tested against a panel of eleven human tumor cell lines, with the exception of steganoate A [4]. The magnitude of this activity tended to correlate with antimitotic activity observed with the ASK assay and in vitro inhibition of microtubule assembly. Steganacin [3] was less cytotoxic than colchicine, but more active in these latter two assay systems.