RESUMO
[structure: see text]. Isolation and structure elucidation of two novel cyclic tetrapeptides that show a variety of potent antiprotozoal activities by reversibly inhibiting HDAC have been reported. These are the new members of a unique family of cyclic tetrapeptides that do not require the electrophilic alpha-epoxyketone moiety of HC-toxin, trapoxin A, or chlamydocin for their potent activities against HDAC and the malarial parasite.
Assuntos
Antiprotozoários/química , Histona Desacetilases/metabolismo , Peptídeos Cíclicos/química , Substituição de Aminoácidos , Animais , Antiprotozoários/farmacologia , Eimeria tenella/efeitos dos fármacos , Inibidores de Histona Desacetilases , Espectroscopia de Ressonância Magnética , Conformação Molecular , Testes de Sensibilidade Parasitária , Peptídeos Cíclicos/farmacologia , Prolina/química , Sarcocystidae/efeitos dos fármacos , Valina/químicaRESUMO
From the screening of a microbial extract library, isocomplestatin (1), a new axial-chiral isomer of complestatin (2) which is a known rigid bicyclic hexapeptide, was identified as a potent natural product inhibitor of HIV-1 integrase, a unique enzyme responsible for viral replication. Isocomplestatin showed inhibitory activities (IC(50)) in coupled 3'-end processing/strand transfer (200 nM), strand transfer (4 microM), and HIV-1 replication (200 nM) in virus-infected cells. Attempted large-scale isolation of 1 by the literature method, used for the isolation of complestatin, led to lower yield and limited availability. We have developed several new, two-step, high-yielding absorption/elution methods of isolation based on reverse-phase chromatography at pH 8 that are applicable to scales from one gram to potential industrial quantities. We have also discovered and determined the structure of two new congeners of 1, namely, complestatins A (4) and B (5), with almost equal HIV-1 integrase activity. They differ from 1 at C2' and C3' of the tryptophan moiety (residue F). Selective acid hydrolysis of chloropeptin I (3), itself a known acid-catalyzed rearranged isomer of 1 and 2 (8'- vs 7'-substitution in tryptophan residue F, respectively), an isomer of complestatin, and isocomplestatin resulted in a number of fragments (6-10) with retention of most of the HIV-1 integrase activity. The structure-activity relationship as revealed by these compounds could possibly lead to the design of better inhibitors or understanding of the HIV-1 integrase target.
Assuntos
Fármacos Anti-HIV/isolamento & purificação , Clorofenóis/isolamento & purificação , Inibidores de Integrase de HIV/isolamento & purificação , Integrase de HIV/metabolismo , HIV-1/enzimologia , Oligopeptídeos/isolamento & purificação , Peptídeos Cíclicos , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Clorofenóis/química , Clorofenóis/farmacologia , Cromatografia Líquida de Alta Pressão , Cromatografia Gasosa-Espectrometria de Massas , Proteína gp120 do Envelope de HIV/metabolismo , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , HIV-1/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Espectroscopia de Ressonância Magnética , Modelos Químicos , Estrutura Molecular , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Estereoisomerismo , Streptomyces/química , Streptomyces/metabolismo , Relação Estrutura-AtividadeRESUMO
[figure: see text] Blockers of the voltage-gated potassium channel Kv1.3 are potential immunosuppressants. Candelalides A-C are three novel diterpenoid pyrones that block this channel. The structure, stereochemistry, and activity against Kv1.3 are described.
Assuntos
Diterpenos/síntese química , Bloqueadores dos Canais de Potássio , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio , Pironas/síntese química , Animais , Células CHO , Cricetinae , Diterpenos/química , Diterpenos/farmacologia , Fermentação , Hypocreales/crescimento & desenvolvimento , Imunossupressores/síntese química , Imunossupressores/química , Imunossupressores/farmacologia , Canal de Potássio Kv1.1 , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Pironas/química , Pironas/farmacologia , Proteínas Recombinantes/antagonistas & inibidoresRESUMO
Two antifungal triterpenoid glycosides, hyalodendrosides A and B (1 and 2), were isolated from a solid matrix fermentation of a lignicolous hyphomycete, Hyalodendron sp. Their structures were determined based upon extensive examination of spectral parameters, particularly NMR and MS data. Both compounds have beta-linked glucose moieties. Compounds 1 and 2 show weak to moderate antifungal activity against some clinically relevant fungi.
Assuntos
Antifúngicos/isolamento & purificação , Fungos Mitospóricos/química , Saponinas/isolamento & purificação , Triterpenos , Antifúngicos/química , Antifúngicos/farmacologia , Configuração de Carboidratos , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Saponinas/química , Saponinas/farmacologiaRESUMO
A resorcylic acid lactone, L-783,277, isolated from a Phoma sp. (ATCC 74403) which came from the fruitbody of Helvella acetabulum, is a potent and specific inhibitor of MEK (Map kinase kinase). L-783,277 inhibits MEK with an IC50 value of 4 nM. It weakly inhibits Lck and is inactive against Raf, PKA and PKC. L-783,277 is an irreversible inhibitor of MEK and is competitive with respect to ATP. L-783,290, the trans-isomer of L-783,277, was isolated from the same culture and evaluated together with several semi-synthetic resorcylic acid lactone analogs. A preliminary structure-activity relationship is presented. Several independent cell-based assays have been carried out to study the biological activities of these resorcylic acid lactone compounds and a brief result summary from these studies is presented.
Assuntos
Inibidores Enzimáticos/farmacologia , Lactonas/farmacologia , MAP Quinase Quinase Quinase 1 , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Resorcinóis/farmacologia , Trifosfato de Adenosina/farmacologia , Humanos , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidoresRESUMO
Farnesyl-protein transferase (FPTase) catalyses the specific transfer of farnesyl to Ras-peptides that is essential for oncogenic activity in oncogene-mediated tumors. Specific inhibition of FPTase activity has been shown to reduce tumor development in nude mice challenged with oncogenic forms of ras, thereby establishing FPTase as a viable therapeutic target. Our continued efforts to discover inhibitors of FPTase has led to the discovery of a triterpenoidal inhibitor, clavaric acid (1). This compound inhibits rHFPTase with an IC50 value of 1.3 microM. Structure elucidation, structure modifications, and biological activity of clavaric acid are herein described.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Basidiomycota/química , Inibidores Enzimáticos/isolamento & purificação , Lanosterol/análogos & derivados , Animais , Inibidores Enzimáticos/farmacologia , Fermentação , Hidrólise , Lanosterol/isolamento & purificação , Lanosterol/farmacologia , Metilação , Camundongos , Espectrofotometria InfravermelhoRESUMO
The mode of action of the known antifungal macrolides rustmicin (1) and galbonolide B (2) has been determined to be the inhibition of sphingolipid biosynthesis. A large scale fermentation and isolation process was developed for production of large quantities of rustmicin. New 21-hydroxy derivatives of both compounds were isolated from pilot scale fermentations and were also produced by biotransformation of rustmicin and galbonolide B.
Assuntos
Antifúngicos/farmacologia , Fungos/metabolismo , Esfingolipídeos/biossíntese , Antifúngicos/química , Antifúngicos/isolamento & purificação , Candida/efeitos dos fármacos , Candida/metabolismo , Candida albicans/efeitos dos fármacos , Candida albicans/metabolismo , Cryptococcus neoformans/efeitos dos fármacos , Cryptococcus neoformans/metabolismo , Avaliação Pré-Clínica de Medicamentos , Fermentação , Fungos/efeitos dos fármacos , Lactonas/química , Lactonas/metabolismo , Lactonas/farmacologia , Testes de Sensibilidade Microbiana , Micromonospora/química , Micromonospora/metabolismo , Estrutura MolecularRESUMO
Farnesyl-protein transferase (FPTase) is a critical enzyme that participates in the post-translational modification of the Ras protein. Inhibitors of this enzyme have the potential of being novel anticancer agents for tumors in which the ras oncogene is found mutated and contributes to cell transformation. Continued screening of natural product extracts led to the isolation of kampanols, which are novel and specific inhibitors of FPTase. The most active kampanols exhibited IC50 values between 7 to 13 microM against human recombinant FPTase. The isolation, structure determination, and biological activity of these compounds are described.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Antineoplásicos/química , Inibidores Enzimáticos/química , Terpenos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Genes ras , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Proteínas Recombinantes/antagonistas & inibidores , Terpenos/isolamento & purificação , Terpenos/farmacologiaRESUMO
Extracts of sclerotia from Sclerotinia sclerotiorum, a fungal phytopathogen, contain two electrochemically-active constituents, D-glycero-pent-2-enono-1,4-lactone (trivial name: D-erythroascorbic acid), and a previously unidentified compound, here characterized as 5-O-(alpha-D-galactopyranosyl)-D-glycero-pent-2-enono-1,4-lactone on the basis of its physical and chemical properties and its two hydrolytic products, D-galactose and D-erythroascorbic acid. Treatment of this galactoside with alkaline hydrogen peroxide produces oxalic acid as observed earlier with erythroascorbic acid.
Assuntos
4-Butirolactona/análogos & derivados , Ascomicetos/química , Galactosídeos/isolamento & purificação , 4-Butirolactona/química , 4-Butirolactona/isolamento & purificação , Galactosídeos/química , Peróxido de Hidrogênio/química , Hidrólise , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , OxirreduçãoRESUMO
Coprophilin, a decalin pentanedienoic acid methyl ester, was isolated from an unidentified fungus by bioassay guided separation. It inhibited (MIC = 1.5 microM) the growth of Eimeria tenella in an in vitro assay. The isolation, structure elucidation, absolute stereochemistry and biology are described.
Assuntos
Alcenos/farmacologia , Coccidiostáticos/farmacologia , Eimeria tenella/efeitos dos fármacos , Ésteres/farmacologia , Fungos/metabolismo , Alcenos/síntese química , Alcenos/química , Animais , Bovinos , Linhagem Celular , Coccidiostáticos/química , Ésteres/síntese química , Ésteres/química , Fezes/microbiologia , Estrutura Molecular , Espectrometria de Massas de Bombardeamento Rápido de Átomos , EstereoisomerismoRESUMO
In the United States, consumer demand for new foods and changes in eating habits and food safety risks are affecting the food processing industry. The population is becoming older on average; moreover, consumers want fresh and minimally processed food without synthetic chemical preservatives. To address the need for safer food and compete for consumer acceptance, manufacturers are exploring new food processing and preservation methods.
Assuntos
Manipulação de Alimentos , Conservação de Alimentos , Conservantes de Alimentos/efeitos adversos , Promoção da Saúde , HumanosRESUMO
We have identified a novel nonsteroidal ecdysteroid agonist. This compound was isolated from a methanol extract of Ajuga reptans L. (Lamiaceae) and the structure was identified by spectroscopic methods as 8-O-acetylharpagide. We have characterised this compound as an ecdysteroid agonist in a transactivation assay using beta-galactosidase as the reporter gene regulated by ecdysteroid response elements. In this assay, 8-O-acetylharpagide has an EC50 of 22 microM. The compound also competes with tritiated-ponasterone A for binding to the Drosophila ecdysteroid receptor. Finally, it induces differentiation of Drosophila Kc cells as would be expected of an ecdysteroid agonist. This iridoid glycoside is common to several plant species and may play a role in the natural defense mechanisms of plants.
Assuntos
Ecdisterona/agonistas , Plantas/metabolismo , Piranos/metabolismo , Animais , Drosophila/metabolismo , Ecdisterona/metabolismo , Hormônios de Inseto , Estrutura Molecular , Extratos Vegetais , Piranos/química , Receptores de Esteroides/metabolismoRESUMO
A series of ophiobolins were isolated from a fungal extract based on their nematocidal activity. These compounds are non-competitive inhibitors of ivermectin binding to membranes prepared from the free-living nematode, Caenorhabditis elegans, with an inhibition constant of 15 microM. The ophiobolins which were most potent in the biological assays, ophiobolin C and ophiobolin M, were also the most potent compounds when evaluated in a C. elegans motility assay. These data suggest that the nematocidal activity of the ophiobolins is mediated via an interaction with the ivermectin binding site. The isolation, structure and biological activity of ophiobolins have been described.
Assuntos
Anti-Helmínticos/antagonistas & inibidores , Antinematódeos/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Ivermectina/antagonistas & inibidores , Terpenos/farmacologia , Animais , Anti-Helmínticos/metabolismo , Antinematódeos/química , Antinematódeos/isolamento & purificação , Ascomicetos/química , Caenorhabditis elegans/metabolismo , Helmintíase/tratamento farmacológico , Ivermectina/metabolismo , Espectroscopia de Ressonância Magnética , Ratos , Ratos Sprague-Dawley , Sesterterpenos , Terpenos/química , Terpenos/isolamento & purificaçãoRESUMO
Quinoxapeptin A and B are novel chromodepsipeptides which were isolated from a nocardioform actinomycete with indeterminant morphology. Quinoxapeptins A and B are potent inhibitors of HIV-1 and HIV-2 reverse transcriptase and almost equally active against two single mutants forms as well as a double mutant form of HIV-1 reverse transcriptase. Quinoxapeptin A and B are specific inhibitors of HIV-1 and HIV-2 reverse transcriptase because they did not inhibit human DNA polymerase alpha, beta, gamma and delta. Quinoxapeptin A and B are structurally similar to luzopeptin A which was also active against HIV-1 and HIV-2 reverse transcriptase.
Assuntos
HIV-1/enzimologia , HIV-2/enzimologia , Peptídeos Cíclicos/metabolismo , Peptídeos Cíclicos/farmacologia , Quinoxalinas/metabolismo , Quinoxalinas/farmacologia , DNA Polimerase Dirigida por RNA/metabolismo , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Actinomycetales/classificação , Actinomycetales/metabolismo , Transcriptase Reversa do HIV , HIV-1/genética , Humanos , Hidroxiquinolinas/química , Hidroxiquinolinas/farmacologia , Técnicas In Vitro , Cinética , Estrutura Molecular , Mutação , Inibidores da Síntese de Ácido Nucleico , Peptídeos Cíclicos/química , Quinoxalinas/química , DNA Polimerase Dirigida por RNA/genética , Inibidores da Transcriptase Reversa/químicaRESUMO
A novel oleic acid ester of the carotane sesquiterpene 14-hydroxy CAF-603 was isolated from Trichoderma virens grown in a solid brown rice-based medium, a solid millet-based medium, or a mannitol-based liquid medium. Its structure was determined on the basis of ms and nmr analysis. It retains distinct biological activity on the high conductance calcium-activated potassium channel, unlike its analogues 14-hydroxy CAF-603, CAF-603 3-oleate, or CAF-603 3-linoleate.
Assuntos
Canais de Potássio/agonistas , Sesquiterpenos/farmacologia , Trichoderma/química , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Cálcio/fisiologia , Bovinos , Cristalografia por Raios X , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Canais de Potássio/efeitos dos fármacos , Sesquiterpenos/isolamento & purificaçãoRESUMO
Three new diphenyl ethers, barceloneic acids A, B, and barceloneic lactone [1, 2, and 3, respectively] were isolated from a fermentation extract of a fungus of the genus Phoma. The structures of compounds 1-3 were determined by a combination of spectroscopic and single-crystal X-ray diffraction methods. The effect of these compounds on the inhibition of farnesyl-protein transferase (FPTase) was evaluated and results are presented. Barceloneic acid A [1] is a novel and modest inhibitor of FPTase with an IC50 value of 40 microM.
Assuntos
Alquil e Aril Transferases , Éteres Fenílicos/isolamento & purificação , Salicilatos/isolamento & purificação , Transferases/antagonistas & inibidores , Xylariales/metabolismo , Farnesiltranstransferase , Fermentação , Genes ras/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Metilação , Oxirredução , Éteres Fenílicos/química , Éteres Fenílicos/farmacologia , Salicilatos/química , Salicilatos/farmacologia , Difração de Raios XRESUMO
Pneumocandin D0 (9), a new member of the echinocandin class of antifungal agents, has been isolated as a minor constituent from fermentation broths of the filamentous fungi Zalerion arboricola (ATCC 20957). The structure of 9 has been determined mainly on the basis of spectroscopic analysis and by comparison with published data for similar compounds. To date, pneumocandin D0 has been found to be the most potent inhibitor of Pneumocystis carinii development in vivo within the natural-occurring echinocandin family of antifungal agents.
Assuntos
Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Peptídeos , Pneumocystis/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Antibacterianos/biossíntese , Antifúngicos/biossíntese , Candidíase/tratamento farmacológico , Equinocandinas , Fermentação , Camundongos , Camundongos Endogâmicos , Fungos Mitospóricos/metabolismo , Dados de Sequência Molecular , Estrutura Molecular , Peptídeos Cíclicos/biossíntese , Peptídeos Cíclicos/isolamento & purificação , Peptídeos Cíclicos/farmacologia , Pneumonia por Pneumocystis/tratamento farmacológico , Espectrometria de Massas de Bombardeamento Rápido de ÁtomosRESUMO
gamma-Pyrone-3-acetic acid (L-741,494) is a novel metabolite produced by a culture of the fungal genus Xylaria. This substance is a water-soluble, competitive, irreversible inhibitor of Interleukin-1 beta Converting Enzyme that is inactive against papain and trypsin. It has a mol wt of 154 and an empirical formula of C7H6O4. We propose the name xylaric acid for this compound.
Assuntos
Acetatos/farmacologia , Cisteína Endopeptidases/química , Metaloendopeptidases/química , Pironas/farmacologia , Xylariales/metabolismo , Acetatos/química , Acetatos/isolamento & purificação , Sequência de Aminoácidos , Caspase 1 , Cromatografia por Troca Iônica , Espectroscopia de Ressonância Magnética , Dados de Sequência Molecular , Pironas/química , Pironas/isolamento & purificaçãoRESUMO
Detailed structure determination of the major and minor base-catalyzed degradation products of the chromophore of the enediyne anticancer antibiotic neocarzinostatin in the absence of DNA demonstrates that the enolate Michael addition reaction leading to a spirolactone cumulene intermediate is a spontaneous, stereoselective process. The implications of these findings for the mechanism of the thiol-independent, site-specific cleavage by the so-generated radical species of the drug at a DNA bulge are described.
Assuntos
DNA/química , Zinostatina/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Conformação Molecular , Estrutura Molecular , Conformação de Ácido Nucleico , Espectrometria de Massas de Bombardeamento Rápido de Átomos , Zinostatina/análogos & derivadosRESUMO
Curcuma comosa is a member of the economically important plant family, Zingiberaceae. A methanolic extract of C. comosa was shown to be nematocidal when tested against the free-living nematode Caenorhabditis elegans. Five diphenylheptanoids [1-5], one new and four known, have been isolated and shown to be responsible for the activity. This is the first report of three of these compounds [1, 2, 4] being isolated from a natural source.