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1.
Bioorg Med Chem ; 28(5): 115229, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32033878

RESUMO

Many human diseases, including cystic fibrosis lung infections, are caused or exacerbated by bacterial biofilms. Specialized modes of motility, including swarming and twitching, allow gram-negative bacteria to spread across surfaces and form biofilms. Compounds that inhibit these motilities could slow the spread of biofilms, thereby allowing antibiotics to work better. We previously demonstrated that a set of plant-derived triterpenes, including oleanolic acid and ursolic acid, inhibit formation of Escherichia coli and Pseudomonas aeruginosa biofilms, and alter expression of genes involved in chemotaxis and motility. In the present study, we have prepared a series of analogs of oleanolic acid. The analogs were evaluated against clinical isolates of E. coli and P. aeruginosa in biofilm formation assays and swarming assays. From these analogs, compound 9 was selected as a lead compound for further development. Compound 9 inhibits E. coli biofilm formation at 4 µg/mL; it also inhibits swarming at ≤1 µg/mL across multiple clinical isolates of P. aeruginosa, E. coli, Burkholderia cepacia, and Salmonella enterica, and at <0.5 µg/mL against multiple agricultural strains. Compound 9 also potentiates the activity of the antibiotics tobramycin and colistin against swarming P. aeruginosa; this is notable, as tobramycin and colistin are inhaled antibiotics commonly used to treat P. aeruginosa lung infections in people with cystic fibrosis. qPCR experiments suggested that 9 alters expression of genes involved in regulating Type IV pili; western blots confirmed that expression of Type IV pili components PilA and PilY1 decreases in P. aeruginosa in the presence of 9.

2.
Gynecol Oncol ; 151(2): 337-344, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30190114

RESUMO

OBJECTIVE: Paclitaxel, a microtubule inhibitor, is subject to tumor resistance while treating high-grade serous ovarian and uterine cancer. This study aims to directly compare the effects of SQ1274, a novel microtubule inhibitor that binds to the colchicine-binding site on tubulin, and paclitaxel in high-grade serous ovarian and uterine cancer cell lines both in vitro and in vivo. METHODS: We assessed the sensitivity of ovarian (OVCAR8) and uterine (ARK1) cancer cell lines to SQ1274 and paclitaxel using XTT assays. We used western blot and quantitative real-time PCR to analyze changes in AXL RNA and protein expression by SQ1274 and paclitaxel. Differences in cell-cycle arrest and apoptosis were investigated using flow cytometry. Finally, we treated ovarian and uterine xenograft models with vehicle, paclitaxel, or SQ1274. RESULTS: First, we demonstrate that SQ1274 has a much lower IC50 than paclitaxel in both ARK1 (1.26 nM vs. 15.34 nM, respectively) and OVCAR8 (1.34 nM vs. 10.29 nM, respectively) cancer cell lines. Second, we show SQ1274 decreases both RNA and protein expression of AXL. Third, we show that SQ1274 causes increased cell-cycle arrest and apoptosis compared to paclitaxel. Finally, we report that SQ1274 more effectively inhibits tumor growth in vivo compared to paclitaxel. CONCLUSIONS: SQ1274 presents as a viable alternative to paclitaxel for treating ovarian and uterine cancer. This study supports the development of SQ1274 as a chemotherapeutic to treat ovarian and uterine cancer.


Assuntos
Neoplasias do Endométrio/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Moduladores de Tubulina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Carcinoma Epitelial do Ovário , Ciclo Celular/efeitos dos fármacos , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Paclitaxel/farmacologia , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Receptores Proteína Tirosina Quinases/biossíntese , Receptores Proteína Tirosina Quinases/genética , Ensaios Antitumorais Modelo de Xenoenxerto
3.
J Med Chem ; 61(15): 6736-6747, 2018 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-29995409

RESUMO

Bifidenone is a novel natural tubulin polymerization inhibitor that exhibits antiproliferative activity against a range of human cancer cell lines, making it an attractive candidate for development. A synthetic route was previously developed to alleviate supply constraints arising from its isolation in microgram quantities from a Gabonese tree. Using that previously published route, we present here 42 analogues that were synthesized to examine the structure-activity relationship of bifidenone derivatives. In addition to in vitro cytotoxicity data, data from murine xenograft and pharmacokinetic studies were used to evaluate the analogues. Compounds 45b and 46b were found to demonstrate promising efficacy in murine xenograft experiments, and 46b had significantly more potent in vitro antiproliferative activity against taxane-resistant cell lines compared to that of paclitaxel.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Lignanas/química , Lignanas/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Camundongos , Multimerização Proteica/efeitos dos fármacos , Estrutura Quaternária de Proteína , Relação Estrutura-Atividade , Tubulina (Proteína)/química , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Biochem J ; 474(22): 3705-3717, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28963347

RESUMO

Plants, fungi, and bacteria synthesize the aromatic amino acids: l-phenylalanine, l-tyrosine, and l-tryptophan. Chorismate mutase catalyzes the branch point reaction of phenylalanine and tyrosine biosynthesis to generate prephenate. In Arabidopsis thaliana, there are two plastid-localized chorismate mutases that are allosterically regulated (AtCM1 and AtCM3) and one cytosolic isoform (AtCM2) that is unregulated. Previous analysis of plant chorismate mutases suggested that the enzymes from early plants (i.e. bryophytes/moss, lycophytes, and basal angiosperms) formed a clade distinct from the isoforms found in flowering plants; however, no biochemical information on these enzymes is available. To understand the evolution of allosteric regulation in plant chorismate mutases, we analyzed a basal lineage of plant enzymes homologous to AtCM1 based on sequence similarity. The chorismate mutases from the moss/bryophyte Physcomitrella patens (PpCM1 and PpCM2), the lycophyte Selaginella moellendorffii (SmCM), and the basal angiosperm Amborella trichopoda (AmtCM1 and AmtCM2) were characterized biochemically. Tryptophan was a positive effector for each of the five enzymes examined. Histidine was a weak positive effector for PpCM1 and AmtCM1. Neither tyrosine nor phenylalanine altered the activity of SmCM; however, tyrosine was a negative regulator of the other four enzymes. Phenylalanine down-regulates both moss enzymes and AmtCM2. The 2.0 ŠX-ray crystal structure of PpCM1 in complex with the tryptophan identified the allosteric effector site and reveals structural differences between the R- (more active) and T-state (less active) forms of plant chorismate mutases. Molecular insight into the basal plant chorismate mutases guides our understanding of the evolution of allosteric regulation in these enzymes.


Assuntos
Bryopsida , Corismato Mutase/química , Corismato Mutase/genética , Extratos Vegetais/química , Extratos Vegetais/genética , Selaginellaceae , Regulação Alostérica/fisiologia , Sequência de Aminoácidos , Arabidopsis , Corismato Mutase/isolamento & purificação , Cristalografia por Raios X/métodos , Evolução Molecular , Extratos Vegetais/isolamento & purificação , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína
5.
J Nat Prod ; 80(3): 616-624, 2017 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-28335606

RESUMO

The pursuit of structurally novel compounds has led to the isolation of a series of neolignans (2-6), for which the structures have been determined from microgram quantities using microcryoprobe NMR technology. Compounds 2-6 provided some unexpectedly clear structure-activity relationship data, with compound 2 demonstrating significantly more potency in the in vitro cytotoxicity assay than the other analogues. Further screening found that compound 2 induces apoptosis with activation of caspase 3/7. The NCI Compare algorithm suggested that compound 2 acts through the inhibition of tubulin/microtubule dynamics. Compound 2 was confirmed to be a tubulin polymerization inhibitor that binds directly to tubulin.


Assuntos
Antineoplásicos/farmacologia , Lignanas/farmacologia , Moduladores de Tubulina/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lignanas/química , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química
6.
J Org Chem ; 82(8): 4235-4241, 2017 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-28351141

RESUMO

The first total synthesis of bifidenone, a novel natural tubulin polymerization inhibitor, has been achieved in 12 steps starting from commercially available 1,4-dioxaspiro[4.5]decan-8-one. The synthesis includes a newly developed method to generate the dihydrobenzodioxolone core by palladium-catalyzed aerobic dehydrogenation. The three stereocenters were installed with an AD-mix-ß dihydroxylation step followed by a late-stage palladium-catalyzed decarboxylation-allylation procedure. The absolute stereochemistry of 3 was determined via 13a by single-crystal X-ray analysis.

7.
ACS Chem Biol ; 11(5): 1445-51, 2016 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-26930136

RESUMO

Natural product metabolic engineering potentially offers sustainable and affordable access to numerous valuable molecules. However, challenges in characterizing and assembling complex biosynthetic pathways have prevented more rapid progress in this field. The anticancer agent Taxol represents an excellent case study. Assembly of a biosynthetic pathway for Taxol has long been stalled at its first functionalization, putatively an oxygenation performed by the cytochrome P450 CYP725A4, due to confounding characterizations. Here, through combined in vivo (Escherichia coli), in vitro (lipid nanodisc), and metabolite stability assays, we verify the presence and likely cause of this enzyme's inherent promiscuity. Thereby, we remove the possibility that promiscuity simply existed as an artifact of previous metabolic engineering approaches. Further, spontaneous rearrangement and the stabilizing effect of a hydrophobic overlay suggest a potential role for nonenzymatic chemistry in Taxol's biosynthesis. Taken together, this work confirms taxadiene-5α-ol as a primary enzymatic product of CYP725A4 and provides direction for future Taxol metabolic and protein engineering efforts.


Assuntos
Alcenos/metabolismo , Antineoplásicos Fitogênicos/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Diterpenos/metabolismo , Escherichia coli/enzimologia , Paclitaxel/metabolismo , Taxus/enzimologia , Alcenos/química , Antineoplásicos Fitogênicos/química , Vias Biossintéticas , Diterpenos/química , Escherichia coli/química , Escherichia coli/metabolismo , Fermentação , Engenharia Metabólica , Modelos Moleculares , Oxirredução , Paclitaxel/química , Especificidade por Substrato , Taxus/química , Taxus/metabolismo
8.
J Nat Prod ; 78(8): 2074-86, 2015 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-26287548

RESUMO

The compass plant, Silphium laciniatum, is an iconic perennial plant of the North American tallgrass prairie. The plants of the tallgrass prairie historically have been subjected to a number of biological and environmental stresses. Among the adaptations developed by S. laciniatum is a large deep taproot. An investigation of the secondary metabolites found in the root of a S. laciniatum specimen has led to the identification of 15 new terpenoids (3-8, 10-17, and 22), which were screened for cytotoxic activity in the NCI-H460 human large-cell lung carcinoma cell line.


Assuntos
Asteraceae/química , Terpenos/isolamento & purificação , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Missouri , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Terpenos/química , Terpenos/farmacologia
9.
Plant J ; 83(5): 783-93, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26119826

RESUMO

Grindelia robusta or gumweed, is a medicinal herb of the sunflower family that forms a diverse suite of diterpenoid natural products. Its major constituents, grindelic acid and related grindelane diterpenoids accumulate in a resinous exudate covering the plants' surfaces, most prominently the unopened composite flower. Recent studies demonstrated potential pharmaceutical applications for grindelic acid and its synthetic derivatives. Mining of the previously published transcriptome of G. robusta flower tissue identified two additional diterpene synthases (diTPSs). We report the in vitro and in vivo functional characterization of an ent-kaurene synthase of general metabolism (GrTPS4) and a class II diTPS (GrTPS2) of specialized metabolism that converts geranylgeranyl diphosphate (GGPP) into labda-7,13E-dienyl diphosphate as verified by nuclear magnetic resonance (NMR) analysis. Tissue-specific transcript abundance of GrTPS2 in leaves and flowers accompanied by the presence of an endocyclic 7,13 double bond in labda-7,13E-dienyl diphosphate suggest that GrTPS2 catalyzes the first committed reaction in the biosynthesis of grindelic acid and related grindelane metabolites. With the formation of labda-7,13E-dienyl diphosphate, GrTPS2 adds an additional function to the portfolio of monofunctional class II diTPSs, which catalytically most closely resembles the bifunctional labda-7,13E-dien-15-ol synthase of the lycopod Selaginella moellendorffii. Together with a recently identified functional diTPS pair of G. robusta producing manoyl oxide, GrTPS2 lays the biosynthetic foundation of the diverse array of labdane-related diterpenoids in the genus Grindelia. Knowledge of these natural diterpenoid metabolic pathways paves the way for developing biotechnology approaches toward producing grindelic acid and related bioproducts.


Assuntos
Alquil e Aril Transferases/metabolismo , Diterpenos de Caurano/metabolismo , Diterpenos/metabolismo , Grindelia/genética , Grindelia/metabolismo , Liases Intramoleculares/metabolismo , Proteínas de Plantas/metabolismo , Alquil e Aril Transferases/genética , Diterpenos de Caurano/genética , Perfilação da Expressão Gênica , Regulação Enzimológica da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Liases Intramoleculares/genética , Dados de Sequência Molecular , Filogenia , Proteínas de Plantas/genética , Plantas Geneticamente Modificadas , Tabaco/genética
10.
Plant J ; 82(6): 991-1003, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25939370

RESUMO

Steroid alkaloids have been shown to elicit a wide range of pharmacological effects that include anticancer and antifungal activities. Understanding the biosynthesis of these molecules is essential to bioengineering for sustainable production. Herein, we investigate the biosynthetic pathway to cyclopamine, a steroid alkaloid that shows promising antineoplastic activities. Supply of cyclopamine is limited, as the current source is solely derived from wild collection of the plant Veratrum californicum. To elucidate the early stages of the pathway to cyclopamine, we interrogated a V. californicum RNA-seq dataset using the cyclopamine accumulation profile as a predefined model for gene expression with the pattern-matching algorithm Haystack. Refactoring candidate genes in Sf9 insect cells led to discovery of four enzymes that catalyze the first six steps in steroid alkaloid biosynthesis to produce verazine, a predicted precursor to cyclopamine. Three of the enzymes are cytochromes P450 while the fourth is a γ-aminobutyrate transaminase; together they produce verazine from cholesterol.


Assuntos
Enzimas/metabolismo , Alcaloides de Veratrum/metabolismo , Veratrum/genética , Veratrum/metabolismo , 4-Aminobutirato Transaminase/genética , 4-Aminobutirato Transaminase/metabolismo , Algoritmos , Animais , Vias Biossintéticas , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Enzimas/genética , Perfilação da Expressão Gênica/métodos , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Análise de Sequência de RNA/métodos , Células Sf9 , Transcriptoma
11.
Nat Prod Commun ; 9(8): 1129-30, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25233589

RESUMO

One new and seven known diterpenes were identified from an antibacterial chromatographic fraction of Taxodium ascendens. Of these, demethylcryptojaponol (2), 6-hydroxysalvinolone (3), hydroxyferruginol (4), and hinokiol (5) demonstrated potent activity against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA). These compounds represent a class of synthetically accessible compounds that could be further developed for treatment of drug-resistant bacterial infections.


Assuntos
Antibacterianos/farmacologia , Diterpenos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Extratos Vegetais/farmacologia , Taxodium/química , Antibacterianos/química , Antibacterianos/isolamento & purificação , Diterpenos/química , Diterpenos/isolamento & purificação , Humanos , Testes de Sensibilidade Microbiana , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação
12.
PLoS One ; 9(7): e103223, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25061748

RESUMO

Galanthamine is an Amaryllidaceae alkaloid used to treat the symptoms of Alzheimer's disease. This compound is primarily isolated from daffodil (Narcissus spp.), snowdrop (Galanthus spp.), and summer snowflake (Leucojum aestivum). Despite its importance as a medicine, no genes involved in the biosynthetic pathway of galanthamine have been identified. This absence of genetic information on biosynthetic pathways is a limiting factor in the development of synthetic biology platforms for many important botanical medicines. The paucity of information is largely due to the limitations of traditional methods for finding biochemical pathway enzymes and genes in non-model organisms. A new bioinformatic approach using several recent technological improvements was applied to search for genes in the proposed galanthamine biosynthetic pathway, first targeting methyltransferases due to strong signature amino acid sequences in the proteins. Using Illumina sequencing, a de novo transcriptome assembly was constructed for daffodil. BLAST was used to identify sequences that contain signatures for plant O-methyltransferases in this transcriptome. The program HAYSTACK was then used to identify methyltransferases that fit a model for galanthamine biosynthesis in leaf, bulb and inflorescence tissues. One candidate gene for the methylation of norbelladine to 4'-O-methylnorbelladine in the proposed galanthamine biosynthetic pathway was identified. This methyltransferase cDNA was expressed in E. coli and the protein purified by affinity chromatography. The resulting protein was found to be a norbelladine 4'-O-methyltransferase (NpN4OMT) of the proposed galanthamine biosynthetic pathway.


Assuntos
Alcaloides/metabolismo , Galantamina/metabolismo , Narcissus/enzimologia , Proteína O-Metiltransferase/genética , Alcaloides/genética , Alcaloides/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Sequência de Aminoácidos , Clonagem Molecular , DNA Complementar , Escherichia coli , Galantamina/genética , Galantamina/uso terapêutico , Humanos , Narcissus/química , Narcissus/genética , Proteína O-Metiltransferase/isolamento & purificação , Proteína O-Metiltransferase/metabolismo
13.
J Nat Prod ; 77(6): 1438-44, 2014 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-24922615

RESUMO

Species extinction is tantamount to loss of chemical diversity, and so it is important to seize all opportunities to study species on the brink of extinction. Such studies are often hampered by the limited material available, but that obstacle is surmountable through collaboration with botanical gardens and advances in instrumentation. The goldenrod Solidago shortii is one example of an endangered species native to the United States. From S. shortii, one known diterpene (1), two new diterpenes (2 and 3), and three new hydrolysis products (4-6) are described. This work was made possible through collaboration with the Missouri Botanical Garden and with the use of highly sensitive microcryoprobe NMR technology for structure elucidation and VCD spectroscopy for the determination of absolute configuration.


Assuntos
Diterpenos/isolamento & purificação , Solidago/química , Cristalografia por Raios X , Diterpenos/química , Espécies em Perigo de Extinção , Missouri , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular
14.
Phytochemistry ; 98: 216-22, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24361290
15.
J Nat Prod ; 76(9): 1592-7, 2013 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-23978065

RESUMO

The first study of the chemical constituents of Combretum inflatum has resulted in the isolation of seven new acetylated dammarane-type bisdesmosides (1-7). Their structures were determined from microgram quantities on hand using Bruker BioSpin TCI 1.7 mm MicroCryoProbe technology, ESIMS, and comparison to data found in the literature. Compounds 1-7 were screened for inhibition of an Escherichia coli strain UTI89 biofilm, MRSA inhibition, and cytotoxicity in NCI-H460 human lung cancer cells. Compounds 3-7 reduced the growth of MRSA at 16 µg/mL by 71-45%, and compound 7 had an IC50 value of 3.9 µM in NCI-H460.


Assuntos
Antibacterianos/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Combretaceae/química , Triterpenos/isolamento & purificação , Acetilação , Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Escherichia coli/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Missouri , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Folhas de Planta/química , Triterpenos/química , Triterpenos/farmacologia
16.
Phytochemistry ; 82: 172-5, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22805176

RESUMO

Seven stilbenes and one alkylresorcinol were isolated from the orchid Phragmipedium calurum during a screen for anticancer compounds. They were evaluated for antiproliferative activity against multiple human cancer cell lines, and two displayed moderate activity against several cell lines.


Assuntos
Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Orchidaceae/química , Resorcinóis/isolamento & purificação , Resorcinóis/farmacologia , Estilbenos/isolamento & purificação , Estilbenos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Resorcinóis/química , Estilbenos/química
17.
J Nat Prod ; 75(7): 1319-25, 2012 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-22758788

RESUMO

High-throughput natural products chemistry methods have facilitated the isolation of eight new (1-8) and two known (9 and 10) beilschmiedic acid derivatives from the leaves of a Gabonese species of Beilschmiedia. Compounds 3-10 were isolated in microgram quantities, and the NMR data for structure elucidation and dereplication were acquired utilizing a Bruker BioSpin TCI 1.7 mm MicroCryoProbe. All of the compounds were screened for cytotoxic and antibacterial activity against NCI-H460 human lung cancer cells and a clinical isolate of methicillin-resistant Staphylococcus aureus, respectively. This is the first report of cytotoxic activity for the endiandric/beilschmiedic acid class of compounds.


Assuntos
Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Ácidos Carboxílicos/isolamento & purificação , Ácidos Carboxílicos/farmacologia , Ácidos Graxos/isolamento & purificação , Ácidos Graxos/farmacologia , Lauraceae/química , Antibacterianos/química , Antineoplásicos/química , Ácidos Carboxílicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Ácidos Graxos/química , Gabão , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Folhas de Planta/química , Staphylococcus aureus/efeitos dos fármacos
18.
Protein Sci ; 21(5): 686-96, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22374910

RESUMO

Bacterial formyl-CoA:oxalate CoA-transferase (FCOCT) and oxalyl-CoA decarboxylase work in tandem to perform a proton-consuming decarboxylation that has been suggested to have a role in generalized acid resistance. FCOCT is the product of uctB in the acidophilic acetic acid bacterium Acetobacter aceti. As expected for an acid-resistance factor, UctB remains folded at the low pH values encountered in the A. aceti cytoplasm. A comparison of crystal structures of FCOCTs and related proteins revealed few features in UctB that would distinguish it from nonacidophilic proteins and thereby account for its acid stability properties, other than a strikingly featureless electrostatic surface. The apparently neutral surface is a result of a "speckled" charge decoration, in which charged surface residues are surrounded by compensating charges but do not form salt bridges. A quantitative comparison among orthologs identified a pattern of residue substitution in UctB that may be a consequence of selection for protein stability by constant exposure to acetic acid. We suggest that this surface charge pattern, which is a distinctive feature of A. aceti proteins, creates a stabilizing electrostatic network without stiffening the protein or compromising protein-solvent interactions.


Assuntos
Acetobacter/fisiologia , Proteínas de Bactérias/química , Coenzima A-Transferases/química , Ácido Acético , Acetobacter/enzimologia , Proteínas de Bactérias/metabolismo , Coenzima A-Transferases/metabolismo , Etanol , Concentração de Íons de Hidrogênio , Modelos Moleculares , Estabilidade Proteica , Eletricidade Estática , Especificidade por Substrato
19.
Planta Med ; 78(2): 160-5, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22002852

RESUMO

High-throughput natural product research produced a suite of anticancer hits among several species of the Orchidaceae family (Oncidium microchilum, O. isthmi, and Myrmecophila humboldtii). A commercial Oncidium sp. was also examined as a convenient source of additional material. Isolation and structure elucidation led to the identification of fifteen stilbenoids including a new phenanthraquinone and two new dihydrostilbenes. NMR data for structure elucidation and dereplication were acquired utilizing a Bruker BioSpin TCI 1.7-mm MicroCryoProbe or a 5-µL CapNMR capillary microcoil. Several compounds inhibited proliferation of NCI-H460 and M14 cancer cell lines. All compounds were also examined for their ability to induce apoptosis. Apoptosis induction was determined by measuring caspase 3/7 activation and LDH release in a NCI-H460 cell line. Based on these results, a portion of the extract from a commercially available Oncidium sp. was chemically modified in an attempt to obtain additional phenanthraquinones.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Orchidaceae/química , Fitoterapia , Extratos Vegetais/uso terapêutico , Estilbenos/uso terapêutico , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Estrutura Molecular , Neoplasias/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Estilbenos/química , Estilbenos/isolamento & purificação , Estilbenos/farmacologia
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