RESUMEN
[reaction: see text] We report a regioselective entry to 3-bromo- and 4-bromo-5-hydroxy-5H-furan-2-ones by photooxidation of 3-bromofuran with a singlet oxygen in the presence of a suitable base. By this procedure, a variety of 3-substituted gamma-hydroxybutenolides have become for the first time easily accessible. Strategies employing these highly functionalized building blocks for the preparation of focused libraries of natural-like molecules are also discussed.
Asunto(s)
4-Butirolactona/análogos & derivados , Hidrocarburos Bromados/síntesis química , 4-Butirolactona/síntesis química , 4-Butirolactona/química , Productos Biológicos/síntesis química , Productos Biológicos/química , Técnicas Químicas Combinatorias , Hidrocarburos Bromados/química , Estructura Molecular , EstereoisomerismoRESUMEN
25-Acetyl-petrosaspongiolide M (PMAc) (1), a mild non-covalent PLA(2) inhibitor, unexpectedly recovers, after incubation with bvPLA(2), the ability to covalently modify the enzyme target. This study demonstrates the catalytic effect of bvPLA(2) in converting 1 in its deacetylated congener petrosaspongiolide M (PM) (2), a strong covalent PLA(2) inhibitor whose molecular mechanism of inhibition has already been clarified. Moreover, our findings outline the potential role of PMAc as anti-inflammatory pro-drug, by virtue of its ability of delivering the active PM agent at the site of inflammation, functioning as a suicide inhibitor.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/farmacología , Fosfolipasas A/metabolismo , Acetilación , Animales , Sitios de Unión , Catálisis , Cromatografía Líquida de Alta Presión , Dicroismo Circular , Inhibidores Enzimáticos/química , Fosfolipasas A2 Grupo II , Concentración de Iones de Hidrógeno , Hidrólisis , Cinética , Ligandos , Espectrometría de Masas , Estructura Molecular , Peso Molecular , Ácido Oleanólico/química , Fosfolipasas A2 , Poríferos/química , Conformación Proteica , Estructura Secundaria de Proteína , Espectrometría de Masa por Ionización de Electrospray , TemperaturaRESUMEN
We present a quantum-mechanical study of the S(N)2 acid-catalyzed solvolysis with methanol of seven simplified duocarmycin SA (DNA alkylating agent) derivatives characterized by spirocyclic systems of increasing complexity, all containing the cyclopropyl/cyclohexadienone substrate. The reaction has been studied at the DFT-PBE0/6-31G(d) level in the gas phase and in methanol solution, using in the latter case the polarizable continuum model (PCM) to describe solvent effects. The results delivered by this computational protocol are in full agreement with the available experimental evidences and are not modified by extension of the basis set or by using a second-order many-body treatment (MP2) in place of DFT. This allows investigation of substituent effects in terms of structure/reactivity relationships and evaluation of the role of stereoelectronic effects. Furthermore, reactivity indices (hardness, electrophilicity) have been computed and shown to correlate well with activation energies. Together with their intrinsic interest, the details of the mechanism of the acid-catalyzed nucleophilic addition to the activated cyclopropane issuing from the present study pave the route for a deeper understanding of the molecular basis for the remarkable profile of the DNA-alkylation by DSA derivatives.
Asunto(s)
Ciclopropanos/química , Indoles/química , Metanol/química , Pirroles/química , Antibióticos Antineoplásicos/química , Catálisis , Duocarmicinas , Gases , Concentración de Iones de Hidrógeno , Estructura Molecular , SolucionesRESUMEN
A new diterpene, N-formyl-7-amino-11-cycloamphilectene (1), was isolated from the apolar extract of the Vanuatu sponge Axinella sp. The structure and relative stereochemistry were established by spectroscopic and single-crystal X-ray studies.
Asunto(s)
Diterpenos/aislamiento & purificación , Poríferos/química , Animales , Cromatografía Líquida de Alta Presión , Cristalografía por Rayos X , Diterpenos/química , Conformación Molecular , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Estereoisomerismo , VanuatuRESUMEN
Two new metabolites, named halipeptins A and B, have been isolated from the marine sponge Haliclona sp. Their structures were determined by extensive use of one- and two-dimensional NMR experiments, mass spectrometry, and UV and IR spectroscopy. Halipeptin A is a novel 17-membered cyclic depsipeptide, consisting of five residues including two alanines (with L stereochemistry) and three new residues that appear to be previously undescribed from natural sources: 1,2-oxazetidine-4-methyl-4-carboxylic acid, 3-hydroxy-2,2,4-trimethyl-7-methoxydecanoic acid (HTMMD), and N-methyl-delta-hydroxyisoleucine. The HTMMD residue is substituted with 3-hydroxy-2,2,4-trimethyl-7-hydroxydecanoic acid in halipeptin B. Halipeptin A was found to possess very potent anti-inflammatory activity in vivo, causing about 60% inhibition of edema in mice at the dose of 300 microg/kg (i.p.).
Asunto(s)
Antiinflamatorios no Esteroideos/química , Depsipéptidos , Péptidos Cíclicos/química , Péptidos Cíclicos/aislamiento & purificación , Poríferos/química , Animales , Antiinflamatorios no Esteroideos/aislamiento & purificación , Antiinflamatorios no Esteroideos/farmacología , Relación Dosis-Respuesta a Droga , Edema/tratamiento farmacológico , Humanos , Leucemia L1210/tratamiento farmacológico , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Resonancia Magnética Nuclear Biomolecular , Péptidos Cíclicos/farmacología , Conformación Proteica , Espectrometría de Masa Bombardeada por Átomos Veloces , Estereoisomerismo , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
A new pyrroloiminoquinone alkaloid (1) belonging to the makaluvamine family has been isolated from the sponge Zyzzya cf. fuliginosa collected in the waters off the Vanuatu Islands. The compound, designated makulavamine P, was characterized on the basis of its spectral data and displayed cytoxicity in the microM range on KB cells and antioxidant activity.
Asunto(s)
Antineoplásicos/aislamiento & purificación , Inhibidores Enzimáticos/aislamiento & purificación , Poríferos/química , Pirroles/aislamiento & purificación , Quinolonas/aislamiento & purificación , Xantina Oxidasa/antagonistas & inhibidores , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Australia , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Células KB/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Estructura Molecular , Neoplasias Nasofaríngeas , Pirroles/química , Pirroles/farmacología , Quinolonas/química , Quinolonas/farmacología , Pruebas de Toxicidad , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
Rosacelose, a new anti-HIV polysaccharide composed of glucose and fucose sulfate, has been isolated from an aqueous extract of the marine sponge Mixylla rosacea. Extensive use of 1H and 13C multidimensional NMR spectroscopy, combined with chemical analysis were used to establish a linear polysaccharide structure composed mainly of 4,6-disulfated 3-O-glycosylated alpha-D-glucopyranosyl and 2,4-disulfated 3-O-glycosylated alpha-L-fucopyranosyl residues (in a 3:1 molar ratio).
Asunto(s)
Fármacos Anti-VIH/química , Fármacos Anti-VIH/aislamiento & purificación , Biología Marina/métodos , Resonancia Magnética Nuclear Biomolecular/métodos , Polisacáridos/química , Poríferos/química , Animales , Secuencia de Carbohidratos , Datos de Secuencia Molecular , Peso Molecular , Polisacáridos/aislamiento & purificación , Ésteres del Ácido SulfúricoRESUMEN
2'-Deoxy-8-(propyn-1-yl)adenosine has been incorporated in synthetic oligodeoxyribonucleotides and its influence on thermal stability of duplex and quadruplex structures investigated by UV, CD and 1H NMR. The obtained results seem to indicate that the presence of the modified base negatively affects the stability of double stranded DNA whereas remarkably increases the stability of parallel quadruplex structures.
Asunto(s)
ADN/química , Oligodesoxirribonucleótidos/química , Adenosina , Dicroismo Circular , Espectroscopía de Resonancia Magnética , Conformación de Ácido NucleicoRESUMEN
Duocarmycin SA is a member of a growing class of interesting lead compounds for chemotherapy, distinguished by the manner in which they bind to and react with DNA substrates. The first three-dimensional structure of a DNA adduct of an unnatural enantiomer from this family has been determined by (1)H NMR methods. Comparison to the previously determined structure of the natural enantiomer bound in the same DNA-binding site provides unique insights into the similarities and critical distinctions producing the respective alkylation products and site selectivities. The results also support the hypothesis that the duocarmycin SA alkylation reaction is catalyzed by the binding to DNA, and provide a deeper understanding of the structural basis for this unique mode of activation.
Asunto(s)
Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/metabolismo , Aductos de ADN/metabolismo , Indoles , Alquilantes/química , Alquilantes/metabolismo , Alquilación , Secuencia de Bases , Sitios de Unión , Aductos de ADN/química , Duocarmicinas , Cinética , Modelos Moleculares , Conformación Molecular , Resonancia Magnética Nuclear Biomolecular , Oligodesoxirribonucleótidos/química , Oligodesoxirribonucleótidos/metabolismo , Pirroles/química , Pirroles/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , TermodinámicaRESUMEN
The marine product petrosaspongiolide M is a novel inhibitor of phospholipase A2 (PLA2), showing selectivity for secretory PLA2 versus cytosolic PLA2, with a potency on the human synovial enzyme (group II) similar to that of manoalide. This compound was more potent than manoalide on bee venom PLA2 (group III) and had no effect on group I enzymes (Naja naja and porcine pancreatic PLA2). Inhibition of PLA2 was also observed in vivo in the zymosan-injected rat air pouch, on the secretory enzyme accumulated in the pouch exudate. Petrosaspongiolide M decreased carrageenan paw edema in mice after the oral administration of 5, 10, or 20 mg/kg. This marine metabolite (0.01-1.0 micromol/pouch) induced a dose-dependent reduction in the levels of prostaglandin (PG)E2, leukotriene B4, and tumor necrosis factor-alpha in the mouse air pouch injected with zymosan 4 h after the stimulus. It also had a weaker effect on cell migration. The inflammatory response of adjuvant arthritis was reduced by petrosaspongiolide M, which also inhibited leukotriene B4 levels in serum and PGE2 levels in paw homogenates. In contrast with indomethacin, this marine compound did not reduce PGE2 levels in stomach homogenates. Petrosaspongiolide M is a new inhibitor of secretory PLA2 in vitro and in vivo, with anti-inflammatory properties in acute and chronic inflammation.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Inhibidores Enzimáticos/farmacología , Inflamación/tratamiento farmacológico , Ácido Oleanólico/análogos & derivados , Fosfolipasas A/antagonistas & inhibidores , Animales , Artritis Experimental/tratamiento farmacológico , Supervivencia Celular/efectos de los fármacos , Dinoprostona/metabolismo , Edema/inducido químicamente , Edema/tratamiento farmacológico , Exudados y Transudados/enzimología , Exudados y Transudados/metabolismo , Humanos , Técnicas In Vitro , Inflamación/patología , Leucocitos/efectos de los fármacos , Leucotrieno B4/metabolismo , Masculino , Ratones , Ácido Oleanólico/farmacología , Fosfolipasas A2 , Poríferos/química , Ratas , Ratas Endogámicas Lew , Ratas Wistar , Factor de Necrosis Tumoral alfa/metabolismo , Células U937RESUMEN
Five new bioactive sesterterpenes (1-5) have been isolated from the New Caledonian marine sponge Petrosaspongia nigra Bergquist and named petrosaspongiolides M-R. Their chemical structures were determined from 1D and 2D NMR studies and MS data. All compounds inhibited different preparations of phospholipase A2 (PLA2) by irreversibly blocking these enzymes (particularly human synovial and bee venom, see Table 3), with IC50 values in the micromolar range. Interestingly, these compounds displayed a much lower activity (or no activity at all) toward porcine pancreas and Naja naja venom PLA2 enzymes. The most potent compound, 1 (IC50 1.6 and 0.6 microM for human synovial and bee venom PLA2 enzymes, respectively), was slightly more active than manoalide (6) (IC50 3.9 and 7.5 microM) under our experimental conditions. Compound 3 is more selective, inhibiting human synovial PLA2 to a greater extent than bee venom PLA2.
Asunto(s)
4-Butirolactona/análogos & derivados , Inhibidores Enzimáticos/aislamiento & purificación , Fosfolipasas A/antagonistas & inhibidores , Poríferos/química , Terpenos/aislamiento & purificación , 4-Butirolactona/química , 4-Butirolactona/aislamiento & purificación , 4-Butirolactona/farmacología , Animales , Venenos de Abeja/enzimología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Espectroscopía de Resonancia Magnética , Estructura Molecular , Páncreas/enzimología , Fosfolipasas A2 , Espectrometría de Masa Bombardeada por Átomos Veloces , Porcinos , Líquido Sinovial/enzimología , Terpenos/química , Terpenos/farmacologíaRESUMEN
The synthetic oligosaccharide moiety of the antibiotic calicheamicin and the head-to-head dimer of this oligosaccharide are known to bind to the minor groove of DNA in a sequence-selective manner preferring distinct target sequences. We tested these carbohydrates for their ability to interfere with transcription factor function. The oligosaccharides inhibit binding of transcription factors to DNA in a sequence-selective manner, probably by inducing a conformational change in DNA structure. They also interfere with transcription by polymerase II in vitro. The effective concentrations of the oligosaccharides for inhibition of transcription factor binding and for transcriptional inhibition are in the micromolar range. The dimer is a significantly more active inhibitor than is the monomer.
Asunto(s)
Aminoglicósidos , Antibacterianos/química , ADN/metabolismo , Oligosacáridos/metabolismo , Factores de Transcripción/metabolismo , Transcripción Genética/efectos de los fármacos , Secuencia de Bases , Secuencia de Carbohidratos , ADN Polimerasa II/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Enediinos , Conformación Molecular , Datos de Secuencia Molecular , Oligodesoxirribonucleótidos/metabolismo , Oligosacáridos/farmacología , Unión Proteica/efectos de los fármacos , Factor de Transcripción STAT3 , Transactivadores/metabolismoRESUMEN
BACKGROUND: The protein kinase C (PKC) family of serine/threonine-specific protein kinases is involved in many cellular processes, and the unregulated activation of PKC has been implicated in carcinogenesis. PKC inhibitors thus have significant potential as chemotherapeutic agents. Recently, the fungal metabolite balanol was shown to be an exceptionally potent inhibitor of PKC. We previously developed a practical and efficient total synthesis of balanol. We set out to use this synthetic molecule, and several synthetic analogs, to probe the mechanism of PKC inhibition and to determine the effect of balanol on the activity of other protein kinases. RESULTS: As well as inhibiting PKC, balanol is a potent inhibitor of cyclic AMP-dependent protein kinase (PKA), another protein serine/threonine kinase. Balanol does not, however, inhibit the Src or epidermal growth factor receptor protein tyrosine kinases. The inhibition of both PKC and PKA by balanol can be overcome by high concentrations of ATP, and molecular modeling studies suggest that balanol may function as an ATP structural analog. Although balanol discriminates rather poorly between PKC and PKA, only minor modifications to its molecular structure are required to furnish compounds that are highly specific inhibitors of PKA. CONCLUSIONS: A number of balanol analogs have been designed and synthesized that, unlike balanol itself, exhibit dramatic selectivity between PKA and PKC. Thus, despite the substantial homology between the catalytic domains of PKA and PKC, there is enough difference to allow for the development of potent and selective inhibitors acting in this region. These inhibitors should be useful tools for analyzing signal transduction pathways and may also aid in the development of drugs with significant therapeutic potential.
Asunto(s)
Azepinas/farmacología , Inhibidores Enzimáticos/farmacología , Hidroxibenzoatos/farmacología , Proteína Quinasa C/antagonistas & inhibidores , Adenosina Trifosfato/metabolismo , Azepinas/síntesis química , Azepinas/química , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Diseño de Fármacos , Receptores ErbB/antagonistas & inhibidores , Hidroxibenzoatos/síntesis química , Hidroxibenzoatos/química , Cinética , Modelos Moleculares , Relación Estructura-Actividad , Familia-src Quinasas/antagonistas & inhibidoresRESUMEN
A novel cyclodepsipeptide, neosiphoniamolide A [1], has been isolated from the sponge Neosiphonia superstes. The structure of 1, which contains a 12-carbon hydroxy acid, glycine, valine, and a halogenated tyrosine residue in an 18-membered ring, is related to jaspamide and the geodiamolides, previously isolated from sponges. The structure was solved by spectroscopic analysis.
Asunto(s)
Antifúngicos/aislamiento & purificación , Péptidos Cíclicos/aislamiento & purificación , Poríferos/química , Animales , Antifúngicos/química , Antifúngicos/farmacología , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacologíaRESUMEN
The structure of a new cytotoxic macrolide, superstolide B [1], isolated from the deep water sponge Neosiphonia superstes, collected off New Caledonia, was elucidated mainly on the basis of nmr data. Compound 1 is closely related to superstolide A [2], a major cytotoxic component isolated from that organism, but lacks the 25-hydroxyl group found in 2 and has a C-24 (C-25)-double bond.
Asunto(s)
Citotoxinas/química , Macrólidos , Poríferos , Tetrahidronaftalenos/química , Animales , Citotoxinas/aislamiento & purificación , Espectroscopía de Resonancia Magnética , Conformación Molecular , Estructura Molecular , Nueva Caledonia , Relación Estructura-Actividad , Tetrahidronaftalenos/aislamiento & purificaciónRESUMEN
BACKGROUND: Taxol is a natural product produced by the Pacific yew, Taxus brevifolia, that has emerged as a prominent chemotherapeutic agent for the treatment of solid tumors. It binds to microtubules, stabilizing them and arresting cells in mitosis. Taxol has been produced synthetically and a wealth of structure-activity data has recently emerged. To data, however, no single conformational model exists for the interpretation of these data. Studies of taxol and its analogs in organic solvents showed two distinct conformations, one in which the 3'-benzamido group and the 2-benzoyl group are in close proximity, and another in which the 2-benzoyl group is instead close to the 3'-phenyl group. We decided to use a derivative of taxol that has improved water-solubility to determine the structure of taxol in water. RESULTS: We have synthesized and characterized a stable water-soluble derivative of taxol that binds to microtubules and has a cytotoxicity profile very similar to that of taxol. 1D and 2D 1H NMR experiments with this bioactive compound in D2O indicate the presence of one conformer with a well-defined structure. In this structure, the 2-benzoyl group is clustered with the 3'-phenyl group. CONCLUSION: The determination of the conformation of taxol in water may allow quantitative three-dimensional interpretation of the structure-activity data obtained for taxol, and hence enable the design of novel taxol mimics.