RESUMEN
A new triene, 12,13-dehydrogeranylgeraniol (1), was isolated from the aquatic plant Saururus cernuus and its structure determined spectroscopically. Compound 1 inhibits PMA-induced peroxide-catalyzed oxidation of 2',7'-dichlorodihydrofluorescein dye (DCFH) by reactive oxygen species (ROS) within human promyelocyctic HL-60 cells.
Asunto(s)
Antioxidantes/farmacología , Diterpenos/química , Plantas Medicinales/química , Especies Reactivas de Oxígeno/metabolismo , Antineoplásicos Fitogénicos/farmacología , Diterpenos/aislamiento & purificación , Citometría de Flujo , Depuradores de Radicales Libres/farmacología , Células HL-60 , Humanos , Espectroscopía de Resonancia Magnética , Espectrofotometría Infrarroja , Espectrofotometría Ultravioleta , Espectroscopía Infrarroja por Transformada de Fourier , Estados UnidosRESUMEN
A new indanone (1) has been isolated from the filamentous marine cyanobacterium Lyngbya majuscula, and its structure determined spectroscopically. Vascular endothelial growth factor (VEGF) is an important regulator of tumor angiogenesis. Compound 1 inhibits hypoxia-induced activation of the VEGF gene promoter in Hep3B human liver tumor cells, in vitro.
Asunto(s)
Cianobacterias/química , Regulación de la Expresión Génica/efectos de los fármacos , Indanos/química , Hipoxia de la Célula , Factores de Crecimiento Endotelial/genética , Humanos , Indanos/aislamiento & purificación , Indanos/farmacología , Linfocinas/genética , Regiones Promotoras Genéticas , Células Tumorales Cultivadas , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
A new bioassay has been developed combining the simplicity of direct bioautography with the improved chromatographic resolution of 2D-TLC. Mixtures of structurally diverse antifungal agents were tested to establish the validity and utility of this method in the discovery of new natural products with activity against agriculturally important fungal pathogens.
Asunto(s)
Antifúngicos/aislamiento & purificación , Ascomicetos/efectos de los fármacos , Carbamatos , Colletotrichum/efectos de los fármacos , Enfermedades de las Plantas/microbiología , Plantas/microbiología , Acrilatos/farmacología , Compuestos de Anilina/farmacología , Antifúngicos/farmacología , Bencimidazoles/farmacología , Bioensayo , Captano/farmacología , Cromatografía en Capa Delgada , Dimetilditiocarbamato/farmacología , Fungicidas Industriales/farmacología , Guanidinas/farmacología , Maneb/farmacología , Metacrilatos , Nitrilos/farmacología , Nitrobencenos , Oxazoles/farmacología , Piperazinas/farmacología , Pirimidinas/farmacología , Estrobilurinas , Tiabendazol/farmacología , Tiofanato/farmacología , Triazoles/farmacologíaRESUMEN
An analogue of dolastatin 13 (2) has been isolated from a marine cyanobacterium, Symploca hydnoides, collected near Guam. This new cyclic depsipeptide contains a L-methionine sulfoxide residue; however, the sulfoxide exists as both R- and S-forms, resulting in the doubling of several signals in the 1H and 13C NMR spectra. Structure elucidation required extensive application of 2-D NMR techniques such as COSY, HMQC, HMBC, and ROESY. The trivial name symplostatin 2 (1) has been assigned to the new metabolite and its isolation from S. hydnoides further supports the proposal that many compounds originally isolated from the sea hare Dolabella auricularia are most probably of cyanobacterial origin.
Asunto(s)
Cianobacterias/química , Depsipéptidos , Oligopéptidos/aislamiento & purificación , Aminoácidos/química , Espectroscopía de Resonancia Magnética , Conformación Molecular , Oligopéptidos/química , Oxidación-Reducción , Espectrometría de Masa Bombardeada por Átomos VelocesRESUMEN
Five new metabolites have been isolated from a lyngbyastatin 1- and dolastatin 12-producing assemblage of Lyngbya majuscula and Schizothrix calcicola collected at Tumon Bay, Guam. Structure elucidation employed 2D NMR techniques and chemical derivatization. These compounds have been assigned the trivial names tumonoic acids A (2), B (1), and C (5); methyl tumonoate A (3), and methyl tumonoate B (4). Compounds 1 and 4 were also found in a lyngbyastatin 1-producing strain of L. majuscula from Guam.
Asunto(s)
Cianobacterias/química , Oligopéptidos/aislamiento & purificación , Guam , Hidrólisis , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Oligopéptidos/química , Espectrofotometría InfrarrojaRESUMEN
Lyngbyastatin 1 (1a), a new cytotoxic analogue of dolastatins 12 (2a) and 11 (4), was isolated as an inseparable mixture with its C-15 epimer (1b) from extracts of a Lyngbya majuscula/Schizothrix calcicola assemblage and a L. majuscula strain collected near Guam. Dolastatin 12 (2a) was also encountered as an inseparable mixture with its C-15 epimer (2b) in L. majuscula/S. calcicola assemblages. At least one of the compounds in each mixture appeared to exist in solution as a mixture of slowly interconverting conformers resulting in broadened signals in 1H NMR spectra. Structure elucidation therefore relied principally on mass spectroscopy and chemical degradation studies. Both 1ab and 2ab proved toxic with only marginal or no antitumor activity when tested against colon adenocarcinoma #38 or mammary adenocarcinoma #16/C. Both 1ab and 2ab were shown to be potent disrupters of cellular microfilament networks.
Asunto(s)
Antineoplásicos/aislamiento & purificación , Cianobacterias/química , Depsipéptidos , Oligopéptidos/aislamiento & purificación , Citoesqueleto de Actina/efectos de los fármacos , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular , Ensayos de Selección de Medicamentos Antitumorales , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Estructura Molecular , Oligopéptidos/química , Oligopéptidos/farmacologíaRESUMEN
A new solid tumor selective cytotoxic analogue of dolastatin 10 (1) has been isolated from the marine cyanobacterium Symploca hydnoides, collected near Guam. This metabolite has been assigned the trivial name symplostatin 1 (2). This discovery supports the proposal that many compounds isolated from the seahare Dolabella auricularia, the original source of the dolastatins, are of dietary origin.
Asunto(s)
Antineoplásicos/química , Cianobacterias/química , Depsipéptidos , Oligopéptidos/química , Antineoplásicos/toxicidad , Guam , Humanos , Células KB , Espectroscopía de Resonancia Magnética , Oligopéptidos/toxicidad , Espectrometría de Masa Bombardeada por Átomos Veloces , Espectrofotometría UltravioletaRESUMEN
Originally purified as a major lipid component of a strain of the cyanobacterium Lyngbya majuscula isolated in Curaçao, curacin A is a potent inhibitor of cell growth and mitosis, binding rapidly and tightly at the colchicine site of tubulin. Because its molecular structure differs so greatly from that of colchicine and other colchicine site inhibitors, we prepared a series of curacin A analogs to determine the important structural features of the molecule. These modifications include reduction and E-to-Z transitions of the olefinic bonds in the 14-carbon side chain of the molecule; disruption of and configurational changes in the cyclopropyl moiety; disruption, oxidation, and configurational reversal in the thiazoline moiety; configurational reversal and substituent modifications at C13; and demethylation at C10. Inhibitory effects on tubulin assembly, the binding of colchicine to tubulin, and the growth of MCF-7 human breast carcinoma cells were examined. The most important portions of curacin A required for its interaction with tubulin seem to be the thiazoline ring and the side chain at least through C4, the portion of the side chain including the C9-C10 olefinic bond, and the C10 methyl group. Only two modifications totally eliminated the tubulin-drug interaction. The inactive compounds were a segment containing most of the side chain, including its two substituents, and analogs in which the methyl group at the C13 oxygen atom was replaced by a benzoate residue. Antiproliferative activity comparable with that observed with curacin A was only reproduced in compounds that were potent inhibitors of the binding of colchicine to tubulin. Molecular modeling and quantitative structure-activity relationship studies demonstrated that most active analogs overlapped extensively with curacin A but failed to provide an explanation for the apparent structural analogy between curacin A and colchicine.
Asunto(s)
Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/embriología , Colchicina/metabolismo , Ciclopropanos/metabolismo , Ciclopropanos/farmacología , Tiazoles/metabolismo , Tiazoles/farmacología , Tubulina (Proteína)/metabolismo , Animales , Sitios de Unión , Neoplasias de la Mama/patología , Bovinos , División Celular/efectos de los fármacos , ADN de Neoplasias/metabolismo , Interacciones Farmacológicas , Fase G2/efectos de los fármacos , Fase G2/fisiología , Humanos , Mitosis , Modelos Químicos , Modelos Moleculares , Conformación Molecular , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Curacin A, the major lipid constituent of a strain of the marine cyanobacterium Lyngbya majuscula obtained off the coast of Curaçao, is a potent antimitotic agent that we have previously shown to inhibit microtubule assembly and colchicine binding to tubulin. In the present study, we report that curacin A probably binds in the colchicine site because it competitively inhibits the binding of [3H]colchicine to tubulin with an apparent Ki value of 0.6 microM and stimulates tubulin-dependent GTP hydrolysis, as do most other colchicine-site agents. The binding of curacin A to tubulin resembled the binding reactions of combretastatin A-4 and podophyllotoxin in contrast to that of colchicine in that it occurred as extensively on ice as at higher temperatures. However, once bound, the dissociation rate of curacin A from tubulin is very slow, more closely resembling that observed with colchicinoids (thiocolchicine was the drug examined) than the faster dissociation that occurs with combretastatin A-4 and podophyllotoxin. Because the molecular structure of curacin A is so different from that of previously described colchicine-site drugs (e.g., there is no aromatic moiety, and there are only two conjugated double bonds in its linear hydrocarbon chain), we have been examining the activities of natural isomers and synthetic derivatives. So far, only modest enhancement or reduction of activity has been observed with a variety of structural changes.
Asunto(s)
Antineoplásicos/farmacología , Colchicina/metabolismo , Cianobacterias/química , Ciclopropanos/farmacología , Tiazoles/farmacología , Tubulina (Proteína)/metabolismo , Animales , Antineoplásicos/metabolismo , Sitios de Unión , Unión Competitiva , Bovinos , Ciclopropanos/metabolismo , Cinética , Relación Estructura-Actividad , Tiazoles/metabolismoRESUMEN
A novel sphingolipid containing an iso-fatty acid, (4E,8E)-N-13'-methyltetradecanoyl-1-O-beta-D-glucopyra nosyl-4-sphingadiene, was isolated from the Oregon marine sponge Halichondria panicea and its structure determined using a combination of spectroscopic and chemical degradation techniques. A second galactosyl-ceramide, which contained an unusually long chain fatty acid amide component, was also isolated from H. panicea.