RESUMEN
Bryostatin 1, a complex macrocyclic lactone isolated from Bugula neritina, has been the subject of multiple clinical trials for cancer. Although it functions as an activator of protein kinase C (PKC) in vitro, bryostatin 1 paradoxically antagonizes most responses to the prototypical PKC activator, the phorbol esters. The bottom half of the bryostatin 1 structure has been shown to be sufficient to confer binding to PKC. In contrast, we have previously shown that the top half of the bryostatin 1 structure is necessary for its unique biological behavior to antagonize phorbol ester responses. Neristatin 1 comprises a top half similar to that of bryostatin 1 together with a distinct bottom half that confers PKC binding. We report here that neristatin 1 is bryostatin 1-like, not phorbol ester-like, in its biological activity on U937 promyelocytic leukemia cells. We conclude that the top half of the bryostatin 1 structure is largely sufficient for bryostatin 1-like activity, provided the molecule also possesses an appropriate PKC binding domain.
Asunto(s)
Brioestatinas/química , Briozoos/química , Proteína Quinasa C/efectos de los fármacos , Animales , Humanos , Modelos Moleculares , Estructura Molecular , Ésteres del Forbol , Proteína Quinasa C/metabolismoRESUMEN
As an extension of our earlier structure/activity investigation of resveratrol (1a) cancer cell growth inhibitory activity compared to the structurally related stilbene combretastatin series (e.g., 2a), an efficient synthesis of E-stilstatin 3 (3a) and its phosphate prodrug 3b was completed. The trans-stilbene 3a was obtained using a convergent synthesis employing a Wittig reaction with phosphonium bromide 9 as the key reaction step. Deprotection of the Z-silyl ether 13 gave E-stilstatin 3 (3a) as the exclusive product. The structure and stereochemistry of 3a was confirmed by X-ray crystal structure determination.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Profármacos/síntesis química , Profármacos/farmacología , Estilbenos/síntesis química , Estilbenos/farmacología , Antineoplásicos/química , Bibencilos/química , Bibencilos/farmacología , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Conformación Molecular , Estructura Molecular , Profármacos/química , Resveratrol , Estereoisomerismo , Estilbenos/química , Relación Estructura-ActividadRESUMEN
An investigation of the Phillippine Ampelocissus sp. roots for cancer cell growth inhibitory components led to the isolation of a new acetogenin characterized as 22-epicalamistrin (1) employing primarily 2D NMR and high-resolution mass spectral analysis. Two other antineoplastic constituents proved to be the known acetogenin uvaribonin (2) and chalcone 3. Constituents 1-3 were all found to show significant cancer cell growth inhibitory activity against a panel of human cancer cell lines.
Asunto(s)
Acetogeninas/aislamiento & purificación , Acetogeninas/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Vitaceae/química , Acetogeninas/química , Animales , Antineoplásicos Fitogénicos/química , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Conformación Molecular , Estructura Molecular , Resonancia Magnética Nuclear BiomolecularRESUMEN
Bioassay-guided fractionation of extracts of various plants, marine organisms, and microorganisms has led to the discovery of new natural sources of a number of known compounds that have significant biological activity. The isolation of interesting and valuable cancer cell growth inhibitors including majusculamide C ( 1), axinastatin 5 ( 5), bengazoles A ( 6), B ( 7), and E ( 8), manzamine A ( 10), jaspamide ( 11), and neoechinulin A ( 19) has been summarized.
Asunto(s)
Antineoplásicos/farmacología , Carbazoles/farmacología , Depsipéptidos/farmacología , Alcaloides Indólicos/farmacología , Oxazoles/farmacología , Péptidos Cíclicos/farmacología , Piperazinas/farmacología , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Carbazoles/química , Carbazoles/aislamiento & purificación , Depsipéptidos/química , Depsipéptidos/aislamiento & purificación , Ensayos de Selección de Medicamentos Antitumorales , Alcaloides Indólicos/química , Alcaloides Indólicos/aislamiento & purificación , Biología Marina , Estructura Molecular , Oxazoles/química , Oxazoles/aislamiento & purificación , Péptidos Cíclicos/química , Péptidos Cíclicos/aislamiento & purificación , Piperazinas/química , Piperazinas/aislamiento & purificaciónRESUMEN
Spongistatin 1 is a macrocyclic lactone polyether from the marine sponge Hyrtios erecta. The aim of this study was to evaluate the in vitro and in vivo antifungal efficacies and mechanism of spongistatin 1. Spongistatin 1 was fungicidal for the majority of 74 reference strains and clinical isolates, including those resistant to flucytosine, ketoconazole or fluconazole, and retained activity in the presence of human serum or at lowered pH. The duration of the postantifungal effect following 1 h exposure to one, four and eight times the minimal inhibitory concentration was strain-dependent. Spongistatin 1 was significantly more efficacious than amphotericin B in reducing kidney infectious burden in a murine model of disseminated candidiasis, and reduced the lung burden in a murine model of pulmonary cryptococcosis. When cryptococcal microtubules were visualized by fluorescence microscopy and iterative deconvolution, spongistatin 1 was shown to disrupt first cytoplasmic and then spindle microtubules in a time- and concentration-dependent manner. Microtubule disruption was accompanied by an abnormal distribution of nuclei in budding cells and an inhibition of cell division, resulting in cells arrested in a large-budded stage. Spongistatin 1 should be pursued as a potential antifungal agent and as a probe to study, major cellular processes.