RESUMO
The cinnabaramides A-G (1-7) were isolated from a terrestrial strain of Streptomyces as potent and selective inhibitors of the human 20S proteasome. Their chemical and biological properties resemble those of salinosporamide A, a recently identified lead compound from an obligate marine actinomycete, which is currently under development as an anticancer agent. Cinnabaramides F and G (6, 7) combine essential structural features of salinosporamide A and lactacystin and show about equal potency in vitro, with IC50 values in the 1 nM range. The properties and phylogenetic position of the producer organism, the production and isolation of compounds 1-7, their structure elucidation by MS and NMR, and their biological activities are reported. Additionally, an X-ray crystal structure was obtained from cinnabaramide A (1).
Assuntos
Acetilcisteína/análogos & derivados , Lactonas , Inibidores de Proteassoma , Pirróis , Streptomyces/química , Acetilcisteína/sangue , Acetilcisteína/química , Acetilcisteína/isolamento & purificação , Acetilcisteína/farmacologia , Cristalografia por Raios X , Humanos , Lactonas/sangue , Lactonas/isolamento & purificação , Lactonas/farmacologia , Conformação Molecular , Estrutura Molecular , Pirróis/sangue , Pirróis/isolamento & purificação , Pirróis/farmacologiaRESUMO
Monorden (1) and the novel resorcylic acid lactones pochonins A (2), B (4), C (6), D (7), and E (8) as well as tetrahydromonorden (5) and pseurotin A (22) were isolated from cultures of the clavicipitaceous hyphomycete Pochonia chlamydosporia var. catenulata strain P 0297. Fermentation of P 0297 in bromide-containing culture media led to a shift in secondary metabolite production and yielded monocillins III (3) and II (9) as major metabolites besides monorden (1) as well as the novel compounds pochonin F (10) and a monocillin II glycoside (11) as minor metabolites. Most of these compounds showed moderate activities in a cellular replication assay against Herpes Simplex Virus 1 (HSV1) and against the parasitic protozoan Eimeria tenella. In contrast to the structurally related zearalenone derivatives none of the metabolites of strain P 0297 were found to be active in a fluorescence polarization assay for determination of modulatory activities on the human estrogenic receptor ERbeta. Beta-zearalenol (17), but not zearalenone (15) and alpha-zearalenol (16), showed antiherpetic effects. We report the production, isolation, and structure elucidation of compounds 1-11 and their biological characterization.
Assuntos
Antiprotozoários/isolamento & purificação , Antivirais/isolamento & purificação , Lactonas/isolamento & purificação , Fungos Mitospóricos/química , Animais , Antiprotozoários/química , Antiprotozoários/farmacologia , Antivirais/química , Antivirais/farmacologia , Eimeria tenella/efeitos dos fármacos , Alemanha , Herpesvirus Humano 1/efeitos dos fármacos , Lactonas/química , Lactonas/farmacologia , Macrolídeos , Microscopia Eletrônica de Varredura , Fungos Mitospóricos/ultraestrutura , Estrutura Molecular , Neurospora/efeitos dos fármacos , EstereoisomerismoRESUMO
The potential of new natural products as an important source for the exploration and development of new drugs and crop protection products is a long way from being exhausted. The statistical analysis of the structures of the natural and synthetically derived compounds has shown conspicuous variations in structural types in the natural products derived from different natural sources, which can be utilized in the search for individual active substances. The occasionally voiced prepossession that natural products have already been sufficiently examined and therefore no more innovations are to be expected can definitely be rejected.