RESUMO
Strains within the genus Salinospora have been shown to produce complex natural products having antibiotic and antiproliferative activities. The biochemical basis for the cytotoxic effects of salinosporamide A has been linked to its ability to inhibit the proteasome. Synthetically accessible salinosporamide A (ML858) was used to determine its biochemical and biological activities and to compare its effects with those of bortezomib. ML858 and bortezomib show time- and concentration-dependent inhibition of the proteasome in vitro. However, unlike bortezomib, which is a reversible inhibitor, ML858 covalently binds to the proteasome, resulting in the irreversible inhibition of 20S proteasome activity. ML858 was equipotent to bortezomib in cell-based reporter stabilization assays, but due to intramolecular instability is less potent in long-term assays. ML858 failed to maintain levels of proteasome inhibition necessary to achieve efficacy in tumor models responsive to bortezomib. Our results show that ML858 and bortezomib exhibit different kinetic and pharmacologic profiles and suggest that additional characterization of ML858 is warranted before its therapeutic potential can be fully appreciated.
Assuntos
Antineoplásicos/farmacologia , Ácidos Borônicos/farmacologia , Lactonas/farmacologia , Inibidores de Proteases/farmacologia , Inibidores de Proteassoma , Pirazinas/farmacologia , Pirróis/farmacologia , Animais , Antineoplásicos/química , Ligação Competitiva , Ácidos Borônicos/química , Bortezomib , Estabilidade de Medicamentos , Feminino , Células HT29 , Células HeLa , Humanos , Lactonas/química , Camundongos , Camundongos Nus , Camundongos SCID , Inibidores de Proteases/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Pirazinas/química , Pirróis/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A MeOH/CH(2)Cl(2) extract of the bud covers of Artocarpus altilis collected in Micronesia showed activity in a cathepsin K inhibition assay. In addition to the three known flavonoids isolated from the bud covers of this species, two new compounds have been identified whose structures were determined on the basis of spectral data. These compounds include a dimeric dihydrochalcone, cycloaltilisin 6 (2), and a new prenylated flavone, cycloaltilisin 7 (3). Novel compounds 2 and 3 have IC(50) values of 98 and 840 nM, respectively, in cathepsin inhibition.
Assuntos
Catepsinas/antagonistas & inibidores , Chalcona/isolamento & purificação , Inibidores de Cisteína Proteinase/isolamento & purificação , Flavonoides/isolamento & purificação , Moraceae/química , Catepsina K , Chalcona/análogos & derivados , Chalcona/química , Chalcona/farmacologia , Cromatografia Líquida de Alta Pressão , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/farmacologia , Flavonoides/química , Flavonoides/farmacologia , Concentração Inibidora 50 , Micronésia , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Plantas Medicinais , Espectrofotometria InfravermelhoRESUMO
As part of a search for novel inhibitors of cathepsin K, the MeOH extract of a Micronesian sponge of the order Haplosclerida was shown to be active. Bioassay-guided fractionation of the extract yielded halitoxins, tryptamine, and a novel tryptamine-derived alkaloid, haploscleridamine (1). The tetrahydro-beta-carboline structure of haploscleridamine (1) was elucidated through spectral techniques. Haploscleridamine (1) was found to be an inhibitor of cathepsin K with an IC(50) of 26 microM.
