RESUMO
The ATPase p97 is a ubiquitin targeted segregase that uses the energy of ATP binding and hydrolysis to extract ubiquitylated substrates from biological membranes, from other proteins, or from protein complexes to carry out myriad tasks in eukaryotes. Increased p97 activity has been linked to a poor prognosis in cancer patients, making p97 an anti-neoplastic target. In the present study, we show that dehydrocurvularin (DHC) and its chlorinated variants are covalent inhibitors of p97, interfering with its ATPase activity. Interestingly, cellular studies revealed both DHC and its monochloro analogue interfere with both the proteasome and p97, whereas its dichloro analogue showed p97 specificity.
Assuntos
Adenosina Trifosfatases/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Halogenação , Proteínas Nucleares/antagonistas & inibidores , Zearalenona/análogos & derivados , Adenosina Trifosfatases/metabolismo , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/metabolismo , Proteínas Nucleares/metabolismo , Especificidade por Substrato , Zearalenona/química , Zearalenona/metabolismo , Zearalenona/farmacologiaRESUMO
Two new metabolites, 6-oxo-12-norcytochalasin D (1) and 4,5-di-isobutyl-2(1H)-pyrimidinone (2), together with seven known metabolites, cytochalasins D (3), Q (4), and N (5), 12-hydroxyzygosporin G (6), heptelidic acid chlorohydrin (7), (+)-heptelidic acid (8), and trichoderonic acid A (9), were isolated from Xylariaceae sp. FL0390, a fungal endophyte inhabiting Spanish moss, Tillandsia usneoides. Metabolite 1 is the first example of a 12-norcytochalasin. All metabolites, except 2 and 9, showed cytotoxic activity in a panel of five human tumor cell lines with IC50S of 0.2-5.0 µM.
Assuntos
Antineoplásicos/farmacologia , Ascomicetos/química , Citocalasinas/farmacologia , Endófitos/química , Tillandsia/microbiologia , Antineoplásicos/química , Citocalasinas/química , Estrutura MolecularRESUMO
Three new delta-elemanolide-type sesquiterpene lactones, zinagrandinolides A-C (1-3), and the known delta-elemanolide 4 have been isolated by a bioassay-guided fractionation of a cytotoxic hexane extract of the aerial parts of Zinnia grandiflora. The structures of 1-3 were determined on the basis of high-resolution mass and NMR data. All compounds exhibited strong cytotoxicity against the cancer cell lines NCI-H460, MCF-7, SF-268, and MIA Pa Ca-2 and the normal human fibroblast cell type WI-38, but none showed significant selectivity.