RESUMEN
Brasilamides K-N (1-4), four new bergamotane sesquiterpenoids; with 4-oxatricyclo (3.3.1.0 (2,7))nonane (1)and 9-oxatricyclo(4.3.0.0 (4,7))nonane (2-4) skeletons; were isolated from the scale-up fermentation cultures of the plant endophytic fungus Paraconiothynium brasiliense Verkley. The previously identified sesquiterpenoids brasilamides A and C (5 and 6) were also reisolated in the current work. The structures of 1-4 were elucidated primarily by interpretation of NMR spectroscopic data. The absolute configurations of 1-3 were deduced by analogy to the co-isolated metabolites 5 and 6; whereas that of C-12 in 4 was assigned using the modified Mosher method. The cytotoxicity of all compounds against a panel of eight human tumor cell lines were assayed.
Asunto(s)
Ascomicetos/química , Dioxoles/aislamiento & purificación , Sesquiterpenos/química , Sesquiterpenos/farmacología , Línea Celular Tumoral , Dioxoles/química , Dioxoles/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Endófitos/química , Humanos , Espectroscopía de Resonancia Magnética/métodos , Piperazinas/química , Piperazinas/aislamiento & purificación , Piperazinas/farmacología , Sesquiterpenos/aislamiento & purificaciónRESUMEN
Brasilamides E-J (1-6), the bisabolane sesquiterpenoids with the 3-cyclohexylfuran (1 and 2) and 3-cyclohexylfuranone (3-6) skeletons, were isolated from the scale-up fermentation cultures of the plant endophytic fungus Paraconiothynium brasiliense Verkley. Although brasilamide E (1) is a known metabolite, its structure elucidation has yet to be described. The structures of 1-6 were elucidated primarily by NMR experiments. Compounds 3-6 were found to be racemic, and 3 was further separated into enantiomers 3a and 3b on a chiral HPLC column. The absolute configurations of 3a and 3b were assigned by electronic circular dichroism calculations. Compound 1 selectively inhibited the proliferation of the breast (MCF-7) and gastric (MGC) cancer cell lines, with IC50 values of 8.4 and 14.7 µM, respectively. Initial mechanistic investigation revealed that compound 1 inhibited the expression of a key energy metabolic enzyme, hexokinase II (HK2), in MCF-7 cells, which resulted in dysfunction of glucose metabolism and ATP depletion and eventually inhibited the proliferation of the breast cancer cells.
Asunto(s)
Antineoplásicos/aislamiento & purificación , Ascomicetos/química , Sesquiterpenos/aislamiento & purificación , Antineoplásicos/química , Antineoplásicos/farmacología , Cromatografía Líquida de Alta Presión , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Hexoquinasa/metabolismo , Humanos , Células MCF-7 , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Sesquiterpenos/química , Sesquiterpenos/farmacología , EstereoisomerismoRESUMEN
Communiols E-H (1-4), four new polyketide-derived natural products containing furanocyclopentane, furanocyclopentene, cyclopentene, or gamma-lactone moieties, have been isolated from two geographically distinct isolates of the coprophilous fungus Podospora communis. The structures of these compounds were determined by analysis of NMR and MS data.