Tyrosyl-DNA Phosphodiesterase 1 Inhibitor from an Anamorphic Fungus

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an enzyme that, Catalyzes hydrolysis of 3'-phosphotyrosl bonds and involved in repair of irreversible topo-isomerase. I (Top1)-DNA covalent complexes Top1 inhabitors which are currently used to treat human cancers. While screening for Top1 inhabitors, we discovered a novel compound JBIR-21 (1) from the culture of an anamorphic fungus, RF-1330S. The structure of 1 was established, by extesive NMR and MS analyses Compound 1 showed inhibitory activity against Tdp1 (IC50 value 18 mu M) and cyctoxicactivity against cancer cell lines. (IC50 values 3.5-13 mu M) Compound 1 also exhibited antitumorlactivity in a mousexenograft model without adverse effects.