Inactivation of Flavoenzyme-Encoding Gene in Fluostatin Biosynthesis Leads to Diversified Angucyclinone Derivatives.

Inactivation of the flavoenzyme-encoding gene in fluostatin biosynthesis led to the isolation of four new angucyclinone derivatives (, , , and ), among which fluostarenes A () and B () featured the unprecedented 6/6/5/6/6 pentacyclic skeleton with fusion of a benzo[]fluorene and a six-membered lactone ring. Both and were putatively generated via quinone methide-mediated nonenzymatic reactions. Fluostarene B () exhibited cytotoxicity against several cancer cell lines with IC values ranging from 7 to 10 μM. Fluostarenes A (), B (), and PK1 () showed α-glucosidase inhibition activity with IC of 0.89, 1.58, and 0.13 μM, respectively. Successful complementation of the Δ mutant with from kinamycin biosynthesis suggests that FlsO1 should function equivalently to AlpK as a putative C-5 hydroxylase.