Discovery and heterologous production of sarubicins and quinazolinone C-glycosides with protecting activity for cardiomyocytes

Glycosylated natural products and their derivatives are important pharmaceutical agents. Genome mining of a C-glycosylated metabolite biosynthetic gene cluster (BGC) from a soil-derived Streptomyces strain led to the isolation of sarubicins A (1) and B (2), of which 1 has a rare 2-oxabicyclo[2.2.2] substructure arising from C-glycosylation and C-C bond formation between the aglycone and the C-4 position of deoxysugar. Heterologous expression of the sar BGC led to the production of sarubicins and three new C-glycosylated quinazolinones 3-5 with a single C-C bond between the aglycone and deoxysugar, indicating the stepwise formation mechanism of the two unusual C-C bonds. A convenient chemical transformation from 1 to 2 and a proposed biosynthetic pathway for sarubicins are presented. Significantly, compounds 1 and 2 showed potent protective effects on neonatal rat cardiomyocytes.