FBMN-Guided Discovery of Cyanogrisides from Mutant Strain CRM005 and Structural Diversification

Abstract Through genome mining and metabolomic analysis of the mutant strain CRM005, combined with feature-based molecular networking (FBMN) deduplication, five novel natural cyanogrisides (1–5) were selectively isolated and characterized, alongside six previously reported analogs (6–11). Antiproliferative assays demonstrated that cyanogriside K (8) exhibited potent and selective cytotoxicity against HCT-116 cells, with an IC50 value of 0.70 μM. In an effort to maximize the reutilization of natural product resources, the major aglycone caerulomycin H (11) was utilized to develop a glycosylation system, affording a small panel of nine glycosylated derivatives (13–21). Subsequent antiproliferative evaluations facilitated a preliminary structure–activity relationship analysis focused on variations in the glycosyl groups. Notably, the synthetic compound 13 displayed submicromolar-level activity against the human glioblastoma cell line SF-126 (IC50 0.49 μM), surpassing the activity of doxorubicin (IC50 0.78 μM). These findings position compound 13 as a promising cytotoxic hit derived from a small semisynthetic library and offer preliminary insight into how glycosyl modification impacts antiproliferative activity.