Natural Lysine-Reactive Meroterpenoids, Stachybenzals A–C, as Covalent Asparagine Synthetase Inhibitors

Asparagine synthetase (ASNS) is a promising molecular target for cancer chemotherapy. We previously reported bisabosqual A (Bis A), a natural covalent ASNS inhibitor that binds to K556 of ASNS. In this study, to discover other natural covalent ASNS inhibitors, we used a Lys derivative (N-Boc-l-Lys) to target Lys-reactive metabolites in crude extract of the fungus Stachybotrys ruwenzoriensis RF-6853. We discovered three new meroterpenoids possessing an o-phthalaldehyde moiety, stachybenzals A–C (1–3), with ASNS inhibitory activity.