Modular Synthesis of Radicicol A and Related Resorcylic Acid Lactones, Potent Kinase Inhibitors

摘要

Radicicol A (F87-25 09.04, 1, Scheme 1) belongs to the family of resorcylic acid lactones[1] (RAL) and was first reported by researchers from Sandoz who identified this fungal metabolite from a screen for IL1β inhibition.[2] While it was observed that 1 accelerated the degradation of specific mRNA sequences including those of IL1β, its precise molecular target was not identified.[2], [3] Subsequently, two other related resorcylic acid lactones containing a cis-enone (3 and 5, Scheme 1) were reported to be potent irreversible yet selective kinase inhibitors.[4], [5] More recently, Santi and co-workers showed that hypothemycin, which also bears the cis-enone moiety, covalently inactivates ERK2 by reacting with a cysteine residue positioned in the active site (Cys166).[6]