Enantioselective Total Synthesis of (-)-Galiellalactone and Biological Evaluation of Novel Galiellalactone-Based Analogues as STAT3 inhibitors

Abstract

(-)-Galiellalactone (1), a fungal metabolite originally isolated from the Galiella rufa in 1990, has been reported to be a potent and specific inhibitor of signal transducer and activator of transcription 3 (STAT3), which is involved in numerous signaling pathways. (-)-Galiellalactone covalently binds to one or more cysteine residues in STAT3 and subsequently blocks the DNA binding of phosphorylated STAT3 without inhibition of phosphorylation and dimerization. (-)-Galiellalactone also induces apoptosis and growth inhibition of human prostate cancer cells expressing constitutively active STAT3 both in vitro and in vivo. For these reasons, (-)-galiellalactone has recently been considered to be a potential therapeutic agent against hormone-refractory prostate cancer. First, we have accomplished an enantioselective total synthesis of (-)-galiellalactone. The key features of our synthesis involve the highly stereoselective construction of the cis-trisubstituted cyclopentane intermediate by a Pd(0)-catalyzed cyclization, the stereospecific introduction of an angular hydroxyl group by Riley oxidation, and the efficient construction of the tricyclic system of (-)-galiellalactone via a combination of diastereoselective Hosomi-Sakurai crotylation and ring-closing metathesis (RCM). Next, we applied the synthetic strategy established in a process of total synthesis of (-)-galiellalactone into the syntheses of tricyclic or bicyclic galiellalactone analogues. In the present study, we investigated the inhibitory effects of (-)-galiellalactone and its structure variants on STAT3 activation and its applications in TNBC (triple-negative breast cancer) cells.