Synthesis and structural modification of the natural product Ivesinol to discover novel autophagy activators

Autophagy is a lysosome-dependent cellular degradation pathway that responds to a variety of environmental and cellular stresses, which is defective in aging and age-related diseases, therefore, targeting autophagy with small-molecule activators has potential therapeutic benefits. In this study, we successfully completed the first total synthesis of Ivesinol, an identified antibacterial natural product, and efficiently constructed a library of its analogs. To measure the effect of Ivesinol analogs on autophagic activity, we performed cell imaging-based screening approach, and observed that several Ivesinol analogs exhibited potent autophagy-regulating activity. Specifically, the derivative B2 significantly activated autophagy activity in concentration- and time-dependent manners, and even outperformed the commonly used activator Torin1 in activating autophagy in MCF-7 cells at 0.5 μM. Bioinformatics analysis showed that B2 treatment significantly impacted ubiquitin mediated proteolysis and AMPK signaling pathway, with functionally related gene sets displaying strong correlations. Based on these findings, we proposed that B2 activates autophagy by mechanisms involved in downregulation of key HSP70 family members, activation of the UPR, and ultimately leading to autophagy. In conclusion, we suggest that B2 could be a promising and valuable autophagy activator with significant potential for further development.