A novel approach was developed for the synthesis of 2-substituted-3-functionalized benzofurans, using an intramolecular Heck reaction which was further applied in the first enantioselective total synthesis of Daphnodorin B.

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Nicotinamide phosphoribosyltransferase (NAMPT) is identified as a promising target for cancer therapy. However, known NAMPT inhibitors are characterized by weak clinical efficacy and dose-dependent toxicity. There is an urgent need to develop new NAMPT intervention strategies. Using the proteolysis-targeting chimera (PROTAC) technology, we designed and synthesized a series of new von Hippel-Lindau (VHL)-recruiting NAMPT-targeting PROTACs. A highly potent NAMPT degrader (B3) was successfully identified, which displayed excellent degradation activity (DC 50 < 0.17 nM, D max > 90%) and antiproliferative potency against A2780 cells (IC 50 = 1.5 nM). PROTAC B3 induced NAMPT depletion in a concentration-and time-dependent manner through the ubiquitin-proteasome system. Particularly, PROTAC B3 achieved good plasma exposure levels via intravenous injection, gained potent tumor growth inhibition (TGI = 88.1%, 2 μM/kg) in the xenograft model, and demonstrated good biosafety without undesired toxicities. This study provides a highly potent VHL-recruiting NAMPT degrader for the treatment of ovarian cancer.