Heat shock protein 90 (Hsp90) family proteins are molecular chaperones that modulate the functions of various substrate proteins (clients) implicated in pro-tumorigenic pathways. In this study, the mitochondria-targeted antioxidant mitoquinone (MitoQ) was identified as a potent inhibitor of mitochondrial Hsp90, known as a tumor necrosis factor receptor-associated protein 1 (TRAP1). Structural analyses revealed an asymmetric bipartite interaction between MitoQ and the previously unrecognized drug binding sites located in the middle domain of TRAP1, believed to be a client binding region. MitoQ effectively competed with TRAP1 clients, and MitoQ treatment facilitated the identification of 103 TRAP1-interacting mitochondrial proteins in cancer cells. MitoQ and its redox-crippled SB-U014/SB-U015 exhibited more potent anticancer activity in vitro and in vivo than previously reported mitochondria-targeted TRAP1 inhibitors. The findings indicate that targeting the client binding site of Hsp90 family proteins offers a novel strategy for the development of potent anticancer drugs.
A metal-free oxidative difunctionalization of N-allylamides and N-allylthioamides has been developed. This system features the use of a hypervalent iodine oxidant with electron-deficient amines to access 5-amino-oxazoline and thiazoline scaffolds under mild conditions. Notably, various electron-deficient amines were systematically evaluated and we verified the reaction profile was originated from an attached (benzene)sulfonyl group.
Hypervalent iodine-mediated olefin functionalization provides a rapid gateway towards accessing both various heterocyclic cores and functional groups. In this regard, we have developed a Ritter-type alkene functionalization utilizing a PhI(OAc)2 ((diacetoxyiodo)benzene, PIDA)/Lewis acid combination in order to access isoxazoline and pyrazoline cores. Based on allyl ketone oximes and allyl ketone tosylhydrazones, we have developed an alkene oxyamidation and amido-amidation protocol en route to accessing both isoxazoline and pyrazoline cores. Additionally, acetonitrile serves as both the solvent and an amine source in the presence of this PIDA/Lewis acid combination. This operationally straightforward and metal-free protocol provides an easy access to isoxazoline and pyrazoline derivatives.
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