Hypervalent iodine reagents are of considerable relevance in organic chemistry as they can provide a complementary reaction strategy to the use of traditional transition metal chemistry. Over the past two decades, there have been an increasing number of applications including stoichiometric oxidation and catalytic asymmetric variations. This review outlines the main advances in the past 10 years in regard to alkene heterofunctionalization chemistry using achiral and chiral hypervalent iodine reagents and catalysts.
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.
Janus
kinase 1 (JAK1) plays a key role in most cytokine-mediated
inflammatory and autoimmune responses through JAK/STAT signaling;
thus, JAK1 inhibition is a promising therapeutic strategy for several
diseases. Analysis of the binding modes of current JAK inhibitors
to JAK isoforms allowed the design of N-alkyl-substituted
1-H-pyrrolo[2,3-b] pyridine carboxamide
as a JAK1-selective scaffold, and the synthesis of various methyl
amide derivatives provided 4-((cis-1-(4-chlorobenzyl)-2-methylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (31g) as a potent JAK1-selective
inhibitor. In particular, the (S,S)-enantiomer of 31g (38a) exhibited excellent
potency for JAK1 and selectivity over JAK2, JAK3, and TYK2. On investigating
the effect of 31g on hepatic fibrosis, it was found that
it reduces the proliferation and fibrogenic gene expression of TGF-β-induced
hepatic stellate cells (HSCs). Specifically, 31g significantly
inhibited TGF-β-induced migration of HSCs at 0.25 μM in
wound-healing assays.
The mechanism of the Brønsted acid-catalyzed aza-Darzens reaction is explored by charting the stereochemical outcome of the triflic acid-promoted conversion of trans-triazolines to cis-aziridines. These experiments are consistent with the intermediacy of an α-diazonium-β-amino ester intermediate.
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