- Enantioselective Imine Reduction Catalyzed by Phosphenium Ions
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The first use of phosphenium cations in asymmetric catalysis is reported. A diazaphosphenium triflate, prepared in two or three steps on a multigram scale from commercially available materials, catalyzes the hydroboration or hydrosilylation of cyclic imin
- Lundrigan, Travis,Welsh, Erin N.,Hynes, Toren,Tien, Chieh-Hung,Adams, Matt R.,Roy, Kayelani R.,Robertson, Katherine N.,Speed, Alexander W. H.
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supporting information
p. 14083 - 14088
(2019/10/11)
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- Small Molecule Inhibitors of Cyclophilin D to Protect Mitochondrial Function as a Potential Treatment for Acute Pancreatitis
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Opening of the mitochondrial permeability transition pore (MPTP) causes mitochondrial dysfunction and necrosis in acute pancreatitis (AP), a condition without specific drug treatment. Cyclophilin D (CypD) is a mitochondrial matrix peptidyl-prolyl isomerase that regulates the MPTP and is a drug target for AP. We have synthesized urea-based small molecule inhibitors of cyclophilins and tested them against CypD using binding and isomerase activity assays. Thermodynamic profiles of the CypD/inhibitor interactions were determined by isothermal titration calorimetry. Seven new high-resolution crystal structures of CypD-inhibitor complexes were obtained to guide compound optimization. Compounds 4, 13, 14, and 19 were tested in freshly isolated murine pancreatic acinar cells (PACs) to determine inhibition of toxin-induced loss of mitochondrial membrane potential (δΨm) and necrotic cell death pathway activation. Compound 19 was found to have a Kd of 410 nM and a favorable thermodynamic profile, and it showed significant protection of δΨm and reduced necrosis of murine as well as human PACs. Compound 19 holds significant promise for future lead optimization.
- Shore, Emma R.,Awais, Muhammad,Kershaw, Neil M.,Gibson, Robert R.,Pandalaneni, Sravan,Latawiec, Diane,Wen, Li,Javed, Muhammad A.,Criddle, David N.,Berry, Neil,O'Neill, Paul M.,Lian, Lu-Yun,Sutton, Robert
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p. 2596 - 2611
(2016/04/10)
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