Mutations in the gene encoding Cu/Zn superoxide dismutase-1 cause amyotrophic lateral sclerosis. Superoxide dismutase-1 mutations decrease protein stability and promote aggregation. The mutant monomer is thought to be an intermediate in the pathway from the superoxide dismutase-1 dimer to aggregate. Here we find that the monomeric copper-apo, zinc-holo protein is structurally perturbed and the apo-protein aggregates without reattainment of the monomer–dimer equilibrium. Intervention to stabilize the superoxide dismutase-1 dimer and inhibit aggregation is regarded as a potential therapeutic strategy. We describe protein–ligand interactions for two compounds, Isoproterenol and 5-fluorouridine, highlighted as superoxide dismutase-1 stabilizers. We find both compounds interact with superoxide dismutase-1 at a key region identified at the core of the superoxide dismutase-1 fibrillar aggregates, β-barrel loop II–strand 3, rather than the proposed dimer interface site. This illustrates the need for direct structural observations when developing compounds for protein-targeted therapeutics.

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.

Lithium metal reductions are widely employed in organic synthesis, where it is common to employ a "mediator" to speed up the electron transfer kinetics. We present experimental data for the electrode kinetics of the reduction of the most common mediator, 4,4'-di-tert-butyl-1,1'-biphenyl (DBB) in tetrahydrofuran (THF) over a range of temperatures. Using corresponding data for the oxidation of lithium we present quantitative estimates of the kinetic advantage for the use of DBB as a mediator in lithium reductions, over, in particular, direct reduction using lithium metal.

Closing the deal: A ring‐closing metathesis (RCM)/aromatization protocol, followed by a regioselective Negishi cross‐coupling reaction and macrolactonization, with subsequent RCM mediate the synthesis of (−)‐(Z)‐deoxypukalide in 12 linear steps and 15 % overall yield (see retrosynthesis; TBS=tert‐butyldimethylsilyl, TIPS=triisopropylsilyl).

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