A Stereocontrolled Total Synthesis of Lipoxin B4 and its Biological Activity as a Pro-Resolving Lipid Mediator of Neuroinflammation

Two stereocontrolled, efficient, and modular syntheses of eicosanoid lipoxin B4 (LXB₄) are reported. One features a stereoselective reduction followed by an asymmetric epoxidation sequence to set the vicinal diol stereocentres. The dienyne was installed via a one-pot Wittig olefination and base-mediated epoxide ring opening cascade. The other approach installed the diol through an asymmetric dihydroxylation reaction followed by a Horner-Wadsworth-Emmons olefination to afford the common dienyne intermediate. Finally, a Sonogashira coupling and an alkyne hydrosilylation/proto-desilylation protocol furnished LXB₄ in 25 % overall yield in just 10 steps. For the first time, LXB₄ has been fully characterized spectroscopically with its structure confirmed as previously reported. We have demonstrated that the synthesized LXB₄ showed similar biological activity to commercial sources in a cellular neuroprotection model. This synthetic route can be employed to synthesize large quantities of LXB₄, enable synthesis of new analogs, and chemical probes for receptor and pathway characterization.     

Metal-Templated,Tight Loop Conformation of a Cys-X-Cys Biomimetic Assembles a Dimanganese Complex

With the goal of generating anionic analogues to MN₂S₂ ⋅ Mn(CO)₃Br we introduced metallodithiolate ligands, MN₂S₂²⁻ prepared from the Cys-X-Cys biomimetic, ema⁴⁻ ligand (ema=N,N′-ethylenebis(mercaptoacetamide); M=Ni^II, [V^IV≡O]²⁺ and Fe^III) to Mn(CO)₅Br. An unexpected, remarkably stable dimanganese product, (H₂N₂(CH₂C=O(μ-S))₂)[Mn(CO)₃]₂ resulted from loss of M originally residing in the N₂S₂⁴⁻ pocket, replaced by protonation at the amido nitrogens, generating H₂ema²⁻. Accordingly, the ema ligand has switched its coordination mode from an N₂S₂⁴⁻ cavity holding a single metal, to a binucleating H₂ema²⁻ with bridging sulfurs and carboxamide oxygens within Mn-μ-S-CH₂-C-O, 5-membered rings. In situ metal-templating by zinc ions gives quantitative yields of the Mn₂ product. By computational studies we compared the conformations of “linear” ema⁴⁻ to ema⁴⁻ frozen in the “tight-loop” around single metals, and to the “looser” fold possible for H₂ema²⁻ that is the optimal arrangement for binucleation. XRD molecular structures show extensive H-bonding at the amido-nitrogen protons in the solid state.     

Metal‐Templated,Tight Loop Conformation of a Cys‐X‐Cys Biomimetic Assembles a Dimanganese Complex

With the goal of generating anionic analogues to MN₂S₂ ? Mn(CO)₃Br we introduced metallodithiolate ligands, MN₂S₂^2? prepared from the Cys‐X‐Cys biomimetic, ema^4? ligand (ema=N,N′‐ethylenebis(mercaptoacetamide); M=Ni^II, [V^IV≡O]²⁺ and Fe^III) to Mn(CO)₅Br. An unexpected, remarkably stable dimanganese product, (H₂N₂(CH₂C=O(μ‐S))₂)[Mn(CO)₃]₂ resulted from loss of M originally residing in the N₂S₂^4? pocket, replaced by protonation at the amido nitrogens, generating H₂ema^2?. Accordingly, the ema ligand has switched its coordination mode from an N₂S₂^4? cavity holding a single metal, to a binucleating H₂ema^2? with bridging sulfurs and carboxamide oxygens within Mn‐μ‐S‐CH₂‐C‐O, 5‐membered rings. In situ metal‐templating by zinc ions gives quantitative yields of the Mn₂ product. By computational studies we compared the conformations of “linear” ema^4? to ema^4? frozen in the “tight‐loop” around single metals, and to the “looser” fold possible for H₂ema^2? that is the optimal arrangement for binucleation. XRD molecular structures show extensive H‐bonding at the amido‐nitrogen protons in the solid state.     

Tides

An elementary analysis of the problem of tides on an ideal Earth from a point of view of the forces involved proves to be a valuable exercise in terms of the applied mathematics as well as the physics. The approximations show their value both for obtaining analytic solutions and for exhibiting the symmetry‐breaking at higher order.     

Connecting pairwise and positional election outcomes

General conclusions relating pairwise tallies with positional (e.g., plurality, antiplurality (“vote-for-two”)) election outcomes were previously known only for the Borda Count. While it has been known since the eighteenth century that the Borda and Condorcet winners need not agree, it had not been known, for instance, in which settings the Condorcet and plurality winners can disagree, or must agree. Results of this type are developed here for all three-alternative positional rules. These relationships are based on an easily used method that connects pairwise tallies with admissible positional outcomes; e.g., a special case provides the first necessary and sufficient conditions ensuring that the Condorcet winner is the plurality winner; another case identifies when there must be a profile whereby each candidate is the “winner” with some positional rule.     

High-Performance Liquid Chromatographic Determination of Cefepime and Cefazolin in Human Plasma and Dialysate

A simple high-performance liquid chromatographic (HPLC) method was developed for the simultaneous determination of cefepime and cefazolin in human plasma and dialysate. For component separation, the method utilized a C₁₈ column with an aqueous mobile phase of dibasic potassium hydrogen phosphate (pH 7.0) and methanol gradient at a flow rate of 1 mL min⁻¹. The method demonstrated linearity from 2.0 to 100.0 μg mL⁻¹ (r > 0.999) with detection limit of 1 μg mL⁻¹ for both cefepime and cefazolin. The method was utilized for evaluation of plasma and dialysate samples in a clinical study evaluating the dialyzer clearance of cefepime and cefazolin using high-flux hemodialysis with varying blood flow rates in chronic kidney failure patients undergoing hemodialysis and peritoneal dialysis treatment.