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The synthesis and characterization of the following bis-pyridine and bis-imidazole complexes of (tetramesitylporphinato)iron(III) are reported: [Fe(TMP)(4-NH2Py)2]C104, 1, [Fe(TMP)(3-EtPy)2]C104, 2, [Fe(TMP)(3-ClPy)2]C104, 3, [Fe(TMP)(2-MeHIm)2]C104, 4, [Fe(TMP)(4-CNPy)2]C104, 5, and [Fe(TMP)(3-CNPy)2]C104, 6. The crystal structures of complexes 2, 3, and 5 are reported. All three complexes have relative perpendicular alignment of the axial ligands with bond lengths consistent with low-spin iron(III). The porphinato cores are strongly S4 ruffled; the Fe-Np bonds show a commensurate shortening. EPR investigations reveal "large gmax" type EPR spectra for complexes 1-4, with complexes 2, 3, and 4 having unusually low g values (<3.2). Complex 1 has a "normal" "large gmax" g value of 3.40. Complexes 5 and 6 have axial EPR spectra with g± = 2.53 and gB = 1.56 or g± = 2.62 and gB unresolved, which result from a substantial change in the usual ground state of low-spin (porphinato)iron(III) complexes, (dx>)2(dxz,d>lz)3, to that having a predominantly (dxz,d>z)4(dx>,)1 ground state. Complexes 2, 3, 4, and 5 have been characterized by Móssbauer spectroscopy. The Móssbauer isomer shifts ( ) range from 0.18 to 0.20 mm/s and the quadrupole splittings (AEq) from 0.97 to 1.48 mm/s. The quadrupole splittings, like the EPR g values of these complexes, are unusually low, compared with AEq values of ~1.7-1.8 mm/s expected for imidazole complexes with perpendicular axial ligand orientation. The NMR isotropic shifts at -80 °C (193 K) of the pyrrole protons of all complexes except 1 and 2, but including additional low-spin bis-pyridine complexes with 4-NMe2, 3,4-Me2, 3,5-Me2, 4-Me, and 3-Me substituents and pyridine itself as axial ligands, varied from -39.5 ppm (4-NMe2Py) to -6.5 ppm (4-CNPy) through this series. This result indicates a smooth change from an electronic ground state which is largely (dxy)2(dxz,d^z)3 to one which is at least 50% (dxz,dyz)4(dv)' in nature at 193 K for the (4-CNPy)2 complex, supporting the conclusions reached on the basis of the variation of EPR and Móssbauer parameters observed at 77 K and below.

Summary In an attempt to find new types of anti‐sickling agents that specifically bind to intracellular sickle haemoglobin (HbS) without inhibition by plasma and tissue proteins or other undesirable consequences, we identified 5‐hydroxymethyl‐2‐furfural (5HMF), a naturally occurring aromatic aldehyde, as an agent that fulfils this criterion. Preliminary studies in vitro showed that 5HMF forms a high‐affinity Schiff‐base adduct with HbS and inhibits red cell sickling by allosterically shifting oxygen equilibrium curves towards the left. Further studies with transgenic (Tg) sickle mice showed that orally administered 5HMF was rapidly absorbed into the bloodstream from the gastrointestinal tract without being destroyed, traversed the red blood cell membrane and specifically bound with, and modified, HbS molecules at levels as high as 90%. Pretreatment of Tg sickle mice with 5HMF inhibited the formation of sickle cells and significantly prolonged survival time under severe hypoxia, compared with untreated mice, which died within 15 min because of sickling‐dependent pulmonary sequestration. These results indicate the feasibility of 5HMF as an attractive potential candidate for therapy of sickle cell disease.

Sphingosine-1-phosphate (S1P) is a bioactive signalling lipid highly enriched in mature erythrocytes, with unknown functions pertaining to erythrocyte physiology. Here by employing nonbiased high-throughput metabolomic profiling, we show that erythrocyte S1P levels rapidly increase in 21 healthy lowland volunteers at 5,260 m altitude on day 1 and continue increasing to 16 days with concurrently elevated erythrocyte sphingonisne kinase 1 (Sphk1) activity and haemoglobin (Hb) oxygen (O2) release capacity. Mouse genetic studies show that elevated erythrocyte Sphk1-induced S1P protects against tissue hypoxia by inducing O2 release. Mechanistically, we show that intracellular S1P promotes deoxygenated Hb anchoring to the membrane, enhances the release of membrane-bound glycolytic enzymes to the cytosol, induces glycolysis and thus the production of 2,3-bisphosphoglycerate (2,3-BPG), an erythrocyte-specific glycolytic intermediate, which facilitates O2 release. Altogether, we reveal S1P as an intracellular hypoxia-responsive biolipid promoting erythrocyte glycolysis, O2 delivery and thus new therapeutic opportunities to counteract tissue hypoxia.