Our efforts to model the oxygen activation chemistry of nonheme iron enzymes have yielded transient intermediates with novel properties. These properties can be dramatically affected by the introduction of a 6-methyl substituent on the pendant pyridines of the tetradentate ligand TPA (TPA = tris(2-pyridylmethyl)amine). A series of Fe(TPA) complexes has thus been synthesized and characterized to provide the structural basis for these dramatic effects. The following complexes have been obtained: [Fe(L)(CH3CN)2](ClO4)2 (1, L = TPA; 2, L = 6-MeTPA; 3, L = 6-Me2TPA; 4, L = 6-Me3TPA) and [Fe(L)(acac)](ClO4)2 (5, L = TPA; 6, L = 5-Me3TPA; 7, L = 6-MeTPA). As indicated by 1H NMR and/or EPR, 1, 5, and 6 with no 6-methyl substituent are low spin, while complexes 2, 3, 4, and 7 with at least one 6-methyl substituent are all high spin, with higher redox potentials than their low-spin counterparts. The ligands with 6-methyl substituents thus favor a metal center with a larger ionic radius, i.e., FeII over FeIII and high spin over low spin. Careful scrutiny of the crystal structures of 1, 4, 6, and 7 reveals that one hydrogen of the 6-methyl group is only 2.7 Å away from the metal center in the high-spin complexes. Its presence thus prevents the pyridine nitrogen from forming an Fe−N bond shorter than 2.1 Å as required for an iron center to adopt a low-spin configuration. This steric effect of the 6-methyl substituent serves as a simple but very useful ligand design tool to tune the electronic properties of the metastable alkylperoxoiron(III) species derived from the reactions of 1−4 with tert-butyl hydroperoxide. These intermediates serve as models for low-spin and high-spin peroxoiron(III) species in the reaction cycles of the antitumor drug bleomycin and lipoxygenase, respectively. Similar principles apply in the design of nonheme diiron(II) complexes that reversibly bind dioxygen and of high-valent bis(μ-oxo)diiron complexes that model the high-valent intermediates in the redox cycles of nonheme diiron enzymes such as methane monooxygenase and ribonucleotide reductase.
In an effort to gain more insight into the factors controlling the formation of low-spin non-heme Fe(III)-peroxo intermediates in oxidation catalysis, such as activated bleomycin, we have synthesized a series of iron complexes based on the pentadentate ligand N4Py (N4Py = N,N-bis(2-pyridylmethyl)-N-(bis-2-pyridylmethyl)amine). The following complexes have been prepared: [(N4Py)Fe(II)(CH(3)CN)](ClO(4))(2) (1), [(N4Py)Fe(II)Cl](ClO(4)) (2), [(N4Py)Fe(III)OMe](ClO(4))(2) (3), and [(N4Py)(2)Fe(2)O](ClO(4))(4) (4). Complexes 1 and 2 have low- and high-spin Fe(II) centers, respectively, whereas 3 is an Fe(III) complex that undergoes a temperature-dependent spin transition. The iron centers in the oxo-bridged dimer 4 are antiferromagnetically coupled (J = -104 cm(-)(1)). Comparison of the crystal structures of 1, 3, and 4 shows that the ligand is well suited to accommodate both Fe(II) and Fe(III) in either spin state. For the high-spin Fe(III) complexes 3 and 4 the iron atoms are positioned somewhat outside of the cavity formed by the ligand, while in the case of the low-spin Fe(II) complex 1 the iron atom is retained in the middle of the cavity with approximately equal bond lengths to all nitrogen atoms from the ligand. On the basis of UV/vis and EPR observations, it is shown that 1, 3, and 4 all react with H(2)O(2) to generate the purple low-spin [(N4Py)Fe(III)OOH](2+) intermediate (6). In the case of 1, titration experiments with H(2)O(2) monitored by UV/vis and (1)H NMR reveal the formation of [(N4Py)Fe(III)OH](2+) (5) and the oxo-bridged diiron(III) dimer (4) prior to the generation of the Fe(III)-OOH species (6). Raman spectra of 6 show distinctive Raman features, particularly a nu(O-O) at 790 cm(-)(1) that is the lowest observed for any iron-peroxo species. This observation may rationalize the reactivity of low-spin Fe(III)-OOH species such as "activated bleomycin".
Fe K-edge X-ray absorption spectroscopy is utilized to study a series of 22 synthetic high-spin iron(I1) complexes.The 1s -3d pre-edge peak of each complex is quantitated and compared with the others in order to explore its correlation with the coordination number and symmetry of the iron center. Like the high-spin iron(II1) complexes (Roe, A. L.; Schneider, D. J.; Mayer, R. J.; Pyrz, J. W.; Que, L., Jr. J . Am. Chem. SOC. 1984,106, 1676-1681, the iron(I1) complexes can be grouped on the basis of their normalized pre-edge peak intensities: the six-coordinate complexes have pre-edge areas from 4 to 6 units, the five-coordinate from 8 to 13 units, and the tetrahedral 16 to 21 units. Three six-coordinate "iron(I1)" nitrosyl complexes examined have pre-edge areas comparable to those of normal iron@) five-coordinate complexes due to their highly distorted geometry. The information obtained here can be used to determine the coordination number of the high-spin iron(I1) centers in iron(I1)-containing proteins and other model complexes and to complement analyses based on extended X-ray absorption fine structure (EXAFS)
We have synthesized the first complexes with bis(μ-oxo)diiron(III) and (μ-oxo)(μ-hydroxo)diiron(III) cores (1 and 2, L = TPA (a), 5-Et3-TPA (b), 6-Me3-TPA (c), 4,6-Me6-TPA (d), BQPA (e), BPEEN (f), and BPMEN (g)) and found them to have novel structural properties. In particular, the presence of two single-atom bridges in these complexes constrains the Fe−Fe distances to 2.7−3.0 Å and the Fe−μ-O−Fe angles to 100° or smaller. The significantly acute Fe−O−Fe angles (e.g., 92.5(2)° for 1c and 100.2(2)° for 2f) enforced by the Fe2O2(H) core endow these complexes with UV−vis, Raman, and magnetic properties quite distinct from those of other (μ-oxo)diiron(III) complexes. Complex 1c exhibits visible absorption bands at 470 (ε = 560 M-1 cm-1) and 760 nm (ε = 80 M-1 cm-1), while complexes 2 show features at ca. 550 (ε ≈ 800 M-1 cm-1) and ca. 800 nm (ε ≈ 70 M-1 cm-1), all of which are red shifted compared to those of other (μ-oxo)diiron(III) complexes. These complexes also exhibit distinct νFe-O - Fe vibrations at ca. 600 and ca. 670 cm-1 assigned to the νsym and the νasym of the Fe−O−Fe units, respectively. The relative intensities of the νsym and νasym bands are affected by the symmetry of the Fe−O−Fe units; an unsymmetric core enhances the intensity of the νasym. Complexes 2 exhibit another band at ca. 500 cm-1, which is assigned to the Fe−(OH)−Fe stretching mode due to its sensitivity to both H2 18O and 2H2O. Magnetic susceptibility studies reveal J = 54 cm-1 for 1c and ca. 110 cm-1 for 2 (H = J S 1·S 2), values smaller than those for the antiferromagnetic interactions found in (μ-oxo)diiron(III) complexes. This weakening arises from the longer Fe−μ-O bonds and the smaller Fe−μ-O−Fe angles in the Fe2O2(H) diamond core structure. These spectroscopic signatures can thus serve as useful tools to ascertain the presence of such core structures in metalloenzyme active sites. These two core structures, Fe2(μ-O)2 (1) and Fe2(μ-O)(μ-OH) (2), can also be interconverted by protonation equilibria with pK a's of 16−18 in CH3CN. Furthermore, the Fe2(μ-O)2 core (1) isomerizes to the Fe3(μ2-O)3 core (7), while the Fe2(μ-O)(μ-OH) core (2) exhibits aquation equilibria to the Fe2(μ-O)(μ-H3O2) core (5), except for L = 6-Me3-TPA and 4,6-Me6-TPA. It is clear from these studies that electronic and steric properties of the ligands significantly affect the various equilibria, demonstrating a rich chemistry involving water-derived ligands alone.
Major injury initiates a systemic inflammatory response that can be detrimental to the host. We have recently reported that burn injury primes innate immune cells for a progressive increase in TLR4 and TLR2 agonist-induced proinflammatory cytokine production and that this inflammatory phenotype is exaggerated in adaptive immune system-deficient (Rag1−/−) mice. The present study uses a series of adoptive transfer experiments to determine which adaptive immune cell type(s) has the capacity to control innate inflammatory responses after injury. We first compared the relative changes in TLR4- and TLR2-induced TNF-α, IL-1β, and IL-6 production by spleen cell populations prepared from wild-type (WT), Rag1−/−, CD4−/−, or CD8−/− mice 7 days after sham or burn injury. Our findings indicated that splenocytes prepared from burn-injured CD8−/− mice displayed TLR-induced cytokine production levels similar to those in WT mice. In contrast, spleen cells from burn-injured CD4−/− mice produced cytokines at significantly higher levels, equivalent to those in Rag1−/− mice. Moreover, reconstitution of Rag1−/− or CD4−/− mice with WT CD4+ T cells reduced postinjury cytokine production to WT levels. Additional separation of CD4+ T cells into CD4+CD25+ and CD4+CD25− subpopulations before their adoptive transfer into Rag1−/− mice showed that CD4+CD25+ T cells were capable of reducing TLR-stimulated cytokine production levels to WT levels, whereas CD4+CD25− T cells had no regulatory effect. These findings suggest a previously unsuspected role for CD4+CD25+ T regulatory cells in controlling host inflammatory responses after injury.
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