Facile Conversion of syn-[Fe-IV(O)(TMC)](2+) into the anti Isomer via Meunier's Oxo-Hydroxo Tautomerism Mechanism

The syn and anti isomers of [Fe-IV(O)(TMC)](2+) (TMC=tetramethylcyclam) represent the first isolated pair of synthetic non-heme oxoiron(IV) complexes with identical ligand topology, differing only in the position of the oxo unit bound to the iron center. Both isomers have previously been characterized. Reported here is that the syn isomer [Fe-IV(O-syn)(TMC)(NCMe)](2+) (2) converts into its anti form [Fe-IV(O-anti)(TMC)(NCMe)](2+) (1) in MeCN, an isomerization facilitated by water and monitored most readily by (HNMR)-H-1 and Raman spectroscopy. Indeed, when (H2O)-O-18 is introduced to 2, the nascent 1 becomes O-18-labeled. These results provide compelling evidence for a mechanism involving direct binding of a water molecule trans to the oxo atom in 2 with subsequent oxo-hydroxo tautomerism for its incorporation as the oxo atom of 1. The nonplanar nature of the TMC supporting ligand makes this isomerization an irreversible transformation, unlike for their planar heme counterparts

High-spin and low-spin iron(II) complexes with facially-coordinated borohydride ligands

Rare examples of monometallic high-spin and low-spin L_3Fe(H_3BH) complexes have been characterized, where the two L_3 ligands are [Tp^(Ph2)] and [PhBP3] ([Tp^(Ph2)] = [HB(3,5-Ph_2pz)_3]− and [PhBP_3] = [PhB(CH_2PPh_2)_3]−). The structures are reported wherein the borohydride ligand is facially coordinated to the iron center in each complex. Density functional methods have been employed to explain the bonding in these unusual iron(II) centers. Despite the differences in spin states, short Fe–B distances are observed in both complexes and there is significant theoretical evidence to support a substantial bonding interaction between the iron and boron nuclei. In light of this interaction, we suggest that these complexes can be described as (L_3)Fe(η^4-H_3BH) complexes

Vibrational Spectroscopy and Analysis of Pseudo-tetrahedral Complexes with Metal Imido Bonds

A number of assignments have been previously posited for the metal−nitrogen stretch (ν(M-NR)), the N−R stretch (ν(MN−R)), and possible ligand deformation modes associated with terminally bound imides. Here we examine mononuclear iron(III) and cobalt(III) imido complexes of the monoanionic tridentate ligand [PhBP_(3)] ([PhBP_(3)] = [PhB(CH_(2)PPh_(2))_(3)]^(-)) to clarify the vibrational features for these trivalent metal imides. We report the structures of [PhBP_(3)]Fe≡N^(t)Bu and [PhBP_(3)]Co≡N^(t)Bu. Pseudo-tetrahedral metal imides of these types exhibit short bond lengths (ca. 1.65 Å) and nearly linear angles about the M−N−C linkages, indicative of multiple bond character. Furthermore, these compounds give rise to intense, low-energy visible absorptions. Both the position and the intensity of the optical bands in the [PhBP_(3)]M≡NR complexes depend on whether the substituent is an alkyl or aryl group. Excitation into the low-energy bands of [PhBP_(3)]Fe≡N^(t)Bu gives rise to two Raman features at 1104 and 1233 cm^(-1), both of which are sensitive to ^(15)N and ^(2)H labeling. The isotope labeling suggests the 1104 cm^(-1) mode has the greatest Fe−N stretching character, while the 1233 cm^(-1) mode is affected to a lesser extent by ^(15)N substitution. The spectra of the deuterium-labeled imides further support this assertion. The data demonstrate that the observed peaks are not simple diatomic stretching modes but are extensively coupled to the vibrations of the ancillary organic group. Therefore, describing these complexes as simple diatomic or even triatomic oscillators is an oversimplification. Analogous studies of the corresponding cobalt(III) complex lead to a similar set of isotopically sensitive resonances at 1103 and 1238 cm^(-1), corroborating the assignments made in the iron imides. Very minimal changes in the vibrational frequencies are observed upon replacement of cobalt(III) for iron(III), suggesting similar force constants for the two compounds. This is consistent with the previously proposed electronic structure model in which the added electron resides in a relatively nonbonding orbital. Replacement of the tBu group with a phenyl ring leads to a significantly more complicated resonance Raman spectrum, presumably due to coupling with the vibrations of the phenyl ring. Polarization studies demonstrate that the observed modes have A1 symmetry. In this case, a clearer resonance enhancement of the signals is observed, supporting a charge transfer designation for the electronic transitions. A series of isotope-labeling experiments has been carried out, and the modes with the greatest metal−nitrogen stretching character have been assigned to peaks at 960 and 1300 cm^(-1) in both the iron and cobalt [PhBP_(3)]M≡NPh complexes. These results are consistent with a multiple M−N bond for these metal imides

Trapping a Highly Reactive Nonheme Iron Intermediate That Oxygenates Strong CH Bonds with Stereoretention

An unprecedentedly reactive iron species (2) has been generated by reaction of excess peracetic acid with a mononuclear iron complex [FeII(CF3SO3)2(PyNMe3)] (1) at cryogenic temperatures, and characterized spectroscopically. Compound 2 is kinetically competent for breaking strong C―H bonds of alkanes (BDE ≈ 100 kcal·mol−1) through a hydrogen-atom transfer mechanism, and the transformations proceed with stereoretention and regioselectively, responding to bond strength, as well as to steric and polar effects. Bimolecular reaction rates are at least an order of magnitude faster than those of the most reactive synthetic high-valent nonheme oxoiron species described to date. EPR studies in tandem with kinetic analysis show that the 490 nm chromophore of 2 is associated with two S = 1/2 species in rapid equilibrium. The minor component 2a (∼5% iron) has g-values at 2.20, 2.19, and 1.99 characteristic of a low-spin iron(III) center, and it is assigned as [FeIII(OOAc)(PyNMe3)]2+, also by comparison with the EPR parameters of the structurally characterized hydroxamate analogue [FeIII(tBuCON(H)O)(PyNMe3)]2+ (4). The major component 2b (∼40% iron, g-values = 2.07, 2.01, 1.95) has unusual EPR parameters, and it is proposed to be [FeV(O)(OAc)(PyNMe3)]2+, where the O―O bond in 2a has been broken. Consistent with this assignment, 2b undergoes exchange of its acetate ligand with CD3CO2D and very rapidly reacts with olefins to produce the corresponding cis-1,2-hydroxoacetate product. Therefore, this work constitutes the first example where a synthetic nonheme iron species responsible for stereospecific and site selective C―H hydroxylation is spectroscopically trapped, and its catalytic reactivity against C―H bonds can be directly interrogated by kinetic methods. The accumulated evidence indicates that 2 consists mainly of an extraordinarily reactive [FeV(O)(OAc)(PyNMe3)]2+ (2b) species capable of hydroxylating unactivated alkyl C―H bonds with stereoretention in a rapid and site-selective manner, and that exists in fast equilibrium with its [FeIII(OOAc)(PyNMe3)]2+ precursor

Acid-Triggered O−O Bond Heterolysis of a Nonheme FeIII (OOH) Species for the Stereospecific Hydroxylation of Strong C−H Bonds

A novel hydroperoxoiron(III) species [FeIII(OOH)(MeCN)(PyNMe3)]2+ (3) has been generated by reaction of its ferrous precursor [FeII(CF3SO3)2(PyNMe3)] (1) with hydrogen peroxide at low temperatures. This species has been characterized by several spectroscopic techniques and cryospray mass spectrometry. Similar to most of the previously described low‐spin hydroperoxoiron(III) compounds, 3 behaves as a sluggish oxidant and it is not kinetically competent for breaking weak C−H bonds. However, triflic acid addition to 3 causes its transformation into a much more reactive compound towards organic substrates that is capable of oxidizing unactivated C−H bonds with high stereospecificity. Stopped‐flow kinetic analyses and theoretical studies provide a rationale for the observed chemistry, a triflic‐acid‐assisted heterolytic cleavage of the O−O bond to form a putative strongly oxidizing oxoiron(V) species. This mechanism is reminiscent to that observed in heme systems, where protonation of the hydroperoxo intermediate leads to the formation of the high‐valent [(Porph.)FeIV(O)] (Compound I)

XAS Characterization of a Nitridoiron(IV) Complex with a Very Short Fe-N Bond

X-ray absorption spectroscopy has been used to characterize the novel nitridoiron(IV) units in two [PhBP^R_3]Fe(N) complexes (R = iPr and CyCH_2) and obtain direct spectroscopic evidence for a very short Fe−N distance. The distance of 1.51−1.55 Å reflects the presence of an FeN triple bond in accord with the observed Fe_≡N vibration observed for one of these species (ν_(FeN) = 1034 cm^(-1)). This highly covalent bonding interaction results in the appearance of an unusually intense pre-edge peak, whose estimated area of 100(20) units is much larger than those of the related tetrahedral complexes with Fe^I−N_2−Fe^I, Fe^(II)−NPh_2, and Fe^(III)_≡NAd motifs, and those of recently described six-coordinate Fe^V≡N and Fe^V≡IN complexes. The observation that the Fe^(IV)−N distances of two [PhBPR_3]Fe(N) complexes are shorter than the Fe^(IV)−O bond lengths of oxoiron(IV) complexes may be rationalized on the basis of the greater π basicity of the nitrido ligand than the oxo ligand and a lower metal coordination number for the Fe(N) complex

RasGRP4 Is a Novel Ras Activator Isolated from Acute Myeloid Leukemia

Although a number of genetic defects are commonly associated with acute myeloid leukemia (AML), a large percentage of AML cases are cytogenetically normal. This suggests a functional screen for transforming genes is required to identify genetic mutations that are missed by cytogenetic analyses. We utilized a retrovirus-based cDNA expression system to identify transforming genes expressed in cytogenetically normal AML patients. We identified a new member of the Ras guanyl nucleotide-releasing protein (RasGRP) family of Ras guanine nucleotide exchange factors, designating it RasGRP4. Subsequently, cDNA sequences encoding rodent and human RasGRP4 proteins were deposited in GenBank. RasGRP4 contains the same protein domain structure as other members of the RasGRP family, including a Ras exchange motif, a CDC25 homology domain, a C1/diacyglycerol-binding domain, and putative calcium-binding EF hands. We show that expression of RasGRP4 induces anchorage-independent growth of Rat1 fibroblasts. RasGRP4 is a Ras-specific activator and, interestingly, is highly expressed in peripheral blood leukocytes and myeloid cell lines. Unlike other RasGRP proteins, RasGRP4 is not expressed in the brain or in lymphoid cells. We demonstrated that 32D myeloid cells expressing RasGRP4 have elevated levels of activated Ras compared with control cells, and phorbol 12-myristate 13-acetate (PMA) treatment greatly enhanced Ras activation. PMA induced membrane localization of RasGRP4 and 32D cells expressing RasGRP4 were capable of cytokine-independent proliferation in the presence of PMA. We conclude that RasGRP4 is a member of the RasGRP family of Ras guanine nucleotide exchange factors that may play a role in myeloid cell signaling growth regulation pathways that are responsive to diacylglycerol levels

Isolation of a NCK-associated Kinase, PRK2, an SH3-binding Protein and Potential Effector of Rho Protein Signaling

The NCK adapter protein is comprised of three consecutive Src homology 3 (SH3) protein-protein interaction domains and a C-terminal SH2 domain. Although the association of NCK with activated receptor protein-tyrosine kinases, via its SH2 domain, implicates NCK as a mediator of growth factor-induced signal transduction, little is known about the pathway(s) downstream of NCK recruitment. To identify potential downstream effectors of NCK we screened a bacterial expression library to isolate proteins that bind its SH3 domains. Two molecules were isolated, the Wiskott-Aldrich syndrome protein (WASP, a putative CDC42 effector) and a serine/threonine protein kinase (PRK2, closely related to the putative Rho effector PKN). Using interspecific backcross analysis the Prk2 gene was mapped to mouse chromosome 3. Unlike WASP, which bound the SH3 domains of several signaling proteins, PRK2 specifically bound to the middle SH3 domain of NCK and (weakly) that of phospholipase Cgamma. PRK2 also specifically bound to Rho in a GTP-dependent manner and cooperated with Rho family proteins to induce transcriptional activation via the serum response factor. These data suggest that PRK2 may coordinately mediate signal transduction from activated receptor protein-tyrosine kinases and Rho and that NCK may function as an adapter to connect receptor-mediated events to Rho protein signaling

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts