Iron Porphyrin Carbenes As Catalytic Intermediates: Structures, Mössbauer and NMR Spectroscopic Properties, and Bonding

Iron porphyrin carbenes (IPCs) are thought to be intermediates involved in the metabolism of various xenobiotics by cytochrome P450, as well as in chemical reactions catalyzed by metalloporphyrins and engineered P450s. While early work proposed IPCs to contain FeII, more recent work invokes a double-bond description of the iron–carbon bond, similar to that found in FeIV porphyrin oxenes. Reported herein is the first quantum chemical investigation of IPC Mössbauer and NMR spectroscopic properties, as well as their electronic structures, together with comparisons to ferrous heme proteins and an FeIV oxene model. The results provide the first accurate predictions of the experimental spectroscopic observables as well as the first theoretical explanation of their electrophilic nature, as deduced from experiment. The preferred resonance structure is FeII←{:C(X)Y}0 and not FeIV{C(X)Y}2−, a result that will facilitate research on IPC reactivities in various chemical and biochemical systems

Structural, EPR Superhyperfine, and NMR Hyperfine Properties of the Cu-Octarepeat Binding Site in the Prion Protein

Previous experimental and computational investigations show that the copper binding in the prion protein that is involved in a number of neurodegenerative diseases is complicated and the exact binding structures remain to be determined. To facilitate structural investigation in this field, we report a quantum chemical investigation of structural, EPR superhyperfine, and NMR hyperfine properties of various copper complexes of the octarepeat domain, which has several copies of highly conserved amino acid sequence of PHGGGWGQ, The predicted metal ligand bond lengths of the X-ray structure of CuHGGGW, involving the central five residues in this domain, from the best method examined here, have a mean absolute deviation (MAD) of 0.030 angstrom, basically the same as found with experimental errors of various metal complexes. Prior controversial results regarding water coordination were resolved here with a more extensive computational investigation on 10 models with various water molecules and sequences (both HGGGW and PHGGGWGQ), which are consistent with the experimental reports. Experimental EPR superhyperfine constants are accurately reproduced with a MAD of 0.95 MHz. Results here suggest that the NMR hyperfine shifts which can be readily measured in NMR experiments and accurately predicted in quantum chemical calculations can provide more extensive and more sensitive structural probes than those from the current EPR studies. These results will be helpful for future experimental and computational investigations of the copper binding structures of the prion protein as well as other related systems

Catalytic and Biocatalytic Iron Porphyrin Carbene Formation: Effects of Binding Mode, Carbene Substituent, Porphyrin Substituent, and Protein Axial Ligand

Iron porphyrin carbenes (IPCs) are important intermediates in various chemical reactions catalyzed by iron porphyrins and engineered heme proteins, as well as in the metabolism of various xenobiotics by cytochrome P450. However, there are no prior theoretical reports to help understand their formation mechanisms and identify key information governing the binding mode, formation feasibility, and stability/reactivity. A systematic quantum chemical study was performed to investigate the effects of carbene substituent, porphyrin substituent, and axial ligand on IPC formation pathways. Results not only are consistent with available experimental data but also provide a number of unprecedented insights into electronic, steric, and H-bonding effects of various structural factors on IPC formation mechanisms. These results shall facilitate research on IPC and related systems for sustainable chemical catalysis and biocatalysis

Myofibroblastoma of the Breast: A Rare Cause of Breast Lump in a Postmenopausal Woman

A breast mass in a postmenopausal age woman is treated with a high index of clinical suspicion for malignancy. Myofibroblastoma (MFB) of the breast is a very rare benign stromal tumor, predominantly occurring in menopausal women and older men. Owing to its rarity, nonspecific radiology, cytomorphology, and many variants, it can be confused with other malignant and benign breast lesions and hence can be a source of diagnostic pitfall. We present a case of an MFB of the breast in a 55-year-old female, which was detected on a routine screening mammography. Fine-needle aspiration cytology was inconclusive. Final diagnosis was made by histopathology and immunohistochemistry examination. We report this case as the likelihood of encountering MFB has increased in recent years due to routine mammographic screening, and this lesion should be kept in the differential diagnosis of spindle-cell lesions of the breast

Synthesis, Characterization, and Theoretical Investigation of a Transition State Analogue for Proton Transfer during C-H Activation by a Rhodium-Pincer Complex

A heterobimetallic rhodium-pincer complex bearing a phenylzinc ligand was synthesized and characterized by multinuclear NMR, COSY, NOESY, and X-ray crystallography. The crystalstructure of this complex shows that it possesses a bridging Rh-Zn-C fragment with a geometry similar to the Rh-H-C fragment in a proposed transition state for metal-to-ligand proton transfer during redox-neutral C-H activation with dearomatized rhodium pincer complexes. Bonding analysis indicates that these fragments are isolobal, suggesting that the transition state analogue models not only the structure but also the bonding interactions that underlie metal-ligand cooperativity in the C-H activation transition state. The similarity of the transition state and its analogue prompted re-evaluation of the relevant rate equations to determine relative contributions of viable proton transfer pathways. Parallel analysis of the transition state and its isolobal analogue thus serves as a bridge between theory and experiment that is rarely available in studies of bonding in transition states

Inhibition of Aβ42 Peptide Aggregation by a Binuclear Ruthenium(II)−Platinum(II) Complex: Potential for Multimetal Organometallics as Anti-amyloid Agents

Design of inhibitors for amyloid-β (Aβ) peptide aggregation has been widely investigated over the years toward developing viable therapeutic agents for Alzheimer’s disease (AD). The biggest challenge seems to be inhibiting Aβ aggregation at the early stages possibly at the monomeric level, because oligomers are known to be neurotoxic. In this regard, exploiting the metal-chelating property of Aβ to generate molecules that can overcome this impediment presents some promise. Recently, one such metal complex containing PtII ([Pt(BPS)Cl2]) was reported to effectively inhibit Aβ42 aggregation and toxicity (Barnham, et al. (2008) Proc. Natl. Acad. Sci. U.S.A.105, 6813). This complex was able bind to Aβ42 at the N-terminal part of the peptide and triggered a conformational change resulting in effective inhibition. In the current report, we have generated a mixed-binuclear metal complex containing PtII and RuII metal centers that inhibited Aβ42 aggregation at an early stage and seemed to have different modes of interaction than the previously reported PtII complex, suggesting an important role of the second metal center. This ‘proof-of-concept’ compound will help in developing more effective molecules against Aβ aggregation by modifying the two metal centers as well as their bridging ligands, which will open doors to new rationale for Aβ inhibition

Hydride Attack on a Coordinated Ferric Nitrosyl: Experimental and DFT Evidence for the Formation of a Heme Model–HNO Derivative

Heme–HNO species are crucial intermediates in several biological processes. To date, no well-defined Fe heme–HNO model compounds have been reported. Hydride attack on the cationic ferric [(OEP)­Fe­(NO)­(5-MeIm)]­OTf (OEP = octaethylporphyrinato dianion) generates an Fe–HNO product that has been characterized by IR and ¹H NMR spectroscopy. Results of DFT calculations reveal a direct attack of the hydride on the N atom of the coordinated ferric nitrosyl

Lewis Acid Activation of the Ferrous Heme–NO Fragment toward the N–N Coupling Reaction with NO To Generate N₂O

Bacterial NO reductase (bacNOR) enzymes utilize a heme/non-heme active site to couple two NO molecules to N₂O. We show that BF₃ coordination to the nitrosyl O-atom in (OEP)­Fe­(NO) activates it toward N–N bond formation with NO to generate N₂O. ¹⁵N-isotopic labeling reveals a reversible nitrosyl exchange reaction and follow-up N–O bond cleavage in the N₂O formation step. Other Lewis acids (B­(C₆F₅)₃ and K⁺) also promote the NO coupling reaction with (OEP)­Fe­(NO). These results, complemented by DFT calculations, provide experimental support for the <i>cis</i>:<i>b</i>₃ pathway in bacNOR

Lewis Acid Activation of the Ferrous Heme–NO Fragment toward the N–N Coupling Reaction with NO To Generate N₂O

Bacterial NO reductase (bacNOR) enzymes utilize a heme/non-heme active site to couple two NO molecules to N₂O. We show that BF₃ coordination to the nitrosyl O-atom in (OEP)­Fe­(NO) activates it toward N–N bond formation with NO to generate N₂O. ¹⁵N-isotopic labeling reveals a reversible nitrosyl exchange reaction and follow-up N–O bond cleavage in the N₂O formation step. Other Lewis acids (B­(C₆F₅)₃ and K⁺) also promote the NO coupling reaction with (OEP)­Fe­(NO). These results, complemented by DFT calculations, provide experimental support for the <i>cis</i>:<i>b</i>₃ pathway in bacNOR