Options for Breast Cancer Prevention in High-Risk Patients

Breast cancer is the most frequently diagnosed non-skin cancer in women, and one in eight women will develop breast cancer within their Iifetimes. Unfortunately, the strongest risk factors for breast cancer (i.e. age, family history, hormonal factors) are not easily modified. There is some evidence that chemopreventative drugs may be able to prevent breast cancer in high-risk patients. Tamoxifen and raloxifene have been shown to reduce the risk of breast cancer in high-risk women but may be associated with several serious adverse events. Clinical trials are currently in progress to determine if aromatase inhibitors are a viable alternative for breast cancer prevention, as they may be considered effective in the early treatment of breast cancer. For patients with BRCA1 and BRCA2 mutations, a bilateral prophylactic mastectomy may be an option. This article discusses the risks and benefits of available treatment options for breast cancer prevention in high-risk patients

Stabilization of a Heme-HNO Model Complex Using a Bulky Bis-Picket Fence Porphyrin and Reactivity Studies with NO

Nitroxyl, HNO/NO–, the one-electron reduced form of NO, is suggested to take part in distinct signaling pathways in mammals and is also a key intermediate in various heme-catalyzed NOx interconversions in the nitrogen cycle. Cytochrome P450nor (Cyt P450nor) is a heme-containing enzyme that performs NO reduction to N2O in fungal denitrification. The reactive intermediate in this enzyme, termed “Intermediate I”, is proposed to be an Fe-NHO/Fe-NHOH type species, but it is difficult to study its electronic structure and exact protonation state due to its instability. Here, we utilize a bulky bis-picket fence porphyrin to obtain the first stable heme-HNO model complex, [Fe(3,5-Me-BAFP)(MI)(NHO)], as a model for Intermediate I, and more generally HNO adducts of heme proteins. Due to the steric hindrance of the bis-picket fence porphyrin, [Fe(3,5-Me-BAFP)(MI)(NHO)] is stable (τ1/2 = 56 min at −30 °C), can be isolated as a solid, and is available for thorough spectroscopic characterization. In particular, we were able to solve a conundrum in the literature and provide the first full vibrational characterization of a heme-HNO complex using IR and nuclear resonance vibrational spectroscopy (NRVS). Reactivity studies of [Fe(3,5-Me-BAFP)(MI)(NHO)] with NO gas show a 91 ± 10% yield for N2O formation, demonstrating that heme-HNO complexes are catalytically competent intermediates for NO reduction to N2O in Cyt P450nor. The implications of these results for the mechanism of Cyt P450nor are further discussed

Ferric Heme-Nitrosyl Complexes: Kinetically Robust or Unstable Intermediates?

We have determined a convenient method for the bulk synthesis of high-purity ferric heme-nitrosyl complexes ({FeNO}⁶ in the Enemark–Feltham notation); this method is based on the chemical or electrochemical oxidation of corresponding {FeNO}⁷ precursors. We used this method to obtain the five- and six-coordinate complexes [Fe­(TPP)­(NO)]⁺ (TPP^2– = tetraphenylporphyrin dianion) and [Fe­(TPP)­(NO)­(MI)]⁺ (MI = 1-methylimidazole) and demonstrate that these complexes are stable in solution in the absence of excess NO gas. This is in stark contrast to the often-cited instability of such {FeNO}⁶ model complexes in the literature, which is likely due to the common presence of halide impurities (although other impurities could certainly also play a role). This is avoided in our approach for the synthesis of {FeNO}⁶ complexes via oxidation of pure {FeNO}⁷ precursors. On the basis of these results, {FeNO}⁶ complexes in proteins do not show an increased stability toward NO loss compared to model complexes. We also prepared the halide-coordinated complexes [Fe­(TPP)­(NO)­(X)] (X = Cl^–, Br^–), which correspond to the elusive, key reactive intermediate in the so-called autoreduction reaction, which is frequently used to prepare {FeNO}⁷ complexes from ferric precursors. All of the complexes were characterized using X-ray crystallography, UV–vis, IR, and nuclear resonance vibrational spectroscopy (NRVS). On the basis of the vibrational data, further insight into the electronic structure of these {FeNO}⁶ complexes, in particular with respect to the role of the axial ligand <i>trans</i> to NO, is obtained

Hidden Non-Innocence in an Expanded Porphyrin: Electronic Structure of the Siamese-Twin Porphyrin’s Dicopper Complex in Different Oxidation States

The Siamese-twin porphyrin (<b>2H</b>_<b>4</b>) is a unique pyrazole-expanded porphyrin providing two adjacent cavities each offering an {N₄} binding motif. It was previously found to form stable dicopper­(II) or dinickel­(II) complexes where both metal ions are nested in a porphyrin-like environment. This work addresses the rich redox chemistry of the dicopper complex <b>2Cu</b>_<b>2</b> that originates from the redox synergy of two proximate metal ions in combination with the potentially non-innocent expanded porphyrin ligand. Complementing previous X-ray crystallographic and SQUID data for solid material, the electronic structure of parent <b>2Cu</b>_<b>2</b> in solution was now investigated by MCD and EPR spectroscopy. This allowed the assignment of UV–vis absorptions and confirmed the drastic twist of the molecule with ferromagnetically coupled copper­(II) ions. <b>2Cu</b>_<b>2</b> was found to exhibit multiple redox events in the potential range from −2.4 to +1.7 V versus Fc/Fc⁺, and singly oxidized [<b>2Cu</b>_<b>2</b>]⁺ as well as doubly oxidized [<b>2Cu</b>_<b>2</b>]²⁺ were characterized in detail by various analytical and spectroscopic methods. [<b>2Cu</b>_<b>2</b>]⁺ was found by EPR spectroscopy and DFT calculations to have an <i>S</i> = 1/2 ground state, while [<b>2Cu</b>_<b>2</b>]²⁺ is diamagnetic. Single crystal X-ray crystallography of [<b>2Cu</b>_<b>2</b>(acetone)₂]­(BF₄)₂ revealed that the <b>2Cu</b>_<b>2</b> core is structurally invariant upon two-fold oxidation, while XAS measurements at the Cu <i>K</i>-edge for <b>2Cu</b>_<b>2</b> and [<b>2Cu</b>_<b>2</b>(acetone)₂]­(BF₄)₂ showed that the copper ions remain in the +2 oxidation state throughout. The combined experimental and computational evidence identified the Siamese-twin porphyrin as a multi-electron redox-active ligand with hidden non-innocence. Each ligand subunit upon oxidation forms a ligand-centered radical, though the spin vanishes because of covalency and strong antiferromagnetic coupling between the ligand radical and the proximate metal ion. Complexes of the Siamese-twin porphyrin may thus serve as a valuable bioinspired platform that combines both metal–ligand and two-metal-ion cooperativities for use in multi-electron processes

Hidden Non-Innocence in an Expanded Porphyrin: Electronic Structure of the Siamese-Twin Porphyrin’s Dicopper Complex in Different Oxidation States

The Siamese-twin porphyrin (<b>2H</b>_<b>4</b>) is a unique pyrazole-expanded porphyrin providing two adjacent cavities each offering an {N₄} binding motif. It was previously found to form stable dicopper­(II) or dinickel­(II) complexes where both metal ions are nested in a porphyrin-like environment. This work addresses the rich redox chemistry of the dicopper complex <b>2Cu</b>_<b>2</b> that originates from the redox synergy of two proximate metal ions in combination with the potentially non-innocent expanded porphyrin ligand. Complementing previous X-ray crystallographic and SQUID data for solid material, the electronic structure of parent <b>2Cu</b>_<b>2</b> in solution was now investigated by MCD and EPR spectroscopy. This allowed the assignment of UV–vis absorptions and confirmed the drastic twist of the molecule with ferromagnetically coupled copper­(II) ions. <b>2Cu</b>_<b>2</b> was found to exhibit multiple redox events in the potential range from −2.4 to +1.7 V versus Fc/Fc⁺, and singly oxidized [<b>2Cu</b>_<b>2</b>]⁺ as well as doubly oxidized [<b>2Cu</b>_<b>2</b>]²⁺ were characterized in detail by various analytical and spectroscopic methods. [<b>2Cu</b>_<b>2</b>]⁺ was found by EPR spectroscopy and DFT calculations to have an <i>S</i> = 1/2 ground state, while [<b>2Cu</b>_<b>2</b>]²⁺ is diamagnetic. Single crystal X-ray crystallography of [<b>2Cu</b>_<b>2</b>(acetone)₂]­(BF₄)₂ revealed that the <b>2Cu</b>_<b>2</b> core is structurally invariant upon two-fold oxidation, while XAS measurements at the Cu <i>K</i>-edge for <b>2Cu</b>_<b>2</b> and [<b>2Cu</b>_<b>2</b>(acetone)₂]­(BF₄)₂ showed that the copper ions remain in the +2 oxidation state throughout. The combined experimental and computational evidence identified the Siamese-twin porphyrin as a multi-electron redox-active ligand with hidden non-innocence. Each ligand subunit upon oxidation forms a ligand-centered radical, though the spin vanishes because of covalency and strong antiferromagnetic coupling between the ligand radical and the proximate metal ion. Complexes of the Siamese-twin porphyrin may thus serve as a valuable bioinspired platform that combines both metal–ligand and two-metal-ion cooperativities for use in multi-electron processes

Hidden Non-Innocence in an Expanded Porphyrin: Electronic Structure of the Siamese-Twin Porphyrin’s Dicopper Complex in Different Oxidation States

The Siamese-twin porphyrin (<b>2H</b>_<b>4</b>) is a unique pyrazole-expanded porphyrin providing two adjacent cavities each offering an {N₄} binding motif. It was previously found to form stable dicopper­(II) or dinickel­(II) complexes where both metal ions are nested in a porphyrin-like environment. This work addresses the rich redox chemistry of the dicopper complex <b>2Cu</b>_<b>2</b> that originates from the redox synergy of two proximate metal ions in combination with the potentially non-innocent expanded porphyrin ligand. Complementing previous X-ray crystallographic and SQUID data for solid material, the electronic structure of parent <b>2Cu</b>_<b>2</b> in solution was now investigated by MCD and EPR spectroscopy. This allowed the assignment of UV–vis absorptions and confirmed the drastic twist of the molecule with ferromagnetically coupled copper­(II) ions. <b>2Cu</b>_<b>2</b> was found to exhibit multiple redox events in the potential range from −2.4 to +1.7 V versus Fc/Fc⁺, and singly oxidized [<b>2Cu</b>_<b>2</b>]⁺ as well as doubly oxidized [<b>2Cu</b>_<b>2</b>]²⁺ were characterized in detail by various analytical and spectroscopic methods. [<b>2Cu</b>_<b>2</b>]⁺ was found by EPR spectroscopy and DFT calculations to have an <i>S</i> = 1/2 ground state, while [<b>2Cu</b>_<b>2</b>]²⁺ is diamagnetic. Single crystal X-ray crystallography of [<b>2Cu</b>_<b>2</b>(acetone)₂]­(BF₄)₂ revealed that the <b>2Cu</b>_<b>2</b> core is structurally invariant upon two-fold oxidation, while XAS measurements at the Cu <i>K</i>-edge for <b>2Cu</b>_<b>2</b> and [<b>2Cu</b>_<b>2</b>(acetone)₂]­(BF₄)₂ showed that the copper ions remain in the +2 oxidation state throughout. The combined experimental and computational evidence identified the Siamese-twin porphyrin as a multi-electron redox-active ligand with hidden non-innocence. Each ligand subunit upon oxidation forms a ligand-centered radical, though the spin vanishes because of covalency and strong antiferromagnetic coupling between the ligand radical and the proximate metal ion. Complexes of the Siamese-twin porphyrin may thus serve as a valuable bioinspired platform that combines both metal–ligand and two-metal-ion cooperativities for use in multi-electron processes