Peter C. Ford

Nitrate and nitrite in biology, nutrition and therapeutics

Inorganic nitrate and nitrite from endogenous or dietary sources are metabolized in vivo to nitric oxide (NO) and other bioactive nitrogen oxides. The nitrate-nitrite-NO pathway is emerging as an important mediator of blood flow regulation, cell signaling, energetics and tissue responses to hypoxia. The latest advances in our understanding of the biochemistry, physiology and therapeutics of nitrate, nitrite and NO were discussed during a recent 2-day meeting at the Nobel Forum, Karolinska Institutet in Stockholm.

Autoxidation kinetics of aqueous nitric oxide

Reports on the kinetics of the autoxidation of aqueous nitric oxide are discussed. It is concluded that the correct rate law is ‐d[NO]/dt = 4k aq[NO]2 [O2] with k aq = 2 × 106 M−2 · s−1 at 25°C and that a recent report of a rate law zero order in NO is incorrect.

Chemical biology of nitric oxide: Regulation and protective and toxic mechanisms

Publisher Summary This chapter discusses the important aspects of the solution chemistry of nitrogen oxide (NO) and reactive nitrogen oxide species (RNOS), biochemical targets of NO and intermediates in the autoxidation (NO X ), and the effect of NO in the presence of other toxic molecules, such as reactive oxygen species (ROS). There are two types of nitric-oxide synthase: constitutive (cNOS) and inducible (iNOS). Since cNOS generates low levels of NO, direct effects rather than indirect effects of NO would be particularly relevant. In case of iNOS, considerably higher concentrations of NO are formed for longer periods of time; therefore, both direct and indirect effects could be relevant. This chapter discusses, from a chemical perspective, those processes that are involved in the interactions with key cellular components as well as detoxification and control of NO in vivo . Defining the chemical, biochemical, and cellular pathways of NO quantitatively can provide insights into the role that NO plays in the etiology of various diseases that in turn can provide a basis for the development of new therapeutic agents. The chemical biology of NO will provide the understanding as to how NO can be regulatory, toxic, and protective in biological systems.

One-Pot Catalytic Conversion of Cellulose and of Woody Biomass Solids to Liquid Fuels

Efficient methodologies for converting biomass solids to liquid fuels have the potential to reduce dependence on imported petroleum while easing the atmospheric carbon dioxide burden. Here, we report quantitative catalytic conversions of wood and cellulosic solids to liquid and gaseous products in a single stage reactor operating at 300-320 °C and 160-220 bar. Little or no char is formed during this process. The reaction medium is supercritical methanol (sc-MeOH) and the catalyst, a copper-doped porous metal oxide, is composed of earth-abundant materials. The major liquid product is a mixture of C(2)-C(6) aliphatic alcohols and methylated derivatives thereof that are, in principle, suitable for applications as liquid fuels.

Luminescent mixed ligand copper(I) clusters (CuI)n(L)m (L=pyridine, piperidine): thermodynamic control of molecular and supramolecular species☆

Abstract The photophysical properties of neutral adducts of CuI and the N-bound ligands pyridine (py) and piperidine (pip) of the type Cu n X n L m were studied as a function of the concentrations of the ligand L. For L=py, variation in the UV–Vis absorption and luminescence spectroscopic properties as a function of ligand concentration is rationalized as the result of labile equilibria involving several species, most prominently the dinuclear complex Cu 2 I 2 (py) 2 and the ‘cubane’ cluster Cu 4 I 4 py 4 . The ease of ligand exchange in solution was exploited for the self-assembly of mixed-ligand tetrameric compounds Cu 4 I 4 (py) n (pip) m (where n + m =4), which were identified through their photophysical properties. Factors determining these emission properties are discussed.

Photochemistry of metal nitrosyl complexes. Delivery of nitric oxide to biological targets

Abstract The discoveries that nitric oxide serves important roles in mammalian bioregulation and immunology have stimulated intense interest in the chemistry and biochemistry of NO and derivatives such as metal nitrosyl complexes. Also of interest are strategies to deliver NO to biological targets on demand. One such strategy would be to employ a precursor which displays relatively low thermal reactivity but is photochemically active to give NO. This proposition led the authors to investigate photochemical properties of metal nitrosyl complexes such as the iron-sulfur-nitrosyl Roussin cluster anions Fe2S2(NO)42− and Fe4S3(NO)7− as well as metalloporphyrin nitrosyls including ferriheme complexes (with M. Hoshino of the Institute of Physical and Chemical Research, Japan) and nitrosyl nitrito complexes of ruthenium porphyrins Ru(P)(ONO)(NO). Continuous and flash photolysis studies of these compounds are reviewed here as are studies (with D.A. Wink and J.B. Mitchell of the Radiation Biology Branch of the US National Cancer Institute) using metal nitrosyl photochemistry as a vehicle for delivering NO to hypoxic cell cultures in order to sensitize γ-radiation damage.

Tissue processing of nitrite in hypoxia : an intricate interplay of nitric oxide-generating and -scavenging systems

Although nitrite (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{NO}_{2}^{-}\) \end{document}) and nitrate (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{NO}_{3}^{-}\) \end{document}) have been considered traditionally inert byproducts of nitric oxide (NO) metabolism, recent studies indicate that \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{NO}_{2}^{-}\) \end{document} represents an important source of NO for processes ranging from angiogenesis through hypoxic vasodilation to ischemic organ protection. Despite intense investigation, the mechanisms through which \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{NO}_{2}^{-}\) \end{document} exerts its physiological/pharmacological effects remain incompletely understood. We sought to systematically investigate the fate of \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{NO}_{2}^{-}\) \end{document} in hypoxia from cellular uptake in vitro to tissue utilization in vivo using the Wistar rat as a mammalian model. We find that most tissues (except erythrocytes) produce free NO at rates that are maximal under hypoxia and that correlate robustly with each tissues capacity for mitochondrial oxygen consumption. By comparing the kinetics of NO release before and after ferricyanide addition in tissue homogenates to mathematical models of \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{NO}_{2}^{-}\) \end{document} reduction/NO scavenging, we show that the amount of nitrosylated products formed greatly exceeds what can be accounted for by NO trapping. This difference suggests that such products are formed directly from \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{NO}_{2}^{-}\) \end{document}, without passing through the intermediacy of free NO. Inhibitor and subcellular fractionation studies indicate that \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{NO}_{2}^{-}\) \end{document} reductase activity involves multiple redundant enzymatic systems (i.e. heme, iron-sulfur cluster, and molybdenum-based reductases) distributed throughout different cellular compartments and acting in concert to elicit NO signaling. These observations hint at conserved roles for the \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{NO}_{2}^{-}\) \end{document}-NO pool in cellular processes such as oxygen-sensing and oxygen-dependent modulation of intermediary metabolism.

Polychromophoric metal complexes for generating the bioregulatory agent nitric oxide by single- and two-photon excitation.

In order to deliver a bioactive agent to a physiological location, it is important to be able to regulate precisely the location and the dosage. Such exquisite control can easily be envisioned for a photochemical drug that is active toward release of the desired bioactive agent upon irradiation of a specific tissue site. These materials should be thermally stable but reactive under excitation at visible (vis) or near-infrared (NIR) wavelengths where tissue transmission is optimal. Two photon excitation (TPE) is of special interest, since the use of focused laser pulses to activate release could provide 3D spatial control in therapeutic applications. This Account describes the preparation and photochemistry of a series of transition metal complexes designed to release the simple bioregulatory compound nitric oxide upon vis or NIR excitation. In order to enhance the light gathering capability of such compounds, we have attached chromophores with high single- or two-photon absorption cross sections to several photochemical NO precursors. For example, the iron nitrosyl clusters Fe2(mu-SR)2(NO)4 (Roussins red esters) have been prepared with various chromophores as pendant groups, an example being the protoporphyrin XI derivative illustrated here. Direct excitation into the vis absorbing Q bands of the porphyrin leads to enhanced rates of NO generation from the Fe/S/NO cluster owing to the larger rate of light absorption by that antenna. Furthermore, femtosecond pulsed laser NIR excitation of the same compound at 810 nm (a spectral region where no absorption bands are apparent) leads to weak emission at approximately 630 nm and generation of NO, both effects providing evidence of a TPE mechanism. Roussins red esters with other chromophores described here are even more effective for TPE-stimulated NO release. Another photochemical NO precursor discussed is the Cr(III) complex trans-Cr(L)(ONO)2(+) where L is a cyclic tetraamine such as cyclam. When L includes a chromophore tethered to the ligand backbone, excitation of that functionality results in energy transfer to the spin-forbidden ligand field double states and light-stimulated release of NO. We are working to develop systems where L is attached to a semiconductor nanoparticle as the antenna. In this context, we have shown that electrostatic assemblies are formed between the anionic surface of water-soluble CdSe/ZnS core/shell quantum dots (QDs) and Cr(L)(ONO)2(+) cations via an ion-pairing mechanism. Photoexcition of such modified QDs leads to markedly enhanced NO generation and suggests promising applications of such nanomaterials as photochemical drugs.

Direct and indirect effects of nitric oxide in chemical reactions relevant to biology

Abstract Categorization of the chemical reactions of NO into direct and indirect effects provides a framework to evaluate the role of NO in different biological situations. The diverse behavior of NO protecting against ROS toxicity yet potentiating the toxicity of other agents implies that the role of NO in each condition must be carefully evaluated. The chemical biology of NO can aid in the mechanistic questions with respect to this unique molecule.

Metal complexes as photochemical nitric oxide precursors: Potential applications in the treatment of tumors

The bioregulatory molecule NO plays key roles in cancer biology and has been implicated in both tumor growth and suppression. Furthermore, it is a gamma-radiation sensitizer that may enhance selective killing of neoplastic tissues. For these reasons, there is considerable interest in developing methods for NO delivery to specific physiological targets. In this Perspective, we describe ongoing investigations focused on photochemical methodologies to deliver therapeutic doses of NO to such targets utilizing transition metal complexes that are nitric oxide precursors. The photochemical strategy has the advantages that it allows for precise control of the timing, location, and dosage for the targeted delivery of a bioactive agent.