http://www.sciencemadness.org/talk/files.php?pid=74947&aid=1716

Chemistry of the nitric oxide-releasing diazeniumdiolate ("nitrosohydroxylamine") functional group and its oxygen-substituted derivatives.

The peroxidation of lipids in biological membranes has been implicated in both the onset and development of most degenerative diseases. The primary products of this autoxidation process are usually lipid hydroperoxides. They form as a consequence of a free radical chain reaction: lipid peroxyl radicals propagate the chain by rate-limiting H-atom abstraction from another lipid. Studies of the mechanism of lipid peroxidation are a specific part of a wider effort to understand the more general phenomenon of hydrocarbon autoxidation, which dates back some 70 years. However, the autoxidation of lipids is generally much more complicated than that of other hydrocarbons because of additional reaction pathways afforded by a variety of uniquely positioned unsaturated bonds. Indeed, polyunsaturation is an important aspect of many of the most relevant of physiological lipids, such as linoleate and arachidonate. In this Account, we present our current understanding of the mechanism of unsaturated lipid peroxidation, effectively updating our Account on the same topic published 25 years ago. Our more recent work has, in large part, been stimulated by the discovery of the nonconjugated linoleate hydroperoxide as a product under certain autoxidation conditions. The identification of this long-elusive bis-allylic hydroperoxide prompted our kinetic characterization of the reaction leading to its formation. The product distributions obtained from autoxidations of newly synthesized model compounds, which vary in either the substitution of the bis-allylic moiety or the configuration of the double bonds, have provided key insights into the overall mechanism. These insights have in turn been reinforced by the results of theoretical calculations. The picture that emerges is one wherein the delocalized carbon-centered radicals, which arise as intermediates in these reactions, first associate with dioxygen to form pre-reaction complexes. These complexes then collapse through transition state structures that maximize the orbital interactions between the delocalized radical SOMO and dioxygen. The energies of these transition states are influenced by steric effects; thus, there are distinct changes in product distribution in the autoxidation of dienes having different substitution patterns. The radical-dioxygen complexes are also intermediates in the isomerization of allylperoxyl and pentadienylperoxyls, helping explain the high regio- and stereochemical fidelity of these processes. We have taken advantage of the rapid fragmentation of nonconjugated peroxyl radicals to develop a powerful peroxyl radical clock methodology, which can be used to determine rate constants for reactions of peroxyl radicals with molecules having rate constants ranging from 1 to 10(7) M(-1) s(-1). We can make use of this methodology to address various questions, both fundamental and applied, relating to lipid peroxidation and its inhibition by radical-trapping antioxidants.

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Free radical oxidation of polyunsaturated lipids: New mechanistic insights and the development of peroxyl radical clocks.

Peptidomimetics represent an important field in chemistry, pharmacology and material science as they circumvent the limitations of traditional peptides used in therapy. Self-structural organizations such as turns, helices, sheets and loops can be accessed by chemical modifications of amino acids or peptides. In-depth structural and conformational analysis and structure–activity relationships (SAR) offer a way to establish peptidomimetic libraries. Herein, we review recent developments in peptidomimetics that are formed via heteroatom replacement within the native amino acid backbone. Each sub-section describes structural features, utility and preparative methods.

Peptidomimetics via modifications of amino acids and peptide bonds

Structural identification of a novel pro-inflammatory epoxyisoprostane phospholipid in mildly oxidized low density lipoprotein

Epoxyisoprostane and Epoxycyclopentenone Phospholipids Regulate Monocyte Chemotactic Protein-1 and Interleukin-8 Synthesis FORMATION OF THESE OXIDIZED PHOSPHOLIPIDS IN RESPONSE TO INTERLEUKIN-1β

Reaction of O-tertiary alkyl arylhydroxamate esters with nitrosyl chloride gives O-tertiary alkyl aryl peresters that can be hydrolyzed to the hydroperoxide. If the hydroxamate ester carbonyl oxyge...

Jennifer R. Lowe

Papers

Preparation of Unsymmetrically Labeled Hydroperoxides. A Hydroxamate Ester−Nitrosation Approach

Preparation of an Unsymmetrically Labeled Allylic Hydroperoxide and Study of Its Allylic Peroxyl Radical Rearrangement

Preparation of Unsymmetrically Labeled Hydroperoxides. A Hydroxamate Ester—Nitrosation Approach.