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Biomedical subjects

Peter J Cragg

Publications and source records attributed to Peter J Cragg.

8 recordsLinked to original sources
PubMed2006

Transmembrane ion transport by calixarenes and their derivatives.

Regulation of transmembrane ion transport is a vital aspect of bioinorganic chemistry. To understand how this highly selective process occurs, how it can become impaired and how impairment may be treated, model compounds are useful tools. Several systems are presently being explored but one of the most widely applicable combines a rigid macrocycle, capable of size-based ion recognition, with membrane-spanning substituents that allow the target ions to traverse a phospholipid bilayer. The calixarene class of macrocycles is ideally suited to this task. This article sets out the biological background to transmembrane ion transport, the methods available to study the phenomenon, examples of model compounds, and proposes areas of further study.

Calixarenes↗
PubMed2006

alpha-Lipoic acid and glutathione protect against the prooxidant activity of SOD/catalase mimetic manganese salen derivatives.

Manganese(III) N,N'-ethylenebis(salicylideneiminato) chloride (Mn-salen chloride) and manganese(III) N,N'-ethylenebis(3-methoxysalicylideneiminato) chloride (Mn-(3,3'-MeO)salen chloride) are in vitro superoxide dismutase and catalase mimetics. They protect against free radical-related disease in animals, but Mn-salen can also be a potent prooxidant, damaging free DNA. Mn-salen protects human fibroblast DNA against hydrogen peroxide damage, however, damage to free DNA was confirmed by the comet assay. The DNA-damaging activity was dramatically reduced by co-administration with glutathione with the combination being less damaging to free DNA than either molecule alone. alpha-Lipoic acid, an antioxidant disulfide commonly used as a dietary supplement, also prevented Mn-salen prooxidant activity. Mn-(3,3'-MeO)salen protected fibroblasts against hydrogen peroxide as efficiently as Mn-salen and showed little damaging activity against free DNA. Protection was invested by both complexes in the presence and in the absence of EDTA, a potential competing chelator. Stabilities of the complexes with respect to decomposition and inactivation were studied by spectroscopic and electrochemical techniques. The complexes' binding to, and cleavage of, DNA was measured using a quartz crystal resonant sensor. Mn-salen was shown to bind strongly to DNA, prior to cleaving it; Mn-(3,3'-MeO)salen bound weakly and left DNA intact. Co-administration of either glutathione or alpha-lipoic acid appears to inhibit binding by Mn-salen thus preventing DNA-cleavage.

Animals↗
PubMed2003

Linoleic acid and antioxidants protect against DNA damage and apoptosis induced by palmitic acid.

Polyunsaturated fats are the main target for lipid peroxidation and subsequent formation of mutagenic metabolites, but diets high in saturated fats are more strongly associated with adverse health effects. We show that the common saturated fatty acid, palmitic acid, is a potent inducer of DNA damage in an insulin-secreting cell line, and in primary human fibroblasts. Damage is not associated with upregulation of inducible nitric oxide synthase, but is prevented by two different antioxidants, alpha-lipoic acid and 3,3'-methoxysalenMn(III) (EUK134), which also partly prevent palmitic acid-induced apoptosis and growth inhibition. Since mutagenic metabolites can be formed from peroxidation of polyunsaturated fatty acids, co-administration of palmitic and a polyunsaturated fatty acid might be particularly harmful. Palmitic acid-induced DNA damage is instead prevented by linoleic acid, which is acting here as a protective agent against oxidative stress, rather than as a source of mutagenic metabolites. These results illustrate the complexity of the relationship of dietary fat intake to genotoxicity.

Antioxidants↗
PubMed2002

Acid-catalyzed formation of hexahomooxacalix[3]arenes.

The role of acid catalysis in oxacalix[3]arene synthesis has been investigated. A range of acids were used to optimize the yield of tert-butyloxacalix[3]arene, the most efficient being p-toluenesulfonic acid, which, with local symmetry complementary with that of the lower rim of the calixarene, provides a templating effect.

Journal Article↗
PubMed2002

Cooperative anion binding and electrochemical sensing by modular podands.

A series of podands based on two or three hydrogen bonding "arms" situated in mutually ortho, meta, or para relationships about an aryl core have been prepared, and their affinities for simple inorganic anions were measured. Of the two-arm hosts the meta compound and to a lesser extent the ortho host exhibit a cooperative anion binding effect. The two arms function essentially independently in the para derivative. The mutually meta three-arm host shows dramatically enhanced cooperative binding. Conformational changes within the meta two-arm host result in significantly enhanced electrochemical anion sensing compared with the more conformationally rigid three-arm host.

Anions↗
PubMed2002

Artificial transmembrane channels for sodium and potassium.

Transport of alkali metals, particularly sodium and potassium, across cell membranes is an essential function performed by special proteins that enable cells to regulate inter- and extracellular ion concentrations with exceptional selectivity. The importance of these channel-forming proteins has led to researchers emulating of their structural features: an ion-specific filter and conduction at rates up to 10(8) ions per second. Synthetic helical and cyclic polypeptides form channels, however, the specificity of ion transport is often low. Ion-specific macrocycles have been used as filters from which membrane-spanning derivatives have been prepared. Success has been limited as many compounds act as ion carriers rather than forming transmembrane channels. Surfactant compounds also allow ions to cross membranes but any specificity is serendipitous. Overall it seems possible to mimic either ion specificity or efficient transmembrane ion transport. The goal for the future will be to combine both characteristics in one artificial system.

Computer Simulation↗