FREE RADICALS, LIPIDS AND ENZYME PHOTOACTIVATION

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This proposal addresses several important issues relating to human health and disease states. Lipid peroxidation has been implicated in the deposition of arterial plaque from low density lipoproteins (LDL) and because of this, the mechanism of lipid peroxidation has been the focus of much attention. Antioxidants such as Vitamin E are known to play important roles in the inhibition of lipid peroxidation in LDL. This proposal addresses several questions relating to the mechanism of autoxidation of lipids and lipoproteins. Time course studies of initiated LDL free radical oxidations give data about oxidation of the lipoprotein core lipids that can be used to probe the antioxidant status of the lipoprotein undergoing oxidation. Substantial cholesterol ester conversion to free cholesterol attends free radical oxidation by a mechanism that is not understood but which will be investigated. A second aspect of free radical chemistry that this proposal addresses is the control of stereochemistry in free radical reactions. Evidence is presented in this proposal that suggests that the general problem of stereochemical control in free radical addition reactions can be solved by the use of Lewis acids and chiral bis(oxazoline) ligands along with oxazolidinone acrylamides. Radical additions and allyl transfers occur with excellent selectivity. This allows the exploration of enantioselective free radical reactions as well as potential free radical processes that are catalytic in the chiral reagent A third problem that this proposal addresses is the design and use of photoreversible enzyme inhibitors. This strategy provides a novel way to control enzyme activity with light and applications and expansion of this strategy are proposed, particularly with regard to the enzymes of the blood coagulation cascade. Triplet based photoactivation tactics are suggested so that photoactivation can be sensitized or quenched. General approaches to immunoassay systems based upon "coagulation times" are suggested that have as a central feature the enzyme photoactivation strategy.