Objective: understanding of redox reactions central in biochemistry, toxicology and oncology. Problems: a to u. Substrates for microsomal mixed function oxidases may be divided into those acted upon by flavoenzyme and those acted upon by cyt. P450's. This separation is likely chemically based and is not understood. Problems c, d and e deal with the reaction of 4a-hydroperoxyflavin with primary amines, alkenes and thiols; b with means by which the reactivity of the hydroperoxide might be increased; a the determination of the basicity of the leaving group formed on monooxygen transfer from 4a-hydroperoxyflavin; f concerns O2 transfer from 4a-hydroperoxyflavin anion to electron-rich aromatic structures. Determination of the mechanism of formation of C-C double bonds Alpha, Beta to carbonyl, thiolester, etc. (succinic dehydrogenase, acyl CoA dehydrogenases) by flavin oxidation of substrate anion is h. Proposed mechanisms for monoamine oxidase (target for many important drugs, protector against action of neuroactive amines) are suspect since they do not correspond to MAO's specificity. Problem i concerns the mechanism of amine oxidation by flavin. Biopterin, the cofactor for Phe hydroxylase (phenylketonuria), Tyr and Trp hydroxylase (syn. of epinephrin and seretonin), is thought to be converted to a dihydro-4a-hydroperoxide during enzyme action. The study of the first stable 1,5-quinoidal pteridine and synthesis of a derived 4a-hydroperoxide constitutes j. Methoxitin is a cofactor for alcohol and amine oxidation in methyltrophic (and other) bacteria. Studies to determine the minimal requirements for cofactor activity, redox mechanisms and pharmacological testing for repression of DNA synthesis is k. Problems m to n concern iron oxygen species of the types encountered in the biochemically important oxidations by cyt P450, prostaglandin synthetase and bleomycins. Existing methods for the generation of the active species of P450 (enzymic and models) degrade the porphyrin; m is devoted to finding how, n and o deal with use of N-oxides (which do not degrade porphyrin) and r is a study using hydroperoxides of widely divergent reactivities. The role of the axial ligand in monooxygen transfer constitutes o. Substrate epoxidation will be investigated (q) by use of pinacol and cyclopropylcarbinyl-allylcarbinyl rearrangements. Radical formation from 1,4-trans-diene is seminal in the prostaglandin synthetase reaction. Investigations of oxidation by porphinato-FeIII and by general base H+ abstraction followed by le- oxidation by porphinato-FeIII (S) using designed substrates and 3H and cyclopropylcarbinyl-allycarbinyl traps. In t the radical initiated events in the bleomycin and ribonucleotide reduction reactions will be modeled to obtain a better understanding of these processes. Problem u concerns the applicability of the nucleophilic addition-elimination mechanism to a variety of reactions of biochemical interest.
| Park, Myunji; Canzio, Daniele; Bruice, Thomas C (2008) Incorporation of positively charged ribonucleic guanidine linkages into oligodeoxyribonucleotides: Development of potent antisense agents. Bioorg Med Chem Lett 18:2377-84 |
