Oxidation, enzymic selective

Optically active epoxides are important building blocks in asymmetric synthesis of natural products and biologically active compounds. Therefore, enantio-selective epoxidation of olefins has been a subject of intensive research in the last years. The Sharpless [56] and Jacobsen [129] epoxidations are, to date, the most efficient metal-catalyzed asymmetric oxidation of olefins with broad synthetic scope. Oxidative enzymes have also been successfully utilized for the synthesis of optically active epoxides. Among the peroxidases, only CPO accepts a broad spectrum of olefinic substrates for enantioselective epoxidation (Eq. 6), as shown in Table 8. 

A somewhat different approach to determining the enantiopurity of a sample is based on the idea that an appropriate enzyme selectively processes one enantiomer, giving rise to a UV/visible signal [17]. An example concerns determination of the enantiopurity of chiral secondary alcohols, the (S) enantiomer being oxidized selectively by the alcohol dehydrogenase from Thermoanaerobium sp. The rate of this process can be monitored by a UV/visible plate reader due to the formation of NADPH (absorption at 340 nm), which relates to the quantity of the (S) enandomer present in the mixture. About 4800 ee determinadons are possible per day, accuracy amoundng to 10%. Although the screen was not specifically developed to evaluate chiral alcohols produced by an enzymadc process, it is conceivable that this could be possible after an appropriate extraction process. 

Extraordinary selectivity has been accomplished with the parathion-type of insecticide by incorporating Q or CH3 groups in the meta position of the aryl ring. These groups interact sterically with acetylcholinesterase (AChE), increasing the affinity for the insect enzyme and decreasing it with the mammalian enzyme. Selectivity also is enhanced by differences in the rates of microsomal oxidation of P=S to P=0 and in hydrolytic detoxication between insects and mammals. The compounds, fenitrothion, fenthion, ronnel, bromophos, iodofenfos, chlorpyrifos—methyl, and pirimiphos —methyl, and dicapthon are used widely in public health, household, and agricultural pest control. 

Common catalytic systems are characterized by the presence of reagent molecules only, whereas the enzymatic system is multicomponent and possesses low concentrations of the substrates in water. The interaction between a substrate with an oxidant or a reducer is most often considered. This makes unnecessary simulation of the enzyme selectivity. However, free contact of reagent molecules with active sites preserves the possibility of various mechanism realizations which is the reason for decrease of the process selectivity. Apparently, a compromise should be found in resolving the question of selectivity in biomimics development in suggesting that, though complex gap mechanism is the effective method for distance and mutual orientation control of reactive groups in the enzyme, it may hardly be implemented in synthetic systems. 

Over the past decade there has been a substantial improvement in the ability to predict metabolism-based in vivo drug interactions from kinetic data obtained in vitro. This advance has been most evident for interactions that occur at the level of cytochrome P450 (CYP)-catalyzed oxidation and reflects the availability of human tissue samples, cDNA-expressed CYPs, and well-defined substrates and inhibitors of individual enzymes. The most common paradigm in the prediction of in vivo drug interactions has been first to determine the enzyme selectivity of a suspected inhibitor and subsequently to estimate the constant that quantifies the potency of reversible inhibition in vitro. This approach has been successful in identifying clinically important potent competitive inhibitors, such as quinidine, fluoxetine, and itraconazole. However, there is a continuing concern that a number of well-established and clinically important CYP-mediated drug interactions are not predictable from the classical approach that assumes reversible mechanisms of inhibition are ubiquitous. 

A thorough study of the use of HLADH for the enantioselective oxidation of meso-diols to lactones has provided a versatile and synthetically useful route to enantiomerically enriched lactones. There are two major advantages of this system in that it appears to accept a fair amount of structural variation and full experimental details are available for preparative scale oxidations. A selection of results obtained with this enzyme system is presented in Scheme 14. 

Imidazoles (ketoconazole, miconazole, fenticonazole, clotrimazole, isoconazole, tioconazole) interfere with fungal oxidative enzymes to cause lethal accumulation of hydrogen peroxide they also reduce the formation of ergosterol, an important constituent of the fungal cell wall which thus becomes permeable to intracellular constituents. Lack of selectivity in these actions results in important adverse effects. 

Since there are many drugs and environmental pollutants that contain sulfur, it is of considerable interest that FMO preferentially catalyzes the oxidation of sulfur in compounds containing both nitrogen and sulfur. Thus, FMO is an important enzyme system for the oxidation of selected classes of xenobiotics, and its spectrum complements that of the P450 system because the latter prefers oxidation of carbon atoms. Other ways in which FMO enzymes differ from many microsomal P450 isozymes include their... 

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