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A Matlab-based computer program termed Discovery of General Endo- and Xenobiotics (DoGEX) was developed, which uses wavelets and morphological analysis to process liquid chromatography-mass spectrometry (LC-MS) data. The output of the program is a list of integration areas as a function of retention time and molecular mass. A feature of the computer program is spectral filtering to facilitate the detection of chromatographic peaks with a particular isotopic ratio. The program DoGEX was used to automatically select oxidation products formed from felodipine (i.e., two chlorine atoms) and bromocriptine (one bromine atom) with cytochrome P450 3A4. The recognized isotope ratio can be changed to permit a natural or artificial mixture of isotopes to be monitored for selections. This computer program can be used to analyze LC-MS data for untargeted metabolic profiling experiments, e.g., to assign endogenous functions to newly characterized cytochrome P450 enzymes. In a representative example, an incubation of testosterone, NADPH, and a 1:1 16O2/18O2 mixture yielded products with M and M+2 ions resembling bromine doublets. Another use of the program is the subtraction of one set of tR, m/z data from another, e.g., in comparisons of changes in patterns during enzyme reactions.
[reaction: see text] Barton esters of beta-silylcarboxylic acids were decomposed by photolysis alone in organic solvents or in the presence of ethanesulfonyl azide or bromotrichloromethane. Products of the reaction, beta-silylthiopyridyl ethers, beta-silyl azides, or alkenes, were formed with significant control of stereochemistry.
Incubation of iodosylbenzene and [125I]iodobenzene with cytochrome P-450 (P-450) leads to the formation of [125I]iodosylbenzene (Burka, L.T., Thorsen, A., and Guengerich, F.P. (1980) J. Am. Chem. Soc. 102, 7615-7616), but to date it has not been possible to observe directly the oxidation of organic halides in NADPH-supported P-450 reactions because of the intrinsic instability of haloso compounds. 4-tert-Butyl-2,5-bis[1-hydroxy-1-(trifluoromethyl)- 2,2,2-trifluoroethyl]iodobenzene (RI) and the corresponding bromine analog (RBr) were utilized as model compounds because their oxidized derivatives (iodinane and brominane) are relatively stable. Several model metalloporphyrins efficiently oxidized RI to the iodinane in the presence of iodosylbenzene. Rates of reduction of Mn(V) = O tetraphenylporphin chloride by RI were considerably faster than for several other organic halides. NADPH-fortified rat liver microsomes oxidized RI to the iodinane, identified by its chromatographic retention time and characteristic UV spectrum. Purified P-450 enzymes also catalyzed the oxidation of RI to the iodinane; more selectivity among individual proteins was seen when the reaction was supported by NADPH and NADPH-P-450 reductase than by iodosylbenzene. Free thiol groups in P-450 and NADPH-P-450 reductase could be oxidized by iodosylbenzene, the iodinane or brominane, or by incubation with NADPH and RI or other organic halides. These results provide evidence that P-450 can oxidize organic halogen atoms. Iodo compounds are definitely oxidized, even though the apparent oxidation-reduction potential differences seem unfavorable. The halogen order seen for the reaction is a function of the oxidation potential. Organic bromine compounds are probably also oxidized by P-450, although the rates are much slower. Chloroperoxidase did not oxidize RI to the iodinane but horseradish peroxidase did so at a lower rate; in this case the iodinane is postulated to form via electron abstraction without oxygen transfer.