1,2,3-Thiadiazole: a novel heterocyclic heme ligand for the design of cytochrome P450 inhibitors.
The 1,2,3-thiadiazole heterocycle has been explored as a heme ligand and mechanism-based inactivator for the design of cytochrome P450 inhibitors. One 4,5-fused bicyclic and three 4,5-disubstituted monocyclic 1,2,3-thiadiazoles have been examined for their spectral interactions, inhibition, mechanism-based inactivation, and oxidation products by the versatile microsomal P450s 2B4, 2E1, and 1A2. The compounds generally show heteroatom coordination to the heme iron; however, the binding mode is influenced by the architecture of the active site. For example, 4,5-diphenyl-1,2,3-thiadiazole shows type I and type II difference spectra with P450s 2B4 and 2E1, respectively, and no spectral perturbation with P450 1A2. Except for the fused bicyclic compound, the spectral dissociation constants are in the 2-50 microM range. The effectiveness as an inhibitor depends on the substituents at the 4- and 5- positions and on the P450 examined. Inhibition of the P450-catalyzed 1-phenylethanol oxidation to acetophenone by the thiadiazoles does not correlate with either the type of binding spectra or the spectral dissociation constants of the compounds. P450s 2E1 and 2B4 are inactivated by the 4,5-fused bicyclic 1,2,3-thiadiazole in a mechanism-based manner. Inactivation of the P450 correlates with loss in absorbance at 450 nm for the ferrous-CO complex. The monocyclic 1,2,3-thiadiazoles do not inactivate any of the P450s examined. The 1,2,3-thiadiazole ring is oxidized by the P450 system. Oxidation of the monocyclic compounds results in extrusion of the three heteroatoms and formation of the corresponding acetylenes, whereas oxidation of the fused bicyclic compound does not yield an acetylenic product.
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Department of Biological Chemistry, Medical School, The University of Michigan, Ann Arbor 48109, USA.
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D000098:Acetophenones / Q000378:metabolism; D000818:Animals; D001592:Benzyl Alcohols / Q000378:metabolism; D002942:Circular Dichroism; D065607:Cytochrome P-450 Enzyme Inhibitors; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006418:Heme / Q000378:metabolism*; D007700:Kinetics; D008024:Ligands; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D008956:Models, Chemical; D010084:Oxidation-Reduction; D017319:Photosensitizing Agents / Q000378:metabolism; D011817:Rabbits; D013830:Thiadiazoles / Q000378:metabolism*
D000098:Acetophenones; D001592:Benzyl Alcohols; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D008024:Ligands; D017319:Photosensitizing Agents; D013830:Thiadiazoles; D006418:Heme; C002017:methylphenyl carbinol; C038699:acetophenone