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 a nd mechanism-based inactivator for the design of cytochrome P450 inhib itors. 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 th e versatile microsomal P450s 2B4, 2E1, and 1A2. The compounds generall y show heteroatom coordination to the heme iron; however the binding m ode 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 sp ectra with P450s 2B4 and 2E1, respectively, and no spectral perturbati on with P450 1A2. Except for the fused bicyclic compound, the spectral dissociation constants are in the 2-50 mu M 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-phenylet hanol 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. Inact ivation of the P450 correlates with loss in absorbance at 450 nm for t he ferrous-CO complex. The monocyclic 1,2,3-thiadiazoles do not inacti vate 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.