Br. Babu et Adn. Vaz, 1,2,3-THIADIAZOLE - A NOVEL HETEROCYCLIC HEME LIGAND FOR THE DESIGN OF CYTOCHROME-P450 INHIBITORS, Biochemistry, 36(23), 1997, pp. 7209-7216
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.