(2,2 ': 6 ',2 ''-terpyridine)platinum(II) complexes are irreversible inhibitors of Trypanosoma cruzi trypanothione reductase but not of human glutathione reductase

(2,2':6',2 " -Terpyridine)platinum(II) complexes possess pronounced cytosta tic activities against trypanosomes and leishmania. As shown here, the comp lexes are irreversible inhibitors of trypanothione reductase (TR) from Tryp anosoma cruzi, the causative agent of Chagas' disease. The most effective d erivatives are the (4'-chloro-2,2':6',2 " -terpyridine)platinum(II) ammine and the (4-picoline)(4'-p-bromophenyl-2,2': 6',2 " -terpyridine)platinum(II ) complexes which in the presence of NADPH inhibit TR with second-order rat e constants of about 1.3 x 10(4) M-1 s(-1) The modified enzyme species poss ess increased oxidase activities. The inhibition is not reversed upon dialy sis or treatment with low-molecular-mass thiols. Kinetic and spectroscopic data suggest that Cys52 in the active site has been specifically altered. I nhibition of this key enzyme of parasite thiol metabolism probably contribu tes to the antitrypanosomal activity of the compounds. In contrast to the p arasite enzyme, most (terpyridine)platinum complexes interact only reversib ly with human glutathione reductase and an initial inhibition is completely abolished during the course of the assay.