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

J Med Chem. 2000 Dec 14;43(25):4812-21. doi: 10.1021/jm000219o.

Abstract

(2,2':6',2"-terpyridine)platinum(II) complexes possess pronounced cytostatic activities against trypanosomes and leishmania. As shown here, the complexes are irreversible inhibitors of trypanothione reductase (TR) from Trypanosoma cruzi, the causative agent of Chagas' disease. The most effective derivatives 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 rate constants of about 1.3 x 10(4) M(-1) s(-1). The modified enzyme species possess increased oxidase activities. The inhibition is not reversed upon dialysis or treatment with low-molecular-mass thiols. Kinetic and spectroscopic data suggest that Cys52 in the active site has been specifically altered. Inhibition of this key enzyme of parasite thiol metabolism probably contributes to the antitrypanosomal activity of the compounds. In contrast to the parasite enzyme, most (terpyridine)platinum complexes interact only reversibly with human glutathione reductase and an initial inhibition is completely abolished during the course of the assay.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2,2'-Dipyridyl / analogs & derivatives
  • 2,2'-Dipyridyl / chemical synthesis*
  • 2,2'-Dipyridyl / chemistry
  • Animals
  • Dialysis
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Glutathione Reductase / antagonists & inhibitors*
  • Glutathione Reductase / chemistry
  • Humans
  • Kinetics
  • Ligands
  • NADH, NADPH Oxidoreductases / antagonists & inhibitors*
  • NADH, NADPH Oxidoreductases / chemistry
  • Organoplatinum Compounds / chemical synthesis*
  • Organoplatinum Compounds / chemistry
  • Oxidation-Reduction
  • Spectrophotometry
  • Sulfhydryl Compounds / chemistry
  • Trypanocidal Agents / chemical synthesis*
  • Trypanocidal Agents / chemistry
  • Trypanosoma cruzi / chemistry*

Substances

  • (4-picoline)(4'-p-bromophenyl-2,2'-6',2''-terpyridine)platinum(II)
  • Enzyme Inhibitors
  • Ligands
  • Organoplatinum Compounds
  • Sulfhydryl Compounds
  • Trypanocidal Agents
  • ammine(4'-chloro-2,2'-6',2''-terpyridine)platinum(II)
  • 2,2'-Dipyridyl
  • NADH, NADPH Oxidoreductases
  • trypanothione reductase
  • Glutathione Reductase