Synthesis of novel Se-substituted selenocysteine derivatives as potential kidney selective prodrugs of biologically active selenol compounds: evaluation of kinetics of beta-elimination reactions in rat renal cytosol

J Med Chem. 1996 May 10;39(10):2040-6. doi: 10.1021/jm950750x.

Abstract

Eighteen Se-substituted selenocysteine derivatives were synthesized as potential kidney selective prodrugs which can be activated by renal cysteine conjugate beta-lyase to selenium-containing chemoprotectants or antitumor agents. Selenocysteine derivatives with aliphatic and benzylic Se-substituents were synthesized by reducing selenocystine to selenocysteine followed by a reaction with the corresponding alkyl and benzyl halogenides. Selenocysteine derivatives with aromatic Se-substitutes were synthesized by reaction of beta-chloroalanine with substituted phenylselenol compounds, which were formed by reducing substituted diphenyl diselenides by NaBH4. The enzyme kinetic parameters (apparent Km and Vmax) of the beta-elimination reaction of the selenocysteine conjugates were studied in rat renal cytosol. The results suggest that Se-substituted L-selenocysteine conjugates are extremely good substrates for renal cysteine conjugate beta-lyases as indicated by low apparent Km and high Vmax values. The benzyl-substituted Se-conjugates appeared to be better substrates than the phenyl- and alkyl-substituted Se-conjugates. Corresponding L-cysteine S-conjugates were too poor substrates to obtain proper enzyme kinetics. Recently, local activation of cysteine S-conjugates by renal cysteine conjugate beta-lyases was proposed as a new strategy to target antitumor agents to the kidney. The present results show that Se-substituted selenocysteine conjugates may be more promising prodrugs because these compounds are much better substrates for beta-lyase.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Biotransformation
  • Carbon-Sulfur Lyases*
  • Chemoprevention
  • Cytosol / drug effects
  • Cytosol / metabolism
  • Kidney / drug effects*
  • Kidney / enzymology
  • Kidney / metabolism
  • Lyases / metabolism
  • Male
  • Prodrugs / pharmacology*
  • Rats
  • Rats, Wistar
  • Selenocysteine / analogs & derivatives*
  • Selenocysteine / chemical synthesis
  • Selenocysteine / pharmacokinetics
  • Selenocysteine / pharmacology
  • Substrate Specificity

Substances

  • Antineoplastic Agents
  • Prodrugs
  • Selenocysteine
  • Lyases
  • Carbon-Sulfur Lyases
  • S-alkylcysteine lyase