Synthesis of Novel Se-Substituted Selenocysteine Derivatives as Potential Kidney Selective Prodrugs of Biologically Active Selenol Compounds: Evaluation of Kinetics of β-Elimination Reactions in Rat Renal Cytosol

Abstract

Eighteen Se-substituted selenocysteine derivatives were synthesized as potential kidney selective prodrugs which can be activated by renal cysteine conjugate β-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-substituents were synthesized by reaction of β-chloroalanine with substituted phenylselenol compounds, which were formed by reducing substituted diphenyl diselenides by NaBH₄. The enzyme kinetic parameters (apparent K_m and V_max) of the β-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 β-lyases as indicated by low apparent K_m and high V_max 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 β-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 β-lyase.