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 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.

Enzyme-Catalyzed Activation of Anticancer Prodrugs

“…The K m value for oxidative deamination of D-alanine for the mutated protein was 0.7 mM, which is comparable with the wildtype protein (0.8 mM) (Stegman et al, 1998). SeCys conjugates were recently proposed as kidneyselective prodrugs of pharmacologically active selenols (Andreadou et al, 1996;Rooseboom et al, 2000). These compounds have been shown to be potent chemopreventive and antitumor agents (Ip, 1998;Ip et al, 1999) ( Table 4).…”

Selenium toxicity: cause and effects in aquatic birds

“…That order in view of the present understanding of selenium as a dose dependent generator of superoxide and oxidative stress would be; methylseleninic acid, selenite, selenate, selenocystine, Se-methylselenocysteine, selenomethionine, dimethylselenoxide and trimethylselenium chloride. Methylseleninic acid and selenite are highly active as redox catalysts, selenate becomes catalytic upon reduction to selenite, selenocystine becomes catalytic upon reduction to selenocysteine, Se-methylselenocysteine and selenomethionine become toxic and catalytic upon metabolism by what is believed to be B-lyases (Andreadou et al, 1996;Ip et al, 2000). Dimethyselenoxide and the trimethylselenionium ion are not catalytic in in vitro assays nor are they very toxic to animals in vivo.…”

Biomarkers of Selenium Action in Prostate Cancer

“…It is believed that they are the direct precursors of methylselenol, possibly the key metabolite responsible for selenium's anticancer activity. Whereas MSC requires the action of cysteine conjugate ␤-lyase or related lyases to be converted to methylselenol, MSA does not (Andreadou et al, 1996; Ganther and Lawrence, 1997; Ip, 1998; Ip et al, 2000b). It is 10 times more potent than MSC in affecting biological processes in vitro, probably because of limited ␤-lyase activity in cultured eukaryotic cells (Ip et al, 2000b).…”