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.
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.
Andreadou
I
I
Leiden Amsterdam Center for Drug Research (LACDR), Vrije Universiteit Amsterdam, The Netherlands.
Menge
W M
WM
Commandeur
J N
JN
Worthington
E A
EA
Vermeulen
N P
NP
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D001711:Biotransformation; D013437:Carbon-Sulfur Lyases; D018890:Chemoprevention; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008190:Lyases / Q000378:metabolism; D008297:Male; D011355:Prodrugs / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017279:Selenocysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D013379:Substrate Specificity
D000970:Antineoplastic Agents; D011355:Prodrugs; D017279:Selenocysteine; D008190:Lyases; D013437:Carbon-Sulfur Lyases; C019969:S-alkylcysteine lyase