71404-98-3Relevant articles and documents
Evaluation of the kinetics of β-elimination reactions of selenocysteine se-conjugates in human renal cytosol: Possible implications for the use as kidney selective prodrugs
Rooseboom, Martijn,Vermeulen, Nico P. E.,Andreadou, Ioanna,Commandeur, Jan N. M.
, p. 762 - 769 (2007/10/03)
This study was performed to evaluate whether selenocysteine Se- conjugates are substrates for human cysteine conjugate β-lyase enzymes. By testing kidney cytosols of three different humans, we studied interindividual differences in β-lyase enzymes in humans. A series of 22 selenocysteine Se- conjugates were tested in rat and human kidney cytosols to compare their ability to form selenol compounds by β-elimination. All compounds appeared to be good substrates for rat and human cysteine conjugate β-lyase enzymes. The β-lyase activity toward the selenocysteine Se-conjugates was comparable with those of the known nephrotoxic cysteine S-conjugate S-(2-chloro-1,1,2- trifluoroethyl)-L-cysteine in rats and humans. In rat kidney cytosol, between 22- and 877-fold higher β-elimination rates were observed compared with human kidney cytosol. Significant correlations (P .0001) between three human kidney cytosols in β-lyase activities were found within the tested series of 22 compounds. Specific β-lyase activities and intrinsic clearances of β-elimination reactions ranged up to 3-fold, indicating that there are quantitative rather than qualitative interindividual differences in β- eliminating enzymes in humans. Furthermore, Se-alkyl selenocysteine conjugates showed a sterically dependent bioactivation to selenol compounds in humans but not in rats. The present study supports the hypothesis that selenocysteine Se-conjugates may be useful as prodrugs to target pharmacologically active selenol compounds (e.g., antitumor or chemoprotective) to the kidney in humans.
Chloroanalyland propargylglycyl dipeptides. Suicide substrate containing antibacterials
Cheung, Kam Sing,Wasserman, Steven A.,Dudek, Edward,Lerner, Stephen A.,Johnston, Michael
, p. 1733 - 1741 (2007/10/02)
A set of dipeptides containing the amino acid residues β-chloroalanine and propargylglycine, which are mechanism-based inactivators of purified microbial enzymes (alanine racemase and cystathionine γ-synthase, respectively), have been synthesized, and their antibacterial properties in vitro have been evaluated. Dipeptides containing a single β-chloro-L-alanyl residue (e.g., 3, 5, 9, and 10) or a single L-propargylglycyl residue (e.g., 12 and 15) are potent antibacterials. The in vitro antibiotic activity of β-chloro-L-alanine and of L-propargylglycine is increased as much as 4000-fold by incorporation of these residues into a dipeptide. Compounds that contain only a single enzyme-inactivating amino acid together with a second L-alanyl residue (3, 5, 12, and 15) have a restricted range of activity: of the species tested, only Streptococcus agalactiae, Staphylococcus aureus, and Staphylococcus epidermidis are sensitive. However, peptides that contain two suicide-substrate residues [e.g., β-Cl-LAla-β-Cl-LAla (8) or LppGly-LppGly (18)] are broad-spectrum antibacterials; as many as 12 different species of the 16 surveyed are sensitive. Dipeptides that contain an amino-terminal L-methionyl (9) or an L-norvalyl (10) residue and a carboxy-terminal β-chloro-L-alanyl unit are also effective against a large number of organisms; the spectra of activity are like those seen for 8 and 18. A 'mixed' dipeptide [β-Cl-LAla-LppGly, (21)] gives apparent synergism of antibiotic action of β-chloro-L-alanine and of L-propargylglycine when these two residues are incorporated into a single structure. Peptides of the D,D configuration (4, 6, 13, 16, and 20) and ones of L,D stereochemistry (e.g., 7) are not antibacterials. Peptides containing one (11 and 14) and two (17) D,L-propargylglycyl residues are unresolved sets of diastereomers; the mixtures of compounds are between two- and fourfold less active than the corresponding resolved L,L dipeptides (12, 15, and 18). These findings are consistent with a mechanism of action for these antibiotics involving stereoselective processing of the peptidyl unit in vivo.
