17015-08-6Relevant articles and documents
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Oh-hashi,J.-I.,Harada,K.
, p. 2977 - 2979 (1967)
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Probing of primed and unprimed sites of calpains: Design, synthesis and evaluation of epoxysuccinyl-peptide derivatives as selective inhibitors
Dókus, Levente E.,Menyhárd, Dóra K.,Tantos, ágnes,Hudecz, Ferenc,Bánóczi, Zoltán
, p. 274 - 280 (2014/06/24)
Calpains are intracellular cysteine proteases with important physiological functions. Up- or downregulation of their expression can be responsible for several diseases, therefore specific calpain inhibitors may be considered as promising candidates for drug discovery. In this paper we describe the synthesis and characterization of a new class of inhibitors derived from the analysis of amino acid preferences in primed and unprimed sites of calpains by incorporation of l- or d-epoxysuccinyl group (Eps). Amino acids for replacement were chosen by considering the substrate preference of calpain 1 and 2 enzymes. The compounds were characterized by RP-HPLC, amino acid analysis and ESI-MS. Selectivity of the compounds was studied by using calpain 1 and 2; and cathepsin B. We have identified five calpain specific inhibitors with different extent of selectivity. Two of these also exhibited isoform selectivity. Compound NH 2-Thr-Pro-Leu-(d-Eps)-Thr-Pro-Pro-Pro-Ser-NH2 proved to be a calpain 2 enzyme inhibitor with at least 11.8-fold selectivity, while compound NH2-Thr-Pro-Leu-(l-Eps)-Ser-Pro-Pro-Pro-Ser-NH2 possesses calpain 1 enzyme inhibition with at least 4-fold selectivity. The results of molecular modeling calculations suggest that the orientation of the bound inhibitor in the substrate binding cleft is markedly dependent on the stereochemistry of the epoxysuccinyl group.
Design, Synthesis, and Evaluation of Aza-Peptide Epoxides as Selective and Potent Inhibitors of Caspases-1, -3, -6, and -8
James, Karen Ellis,Asgian, Juliana L.,Li, Zhao Zhao,Ekici, ?zlem Do?an,Rubin, John R.,Mikolajczyk, Jowita,Salvesen, Guy S.,Powers, James C.
, p. 1553 - 1574 (2007/10/03)
Aza-peptide epoxides, a novel class of irreversible protease inhibitors, are specific for the clan CD cysteine proteases. Aza-peptide epoxides with an aza-Asp residue at P1 are excellent irreversible inhibitors of caspases-1, -3, -6, and -8 with second-order inhibition rates up to 1 910 000 M-1 s-1. In general, the order of reactivity of aza-peptide epoxides is S,S > R,R > trans > cis. Interestingly, some of the R,R epoxides while being less potent are actually more selective than the S,S epoxides. Our aza-peptide epoxides designed for caspases are stable, potent, and specific inhibitors, as they show little to no inhibition of other proteases such as the aspartyl proteases porcine pepsin, human cathepsin D, plasmepsin 2 from P. falciparum, HIV-1 protease, and the secreted aspartic proteinase 2 (SAP-2) from Candida albicans; the serine proteases granzyme B and α-chymotrypsin; and the cysteine proteases cathepsin B and papain (clan CA), and legumain (clan CD).
Kinetics and mechanism of the oxidation of some unsaturated acids by quinolinium bromochromate
Vyas, Shweta,Sharma, Pradeep K.
, p. 820 - 823 (2007/10/03)
The oxidation of maleic, fumaric, crotonic and cinnamic acids by quinolinium bromochromate (QBC) in dimethylsulphoxide (DMSO) leads to the formation of corresponding epoxide. The reaction is of first order with respect to QBC and the acid. The reaction is catalysed by hydrogen ions. The hydrogen-ion dependence has the form: kobs = a + b [H+]. The oxidation of these acids was studied in nineteen different organic solvents. The solvent effect was analyzed by Kamlet's and Swain's multiparametric equations. Solvent effect indicated the importance of the cation-solvating power of the solvent. A mechanism involving a three-centre transition state has been postulated.
