199005-57-7Relevant articles and documents
Glutamine vinyl ester proteasome inhibitors selective for trypsin-like (β2) subunit
Baldisserotto, Anna,Marastoni, Mauro,Trapella, Claudio,Gavioli, Riccardo,Ferretti, Valeria,Pretto, Loretta,Tomatis, Roberto
, p. 586 - 592 (2007)
Here we report the study of a new series of peptide-based proteasome inhibitors with a vinyl ester moiety at C-terminal. The presence of Tic, a rigid analogue of phenylalanine, in the central portion of some derivatives is not favourable for the activity.
Michael acceptor based antiplasmodial and antitrypanosomal cysteine protease inhibitors with unusual amino acids
Breuning, Alexander,Degel, Bj?rn,Schulz, Franziska,Büchold, Christian,Stempka, Martin,Machon, Uwe,Heppner, Saskia,Gelhaus, Christoph,Leippe, Matthias,Leyh, Matthias,Kisker, Caroline,Rath, Jennifer,Stich, August,Gut, Jiri,Rosenthal, Philip J.,Schmuck, Carsten,Schirmeister, Tanja
experimental part, p. 1951 - 1963 (2010/08/03)
New peptidic Michael acceptor based cysteine protease inhibitors displaying antiparasitic activity were identified by testing a broad series of 45 compounds in total, containing Asn, Gln, or Phe. As target enzymes, falcipain-2 and -3 from P. falciparum and rhodesain from T. b. rhodesiense were used. In the case of the Asn/Gln containing compounds, the trityl-protected, diastereomeric ?'-configured vinylogous dipeptide esters 16 (Boc-(S)-Phg-(R/S)-vGln(Trt) -OEt) were discovered as most active inhibitors concerning both protease inhibition and antiparasitic acitivity, with inhibition constants in the submicromolar range. The compounds were shown to display time-dependent and competitive inhibition. In the case of the Phe containing compounds, the maleic acid derivatives 42 and 43 (BnOPhe←Mal-Phe-OBn, BnO-Phe-Mal←Phe-Ala- OBn, Mal = maleic acid) displayed good inhibition of rhodesain as well as good antitrypanosomal activity, while the fumaric acid derived E-analogue 14 (BnO-Phe-Fum-Phe-OBn) only displayed inhibition of the target enzymes but no antiparasitic activity. Inhibition by these Phe derivatives was shown to be time-independent and competitive.
Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 2. Peptide structure- activity studies
Dragovich, Peter S.,Webber, Stephen E.,Babine, Robert E.,Fuhrman, Sheila A.,Patick, Amy K.,Matthews, David A.,Reich, Siegfried H.,Marakovits, Joseph T.,Prins, Thomas J.,Zhou, Ru,Tikhe, Jayashree,Littlefield, Ethel S.,Bleckman, Ted M.,Wallace, Michael B.,Little, Thomas L.,Ford, Clifford E.,Meador III, James W.,Ferre, Rose Ann,Brown, Edward L.,Binford, Susan L.,DeLisle, Dorothy M.,Worland, Stephen T.
, p. 2819 - 2834 (2007/10/03)
The structure-based design, chemical synthesis, and biological evaluation of various peptidederived human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds are comprised of an ethyl propenoate Michael acceptor moiety and a tripeptidyl binding determinant. The systematic modification of each amino acid residue present in the binding determinant as well as the N-terminal functionality is described. Such modifications are shown to provide irreversible HRV-14 3CP inhibitors with anti-3CP activities (k(obs)/[I]) ranging from 60 to 280 000 M-1 s-1 and antiviral EC50's which approach 0.15 μM. An optimized inhibitor which incorporates several improvements identified by the structure-activity studies is also described. This molecule displays very rapid irreversible inhibition of HRV-14 3CP (k(obs)/[I] = 800 000 M-1 s-1) and potent antiviral activity against HRV-14 in cell culture (EC50 = 0.056 μM). A 1.9 A? crystal structure of an S-alkylthiocarbamate-containing inhibitor complexed with HRV-2 3CP is also detailed.
Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 1. Michael acceptor structre-activity studies
Dragovich, Peter S.,Webber, Stephen E.,Babine, Robert E.,Fuhrman, Shella A.,Patick, Amy K.,Matthews, David A.,Lee, Caroline A.,Reich, Siegfried H.,Prins, Thomas J.,Marakovits, Joseph T.,Littlefield, Ethel S.,Zhou, Ru,Tikhe, Jayashree,Ford, Clifford E.,Wallace, Michael B.,Meador III, James W.,Ferre, Rose Ann,Brown, Edward L.,Binford, Susan L.,Harr, James E. V.,DeLisle, Dorothy M.,Worland, Stephen T.
, p. 2806 - 2818 (2007/10/03)
The structure-based design, chemical synthesis, and biological evaluation of peptide-derived human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds incorporate various Michael acceptor moieties and are shown to irreversibly bin
Synthesis of chiral vinylogous sulfonamidopeptides (vs-peptides)
Gennari, Cesare,Longari, Chiara,Ressel, Stefano,Salom, Barbara,Mielgo, Antonia
, p. 945 - 959 (2007/10/03)
Chiral vinylogous amino sulfonic acids (vs-amino acids) were synthesized starting from either L- or D-α-amino acids via N-Boc-α-amino aldehydes. Wittig-Horner reaction with methyl (or ethyl) diethylphosphoryl methanesulfonate and nBuLi gave the corresponding α,β-unsaturated sulfonates in high yield and complete (E) stereoselectivity. Cleavage of the methyl (ethyl) ester was effected by treatment of the sulfonates with nBu4NI in refluxing acetone. Treatment of the nBu4N+ sulfonate salts with SO2Cl2/PPh3/CH2Cl2 gave the corresponding sulfonyl chlorides as stable chromatographable compounds. The synthetic sequence proved successful not only starting from α-amino acids carrying unfunctionalized side-chains (Ala, Val, Phe, Leu, Pro), but also with functionalized α-amino acids (Ser, Tyr, Gln) provided that the side chains were suitably protected. The sulfonyl chlorides were coupled with the amine salts to give vs-dipeptides. Amine hydrochlorides were prepared from N-Boc derivatives by treatment with HCl in methanol or ethyl acetate. The process was further iterated to give vstripeptides and vs-tetrapeptides. The above procedure was also used to synthesize "mixed" peptides, which incorporate both proteinogenic α-amino acids and vs-amino acids. Proteinogenic α-amino acids were incorporated at both the C-terminal and the N-terminal position.
