336818-78-1Relevant articles and documents
Disulfide-Bridged Peptides That Mediate Enantioselective Cycloadditions through Thiyl Radical Catalysis
Ryss, Jonathan M.,Turek, Amanda K.,Miller, Scott J.
, p. 1621 - 1625 (2018/03/23)
An enantioselective vinylcyclopropane ring-opening/cycloaddition cascade is described. The active thiyl radical catalysts are generated in situ via UV light-promoted homolysis of cystine-based dimers. Amide-functionalization of the peptide at the 4-proline position is essential for effective asymmetric induction. Stereochemical communication is dependent on steric interactions with this substituent that are enforced by H-bonding to the peptide backbone.
Discovery of potent and specific dihydroisoxazole inhibitors of human transglutaminase 2
Kl?ck, Cornelius,Herrera, Zachary,Albertelli, Megan,Khosla, Chaitan
, p. 9042 - 9064 (2015/03/14)
Transglutaminase 2 (TG2) is a ubiquitously expressed enzyme that catalyzes the posttranslational modification of glutamine residues on protein or peptide substrates. A growing body of literature has implicated aberrantly regulated activity of TG2 in the pathogenesis of various human inflammatory, fibrotic, and other diseases. Taken together with the fact that TG2 knockout mice are developmentally and reproductively normal, there is growing interest in the potential use of TG2 inhibitors in the treatment of these conditions. Targeted-covalent inhibitors based on the weakly electrophilic 3-bromo-4,5-dihydroisoxazole (DHI) scaffold have been widely used to study TG2 biology and are well tolerated in vivo, but these compounds have only modest potency, and their selectivity toward other transglutaminase homologues is largely unknown. In the present work, we first profiled the selectivity of existing inhibitors against the most pertinent TG isoforms (TG1, TG3, and FXIIIa). Significant cross-reactivity of these small molecules with TG1 was observed. Structure-activity and -selectivity analyses led to the identification of modifications that improved potency and isoform selectivity. Preliminary pharmacokinetic analysis of the most promising analogues was also undertaken. Our new data provides a clear basis for the rational selection of dihydroisoxazole inhibitors as tools for in vivo biological investigation.
Synthesis and evaluation of some hydroxyproline-derived peptidomimetics as isoprenyltransferase inhibitors
O'Connell, Celeste E.,Rowell, Cheryl A.,Ackermann, Karen,Garcia, Ana Maria,Lewis, Michael D.,Kowalczyk, James J.
, p. 740 - 742 (2007/10/03)
CA1A2X peptidomimetics containing a modified proline at position A2 were prepared and evaluated for their ability to inhibit farnesyltransferase (FTase) and geranylgeranyltransferase I (GGTase I) in enzymatic and cell- bas
