93836-43-2Relevant articles and documents
Reversible ketomethylene-based inhibitors of human neutrophil proteinase 3
Budnjo, Adnan,Narawane, Shailesh,Grauffel, Cédric,Schillinger, Anne-Sophie,Fossen, Torgils,Reuter, Nathalie,Haug, Bengt Erik
, p. 9396 - 9408 (2015/02/02)
Neutrophil serine proteases, proteinase 3 (PR3) and human neutrophil elastase (HNE), are considered as targets for chronic inflammatory diseases. Despite sharing high sequence similarity, the two enzymes have different substrate specificities and functions. While a plethora of HNE inhibitors exist, PR3 specific inhibitors are still in their infancy. We have designed ketomethylene-based inhibitors for PR3 that show low micromolar IC50 values. Their synthesis was made possible by amending a previously reported synthesis of ketomethylene dipeptide isosteres to allow for the preparation of derivatives suitable for solid phase peptide synthesis. The best inhibitor (Abz-VADnV[ψ](COCH2)ADYQ-EDDnp) was found to be selective for PR3 over HNE and to display a competitive and reversible inhibition mechanism. Molecular dynamics simulations show that the interactions between enzyme and ketomethylene-containing inhibitors are similar to those with the corresponding substrates. We also confirm that N- and C-terminal FRET groups are important for securing high inhibitory potency toward PR3.
Solid-phase synthesis and biological evaluation of a teleocidin library - Discovery of a selective PKCδ down regulator
Meseguer, Benjamin,Alonso-Diaz, Daniel,Griebenow, Nils,Herget, Thomas,Waldmann, Herbert
, p. 3943 - 3957 (2007/10/03)
Protein kinase C (PKC) is linked to the signal-induced modulation of a wide variety of cellular processes, such as growth, differentiation, secretion, apoptosis, and tumor development. The design and synthesis of small molecules that regulate these different cellular signaling systems is at the forefront of modern drug design. Herein we report a) an efficient method for the synthesis of indolactam V (6), a PKC activator, and its N13-des(methyl) analogues (19) using a regioselective organometallic transformation, a convenient aminomalonate derivative (10) to introduce the appropriate functionality and an enantiospecific enzymic hydrolysis as key steps; b) the use of this method in the first solid-phase synthesis of a teleocidin library modifying the N-13, C-12 and C-7 alkyl chains, and, therefore, producing a library of potential activators and/or inhibitors of PKC of the general structure (32); c) the activation of PKC by selected members of the library using a MARCKS translocation in vivo assay system; d) the observation that some of these analogues are nearly as effective as the natural PKC activators phorbol dibutyrate and (-)-indolactam V (6), and e) the observation that some of these analogues have different potential to induce down-regulation of members of the PKC gene family after chronic stimulation.
Direct Synthesis of N-Protected Chiral Amino Acids from Imidodicarbonates employing either Mitsunobu or Triflate Alkylation. Feasibility Study using Lactate with Particular Reference to 15N-Labelling
Degerbeck, Fredrik,Fransson, Bengt,Grehn, Leif,Ragnarsson, Ulf
, p. 245 - 254 (2007/10/02)
Two novel approaches to N,N-diprotected chiral α-amino acid esters, based on selected imidodicarbonates as amine synthons, have been explored.Thus, N-alkylation of these substrates was smoothly accomplished by the Gabriel or Mitsunobu methods as well as by the use of triflates.Ethyl (R,S)-2-bromopropionate underwent nucleophilic substitution when treated with the potassium salt of selected imidodicarbonates in dry dimethylformamide to furnish the corresponding fully blocked (R,S)-alanines in high yield. the chirality of ethyl (S)-lactate was largely conserved when it was condensed with free imidodicarbonates and tosylcarbamates under conventional Mitsunobu conditions.The yield of the corresponding N,N-di-protected ethyl (R)-alaninate was strongly dependent of the electron-withdrawing properties of the imidodicarbonate alkyl groups.Thus, Boc2NH gave 5 percent of the product whereas Troc-NH-Z afforded the corresponding analogue in 83 percent yield under comparable conditions.On the other hand, triflates of various lactic acid esters reacted smoothly with the lithium salt of Boc2NH, also with clean inversion, as a result of which, after selective removal of two blocking groups, the N-protected alanine of opposite configuration could be isolated in high yield and excellent stereochemical purity.Both methods have been used for the synthesis of 15N-labelled N-protected (R)- and (S)-alanines, suitable for direct application to peptide synthesis.
