This report describes the design and synthesis of a series alpha(V)beta(3) integrin-directed monomeric, dimeric tetrameric cyclo[Arg-Gly-Asp-d-Phe-Lys] dendrimers using "click chemistry". It was found that unprotected N-epsilon-azido derivative underwent highly chemoselective conjugation to amino acid-based bearing terminal alkynes microwave-assisted Cu(I)-catalyzed 1,3-dipolar cycloaddition. The binding characteristics were determined in vitro their vivoalpha(V)beta(3) targeting properties...

Multivalent dendrimeric peptides were synthesized via a microwave-assisted Huisgen 1,3-dipolar cycloaddition between azido and alkynes in yields ranging from 46 to 96%.

Abstract The concept of proteasome inhibition ranks among the latest achievements in treatment blood cancer and represents a promising strategy for modulating autoimmune diseases. In this study, we describe peptidic sulfonyl fluoride inhibitors that selectively block catalytic β5 subunit immunoproteasome by inducing only marginal cytotoxic effects. Structural mass spectrometric analyses revealed novel reaction mechanism involving polarity inversion irreversible crosslinking proteasomal...

Abstract A facile and high‐yielding synthesis of multivalent 1,4‐disubstituted 1,2,3‐triazole‐linked glycodendrimers is described. Azido carbohydrates are linked by a Cu I ‐catalyzed [3+2] cycloaddition reaction to dendritic acetylenes using microwave irradiation. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

[reaction: see text] A highly efficient coupling of protected beta-substituted aminoethane sulfonyl azides with thio acids is reported. In the case peptide acids, this method encompasses a new chemoselective ligation method. Furthermore, resulting alpha-amino acyl sulfonamides can be alkylated suitable electrophiles to obtain densely functionalized sulfonamide scaffolds.

A new class of potent proteasome inhibitors is described, which the members contain an amino acid inspired sulfonyl fluoride as electrophilic trap. In total, 24 peptido have been designed and synthesized, were by backbone sequences bortezomib, epoxomicin, Cbz-Leu(3)-aldehyde. Nine them very inhibitors, best had IC(50) 7 nM. number found to be highly selective for β5 subunit.

Rhomboid proteases are evolutionary conserved intramembrane serine proteases. Because of their emerging role in many important biological pathways, rhomboids potential drug targets. Unfortunately, few chemical tools available for study. Here, we describe a mass spectrometry-based assay to measure rhomboid substrate cleavage and inhibition. We have identified isocoumarin inhibitors developed activity-based probes The can distinguish between active inactive due covalent, reversible binding the...

A unique category of basic side chain containing amino acid derived sulfonyl fluorides (SFs) has been synthesized for incorporation into new proteasome inhibitors targeting the trypsin-like site 20S proteasome. Masking former α-amino functionality starting derivatives as an azido allowed elegant conversion to corresponding fluorides. The inclusion different SFs at P1 a inhibitor resulted in 14 peptidosulfonyl (PSFs) having high potency and excellent selectivity proteolytic activity β2...

Prolyl oligopeptidase (POP), a serine protease highly expressed in the brain, has recently emerged as an enticing therapeutic target for treatment of cognitive and neurodegenerative disorders. However, most reported inhibitors suffer from short duration action, poor selectivity, low blood-brain barrier (BBB) permeability, which altogether limit their potential drugs. Here, we describe structure-based design first irreversible, selective, brain-permeable POP inhibitors. At low-nanomolar...

Abstract The ‘sulfo‐click’ reaction, which is a chemoselective amidation reaction involving the of an aminoethane sulfonyl azide with thio acid, encompasses new approach for ligation and conjugation. Detailed protocols are provided decorating biologically active peptides or dendrimers biophysical tags, fluorescent probes, metal chelators, small by using this as novel, metal‐free approach. Copyright © 2009 European Peptide Society John Wiley & Sons, Ltd.

On the basis of a pyrrolidine tweezer 1, library peptidosulfonamide tweezers (15a-e, 16a-e) was synthesized on solid phase. This screened in simultaneous substrate screening procedure for ability to enantioselectively catalyze Ti(O-i-Pr)(4)-mediated addition diethylzinc aldehydes. One best solid-phase catalyst (i.e., 16d, giving an ee 32% catalysis) resynthesized solution (compounds 20 and 21). The now homogeneous solution-phase catalysis showed even better enantioselectivity up 66%).

ABSTRACT Despite declining numbers of cases and deaths, malaria remains a major public health problem in many parts the world. Today, case management relies heavily on single class antimalarial compounds: artemisinins. Hence, development resistance against artemisinins may destroy current control strategies. Beyond are elimination eradication programs that will require drugs with good activity acute infection but also preventive transmission-blocking properties. Consequently, new...

The synthesis of amino acid based dendrimers 25 (fifth generation, 32 endgroups), 30 (fourth 81 chiral dendrimer 23 (third 8 endgroups) as well core-modified 34 and 38 by the convergent method is described. building blocks are derived from hydroxybenzoic derivatives alcohol derivatives, access to a considerable molecular diversity these novel can be achieved. carried out on relatively large scale, this easy may lead many potential applications.

N-Protected beta-aminoethanesulfonyl chlorides (2a-e) were used in the preparation of sulfonamides 4, 8, 11a-c, and 15. Ring-closing metathesis 4 8 did not lead to expected nine-membered cyclic peptidosulfonamides. In contrast, allylated peptidosulfonamides 11a-c 15 turned out be suitable precursor systems for ring-closing using second-generation Grubbs catalyst obtained 47-60% yields. The possibility incorporation these into a peptide sequence was illustrated by an amino acid on "S"- or...

With preservation of selectivity, the hinge part tweezerlike synthetic receptor molecules can be varied to achieve a higher affinity. The peptidosulfonamide (below left; R=Disperse Red 1) with bis(aminomethyl)benzoic acid selectively bound tripeptide shown below on right (Ka=4100 M−1). Combination diversity in that present tweezer arms will provide access large and diverse libraries.

A very efficient method for the synthesis of β-aminoethanesulfonyl chlorides is described. These aliphatic functionalized sulfonyl are accessible starting from a variety protected amino acids, including those having side chains.

Abstract Das Konzept der Proteasom‐Inhibition zählt zu den jüngsten Errungenschaften Blutkrebstherapie und stellt eine vielversprechende Strategie zur Regulierung von Autoimmunerkrankungen dar. Diese Arbeit beschreibt die selektive Hemmung katalytischen β5‐Untereinheit des Immunoproteasoms durch peptidische Sulfonylfluoride, nur geringen zytotoxischen Effekt haben. Strukturelle massenspektrometrische Analysen offenbarten einen neuartigen Inhibitionsmechanismus, einer Umpolung irreversiblen...