Arwin J. Brouwer

Efficient microwave-assisted synthesis of multivalent dendrimeric peptides using cycloaddition reaction (click) chemistry

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

Activity-based probes for rhomboid proteases discovered in a mass spectrometry-based assay.

Rhomboid proteases are evolutionary conserved intramembrane serine proteases. Because of their emerging role in many important biological pathways, rhomboids are potential drug targets. Unfortunately, few chemical tools are available for their study. Here, we describe a mass spectrometry-based assay to measure rhomboid substrate cleavage and inhibition. We have identified isocoumarin inhibitors and developed activity-based probes for rhomboid proteases. The probes can distinguish between active and inactive rhomboids due to covalent, reversible binding of the active-site serine and stable modification of a histidine residue. Finally, the structure of an isocoumarin-based inhibitor with Escherichia coli rhomboid GlpG uncovers an unusual mode of binding at the active site and suggests that the interactions between the 3-substituent on the isocoumarin inhibitor and hydrophobic residues on the protease reflect S′ subsite binding. Overall, these probes represent valuable tools for rhomboid study, and the structural insights may facilitate future inhibitor design.

‘Sulfo‐click’ for ligation as well as for site‐specific conjugation with peptides, fluorophores, and metal chelators

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

SYNTHESIS OF A NOVEL AMINO ACID BASED DENDRIMER

An easy accessible dendrimer monomer 3,5-bis(2-tert-butyloxycarbonyl aminoethoxy) benzoic acid methyl ester 1 was designed. The monomer was converted to both the “surface” and “braching” monomer in a versatile synthesis of a novel amino acid based dendrimer by the covergent method, using the well established and high-yielding BOP-peptide coupling method.

Convergent Synthesis and Diversity of Amino Acid Based Dendrimers

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

Molecular Diversity of Novel Amino Acid Based Dendrimers

Abstract We have expanded the recently introduced methodology for the preparation of a novel amino acid based dendrimer in order to be able to synthesize a diversity of dendrimers. For this purpose different hydroxybenzoic acids and amino alcohols were used to prepare the required monomers, necessary for construction of the respective dendrimers.

Synthesis and catalytic application of amino acid based dendritic macromolecules

The use of amino acid based dendrimers as molecular scaffolds for the attachment of catalytically active organometallic Ni “pincer” complexes, via a urea functionality, is described; the dendrimer catalysts have comparable activity to their mononuclear (NCN)NiX analogues.

Tweezers with Different Bite: Increasing the Affinity of Synthetic Receptors by Varying the Hinge Part

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

A practical solid phase synthesis of oligopeptidosulfonamide foldamers

Abstract Oligopeptidosulfonamide foldamers were efficiently synthesized on the solid phase using Fmoc protected β-aminoethanesulfonylchlorides in the presence of N -methylmorpholine.

Selective Inhibition of the Immunoproteasome by Ligand-Induced Crosslinking of the Active Site †

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