More than 100 hydrophobicity scales have been introduced, with each being based on ad istinct condensedphase approach.However,acomparison of the hydrophobicity values gained from different techniques,a nd their relative ranking,isnot straightforward, as the interactions between the environment and the amino acid are unique to each method. Here,weovercome this limitation by studying the properties of amino acids in the clean-room environment of the gas phase.In the gas phase,e ntropic contributions from the hydrophobic effect are by default absent and only the polarity of the side chain dictates the self-assembly.This allows for the derivation of an ovel hydrophobicity scale,w hichi sb ased solely on the interaction between individual amino acid units within the cluster and thus more accurately reflects the intrinsic nature of as ide chain. This principle can be further applied to classify non-natural derivatives,a ss hown here for fluorinated amino acid variants.The accurate determination of the intrinsic hydrophobicity of amino acids is crucial for understanding the key aspects of biology and the application of noncanonical amino acids in the rational design of peptides and proteins.M any fundamental biological processes such as the folding, [1] stability, [2] and oligomerization [3] of proteins as well as protein-ligand interactions [4] are strongly influenced by the hydrophobic effect in solution, where the entropically unfavored solvent shell around nonpolar residues is released to the bulk water. To date,m ore than 100 hydrophobicity scales [5] have been established, with most of them being derived from condensedphase methods such as water/octanol partitioning, [6] calculations of the accessible surface area, [7] direct measurements of physical properties, [8] and chromatographic techniques. [9]

α,α-Difluoro-benzyl phosphonates are currently the most popular class of phosphotyrosine mimetics. Structurally derived from the natural substrate phosphotyrosine, they constitute classical bioisosteres and have enabled the development of potent inhibitors of protein tyrosine phosphatases (PTP) and phosphotyrosine recognition sites such as SH2 domains. Being dianions bearing two negative charges, phosphonates, however, do not permeate membranes and thus are often inactive in cells and have not been a successful starting point toward therapeutics, yet. In this work, benzyl phosphonates were modified by replacing phosphorus-bound oxygen atoms with phosphorus-bound fluorine atoms. Surprisingly, mono-P-fluorophosphonates were fully stable under physiological conditions, thus enabling the investigation of their mode of action toward PTP. Three alternative scenarios were tested and mono-P-fluorophosphonates were identified as stable reversible PTP1B inhibitors, despite of the loss of one negative charge and the replacement of one oxygen atom as an H-bond donor by fluorine. In extending this replacement strategy, α,α-difluorobenzyl penta-P-fluorophosphates were synthesized and found to be novel phosphotyrosine mimetics with improved affinity to the phosphotyrosine binding site of PTP1B.

The flexible variation of peptidomimetics is of great interest for the identification of optimized protein ligands. Here we present a general concept for introducing side-chain modifications into peptides using triarylphosphonium amino acids. Building blocks 4a and 4b are activated for amidation and incorporated into stable peptides. The obtained phosphoranylidene peptides undergo Wittig olefinations and 1,3-dipolar cycloaddition reactions, yielding peptidomimetics with vinyl ketones and 5-substituted 1,2,3triazoles as non-native peptide side chains.

Phosphotyrosine residues are essential functional switches in health and disease. Thus, phosphotyrosine biomimetics are crucial for the development of chemical tools and drug molecules. We report here the discovery and investigation of pentafluorophosphato amino acids as novel phosphotyrosine biomimetics. A mild acidic pentafluorination protocol was developed and two PF 5 -amino acids were prepared and employed in peptide synthesis. Their structures, reactivities, and fluorine-specific interactions were studied by NMR and IR spectroscopy, X-ray diffraction, and in bioactivity assays. The mono-anionic PF 5 motif displayed an amphiphilic character binding to hydrophobic surfaces, to water molecules, and to protein-binding sites, exploiting charge and HÀ F-bonding interactions. The novel motifs bind 25-to 30-fold stronger to the phosphotyrosine binding site of the protein tyrosine phosphatase PTP1B than the best current biomimetics, as rationalized by computational methods, including molecular dynamics simulations.

Es existieren über 100 Hydrophobieskalen für Aminosäuren, die auf unterschiedlichen Ansätzen basieren und einheitlich in kondensierter Phase ermittelt werden. Ein Vergleichder Hydrophobiewerte aus verschiedenen Methoden und die Ermittlung ihrer relativen Rangfolge sind jedoch anspruchsvoll, da die Wechselwirkungen zwischen der Umgebung und der Aminosäure in jeder Methode spezifischs ind. Hier überwinden wir diese Einschränkung, indem wir die Eigenschaften von Aminosäuren in der Reinraumumgebung der Gasphase untersuchen. In der Gasphase bleiben standardmäßig entropische Beiträge des hydrophoben Effektes aus,u nd nur die Polaritätd er Seitenkette ist fürd ie Selbstorganisation entscheidend. Dies ermçglicht die Ableitung einer neuartigen Hydrophobieskala, die ausschließlich auf der Interaktion einzelner Aminosäureeinheiten innerhalb des Clusters basiert und somit die Eigenschaften der Seitenketten besser abbildet. Dieses Prinzip kann fürdie Klassifizierung von nicht-natürlichen Derivaten angewendet werden, wie hier fürf luorierte Aminosäurevarianten gezeigt ist.