25 research outputs found
Darstellung und Charakterisierung von Uracil- und Adeninnucleotid-Mimetika als selektive Ectonucleotidase-Inhibitoren
Das Ziel der vorliegenden Arbeit war die Synthese von Uridin- und Adenosin-5'-Amiden. Ăber diese Amidbindung tragen die Nucleoside verschiedene Dipeptide und phosphonoanaloge Dipeptide als Phosphatmimetika. Die neu dargestellten Substanzen wurden im Arbeitskreis auf AffinitĂ€t zu P2-Nucleotid-Rezeptoren und Inhibitionspotential an Nucleotid-metabolisierenden Ectonucleotidasen (E-NTPDasen1,2,3,8 und Ecto-5'-Nucleotidase) getestet. Die metabolische StabilitĂ€t ausgewĂ€hlter Verbindungen wurde in kĂŒnstlichem Magensaft und durch Inkubation mit Rattenlebermikrosomen untersucht. Es konnten selektive Inhibitoren der humanen NTPDase1 und 2, sowie der Ratten-Ecto-5'-Nucleotidase gefunden werden. Sie besaĂen keine AffinitĂ€t zu P2-Nucleotid-Rezeptoren. Die Inhibitoren der NTPDase2 erwiesen sich als metabolisch sehr stabil
Reaction optimization of a SuzukiâMiyaura crossâcoupling using design of experiments
The combination of lab automation and design of experiments for the execution of screening experiments increases productivity and reduces error-prone manual work. A self-developed software tool allows for creating fractional-factorial experimental design (FFED). Application of FFED on the screening of a Suzuki-Miyaura cross-coupling leads to a 93â% reduced design compared to full-factorial design. The resulting regression model qualitatively shows the positive effect of educt concentrations, time, and temperature and reveals the decrease in conversion at high base concentrations
Isocyanide Multicomponent Reactions on Solid-Phase-Coupled DNA Oligonucleotides for Encoded Library Synthesis
Isocyanide multicomponent reactions play a prominent role in drug discovery. This chemistry has hardly been investigated for compatibility with DNA-encoded combinatorial synthesis. The Ugi, Ugi-azide, and Groebke-Blackburn-Bienaymé reactions are well-tolerated by DNA on the solid phase and show a broad scope. However, an oxadiazole-forming variant of the Ugi reaction caused DNA depurination, requiring a more stable hexathymidine DNA for encoded library synthesis. Cheminformatic analysis revealed that isocyanide multicomponent-reaction-based encoded libraries cover a diverse chemical space
Scanning protein surfaces with DNA-encoded libraries
Understanding the ligandability of a target protein, defined as the capability of a protein to bind drug-like compounds on any site, can give important stimuli to drug-development projects. For instance, inhibition of proteinâprotein interactions usually depends on the identification of protein surface binders. DNA-encoded chemical libraries (DELs) allow scanning of protein surfaces with large chemical space. Encoded library selection screens uncovered several proteinâprotein interaction inhibitors and compounds binding to the surface of Gâ
protein-coupled receptors (GPCRs) and kinases. The protein surface-binding chemotypes from DELs are predominantly chemically modified and cyclized peptides, and functional small-molecule peptidomimetics. Peptoid libraries and structural peptidomimetics have been less studied in the DEL field, hinting at hitherto less populated chemical space and suggesting alternative library designs. Roughly a third of bioactive molecules evolved from smaller, target-focused libraries. They showcase the potential of encoded libraries to identify more potent molecules from weak, for example, fragment-like, starting points
Development of a two-phase flow reaction system for DNA-encoded amide coupling
Synthesis platforms are of particular interest to DNA-encoded library (DEL) technologies to facilitate chemistry development, building block validation, and high-throughput library synthesis. A liquidâliquid two-phase flow reactor was designed that enables parallel conduction of reactions on DNA-coupled substrates. The dispersed phase in capillary slug flow contained the DNA reaction mixture and allowed for spatially separated batch experiments in a microchannel. A coiled flow inverter (CFI) tubular reactor with a 3D-printed internal structure on which a capillary is coiled was used for improved mixing and compact setup. An inert continuous phase was introduced, which generated slug flow and prevented backmixing of the individual reactants. In order to enable parallelized reactions, slugs containing a variety of different carboxylic acids were successfully generated to act as individual reaction compartments representing single batch experiments. As a widely used exemplary DEL reaction, the amide coupling reaction was successfully transferred to the tailored flow reaction system and DNA was recovered
Chemically stabilized DNA barcodes for DNA-encoded chemistry
DNA-encoded compound libraries are a widely used small molecule screening technology. One important aim in library design is the coverage of chemical space through structurally diverse molecules. Yet, the chemical reactivity of native DNA barcodes limits the toolbox of reactions for library design. Substituting the chemically vulnerable purines by 7-deazaadenine, which exhibits tautomerization stability similar to natural adenine with respect to the formation of stable WatsonâCrick pairs, yielded ligation-competent, amplifiable, and readable DNA barcodes for encoded chemistry with enhanced stability against protic acid- and metal ion-promoted depurination. The barcode stability allowed for straightforward translation of 16 exemplary reactions that included isocyanide multicomponent reactions, acid-promoted PictetâSpengler and Biginelli reactions, and metal-promoted pyrazole syntheses on controlled pore glass-coupled barcodes for diverse DEL design. The Boc protective group of reaction products offered a convenient handle for encoded compound purification
Towards DNA-encoded micellar chemistry: DNA-micelle association and environment sensitivity of catalysis
The development of DNA-compatible reaction methodologies is a central theme to advance DNA-encoded screening library technology. Recently, we were able to show that sulfonic acid-functionalized block copolymer micelles facilitated BrĂžnsted acid-promoted reactions such as the Povarov reaction on DNA-coupled starting materials with minimal DNA degradation. Here, the impact of polymer composition on micelle shape, and reaction conversion was investigated. A dozen sulfonic acid-functionalized block copolymers of different molar mass and composition were prepared by RAFT polymerization and were tested in the Povarov reaction, removal of the Boc protective group, and the Biginelli reaction. The results showed trends in the polymer structure-micellar catalytic activity relationship. For instance, micelles composed of block copolymers with shorter acrylate ester chains formed smaller particles and tended to provide faster reaction kinetics. Moreover, fluorescence quenching experiments as well as circular dichroism spectroscopy showed that DNA-oligomer-conjugates, although highly water-soluble, accumulated very effectively in the micellar compartments, which is a prerequisite for carrying out a DNA-encoded reaction in the presence of polymer micelles
TEAD-YAP interaction inhibitors and MDM2 binders from DNA-encoded indole-focused Ugi-peptidomimetics
DNA-encoded combinatorial synthesis provides efficient and dense coverage of chemical space around privileged molecular structures. The indole side chain of tryptophan plays a prominent role in key, or âhot spotâ, regions of proteinâprotein interactions. A DNA-encoded combinatorial peptoid library was designed based on the Ugi four-component reaction by employing tryptophan-mimetic indole side chains to probe the surface of target proteins. Several peptoids were synthesized on a chemically stable hexathymidine adapter oligonucleotide âhexTâ, encoded by DNA sequences, and substituted by azide-alkyne cycloaddition to yield a library of 8112 molecules. Selection experiments for the tumor-relevant proteins MDM2 and TEAD4 yielded MDM2 binders and a novel class of TEAD-YAP interaction inhibitors that perturbed the expression of a gene under the control of these Hippo pathway effectors
TEAD-YAP Interaction Inhibitors and MDM2 Binders from DNA-Encoded Indole-Focused Ugi Peptidomimetics
DNA-encoded combinatorial synthesis provides efficient and dense coverage of chemical space around privileged molecular structures. The indole side chain of tryptophan plays a prominent role in key, or âhot spotâ, regions of proteinâprotein interactions. A DNA-encoded combinatorial peptoid library was designed based on the Ugi four-component reaction by employing tryptophan-mimetic indole side chains to probe the surface of target proteins. Several peptoids were synthesized on a chemically stable hexathymidine adapter oligonucleotide âhexTâ, encoded by DNA sequences, and substituted by azide-alkyne cycloaddition to yield a library of 8112 molecules. Selection experiments for the tumor-relevant proteins MDM2 and TEAD4 yielded MDM2 binders and a novel class of TEAD-YAP interaction inhibitors that perturbed the expression of a gene under the control of these Hippo pathway effectors
Probing Substituents in the 1- and 3-Position: Tetrahydropyrazino-Annelated Water-Soluble Xanthine Derivatives as Multi-Target Drugs With Potent Adenosine Receptor Antagonistic Activity
Tetrahydropyrazino-annelated theophylline (1,3-dimethylxanthine) derivatives have previously been shown to display increased water-solubility as compared to the parent xanthines due to their basic character. In the present study, we modified this promising scaffold by replacing the 1,3-dimethyl residues by a variety of alkyl groups including combinations of different substituents in both positions. Substituted benzyl or phenethyl residues were attached to the N8 of the resulting 1,3-dialkyl-tetrahydropyrazino[2,1-f ]purinediones with the aim to obtain multi-target drugs that block human A1 and A2A adenosine receptors (ARs) and monoaminoxidase B (MAO-B). 1,3-Diethyl-substituted derivatives showed high affinity for A1 ARs, e.g., 15d (PSB-18339, 8-m-bromobenzyl-substituted) displayed a Ki value of 13.6 nM combined with high selectivity. 1-Ethyl-3-propargyl-substituted derivatives exhibited increased A2A AR affinity. The 8-phenethyl derivative 20h was selective for the A2A AR (Ki 149 nM), while the corresponding 8-benzyl-substituted compound 20e (PSB-1869) blocked A1 and A2A ARs with equal potency (Ki A1, 180 nM; A2A, 282 nM). The 1-ethyl-3-methyl-substituted derivative 16a (PSB-18405) bearing a m,p-dichlorobenzyl residue at N8 blocked all three targets, A1 ARs (Ki 396 nM), A2A ARs (Ki 1,620 nM), and MAO-B (IC50 106 nM) with high selectivity vs. the other subtypes (A2B and A3 ARs, MAO-A), and can thus be considered as a multi-target drug. Our findings were rationalized by molecular docking studies based on previously published X-ray structures of the protein targets. The new drugs have potential for the treatment of neurodegenerative diseases, in particular Parkinson's disease