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TEAD–YAP Interaction Inhibitors and MDM2 Binders from DNA-Encoded Indole-Focused Ugi Peptidomimetics
Verena B. K. Kunig Dr. Marco Potowski Dr. Mohammad Akbarzadeh Dr. Mateja Klika Škopić Denise dos Santos Smith Lukas Arendt Ina Dormuth Dr. Hélène Adihou Blaž Andlovic Dr. Hacer Karatas Shabnam Shaabani Tryfon Zarganes-Tzitzikas Prof. Dr. Constantinos G. Neochoritis Ran Zhang Prof. Dr. Matthew Groves Dr. Stéphanie M. Guéret Dr. Christian Ottmann Prof. Dr. Jörg Rahnenführer Prof. Dr. Roland Fried Prof. Dr. Alexander Dömling Dr. Andreas Brunschweiger 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(46):20518-20522
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 “hot spot”, regions of protein–protein 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 “hexT”, 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. 相似文献
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Zarganes-Tzitzikas T Terzidis MA Stephanidou-Stephanatou J Tsoleridis CA Kostakis GE 《The Journal of organic chemistry》2011,76(21):9008-9014
Another aspect concerning chromone chemistry leading to the one-pot synthesis of functionalized novel spirobenzofuranones has been described. The synthesis involves reaction of the zwitterionic intermediates formed by the 1:1 interaction between isocyanides and acetylenecarboxylates with 3-cyanochromones, whereupon through an unexpected and unprecedented reaction of the chromone moiety the isolated benzofuranones are formed. The regioselectivity of the reaction was investigated by DFT calculations. The geometries of the intermediates, transition structures, and intermediate products, leading to the final products, were optimized using the B3LYP functional with the 6-31G(d) basis set. The structures of the products were elucidated by 1D and 2D NMR experiments. Full assignment of all (1)H and (13)C NMR chemical shifts has been achieved. A plausible mechanistic rationale is proposed. 相似文献
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Shabnam Shaabani Louis Gadina Ewa Surmiak Zefeng Wang Bidong Zhang Roberto Butera Tryfon Zarganes-Tzitzikas Ismael Rodriguez Justyna Kocik-Krol Katarzyna Magiera-Mularz Lukasz Skalniak Alexander Dmling Tad A. Holak 《Molecules (Basel, Switzerland)》2022,27(11)
New biphenyl-based chimeric compounds containing pomalidomide were developed and evaluated for their activity to inhibit and degrade the programmed cell death-1/programmed cell death- ligand 1 (PD-1/PD-L1) complex. Most of the compounds displayed excellent inhibitory activity against PD-1/PD-L1, as assessed by the homogenous time-resolved fluorescence (HTRF) binding assay. Among them, compound 3 is one of the best with an IC50 value of 60 nM. Using an ex vivo PD-1/PD-L1 blockade cell line bioassay that expresses human PD-1 and PD-L1, we show that compounds 4 and 5 significantly restore the repressed immunity in this co-culture model. Western blot data, however, demonstrated that these anti-PD-L1/pomalidomide chimeras could not reduce the protein levels of PD-L1. 相似文献
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Tryfon Zarganes‐Tzitzikas Ajay L. Chandgude Alexander Dömling 《Chemical record (New York, N.Y.)》2015,15(5):981-996
Multicomponent reactions (MCRs), which are located between one‐ and two‐component and polymerization reactions, provide a number of valuable conceptual and synthetic advantages over stepwise sequential approaches towards complex and valuable molecules. To address current limitations in the number of MCRs and the resulting scaffolds, the concept of union of MCRs was introduced two decades ago by Dömling and Ugi and is rapidly advancing, as is apparent by several recently published works. MCR technology is now widely recognized for its impact on drug discovery projects and is strongly endorsed by industry in addition to academia. Clearly, novel scaffolds accessible in few steps including MCRs will further enhance the field of applications. Additionally, broad expansion of MCR applications in fields such as imaging, materials science, medical devices, agriculture, or futuristic applications in stem cell therapy and theragnostics or solar energy and superconductivity are predicted. 相似文献
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Domna Iordanidou Michael G. Kallitsakis Marina A. Tzani Dimitris I. Ioannou Tryfon Zarganes-Tzitzikas Constantinos G. Neochoritis Alexander Dmling Michael A. Terzidis Ioannis N. Lykakis 《Molecules (Basel, Switzerland)》2022,27(14)
The synthesis of 3,4-dihydroquinoxalin-2-ones via the selective reduction of aromatic, multifunctional nitro precursors catalyzed by supported gold nanoparticles is reported. The reaction proceeds through the in situ formation of the corresponding amines under heterogeneous transfer hydrogenation of the initial nitro compounds catalyzed by the commercially available Au/TiO2-Et3SiH catalytic system, followed by an intramolecular C-N transamidation upon treatment with silica acting as a mild acid. Under the present conditions, the Au/TiO2-TMDS system was also found to catalyze efficiently the present selective reduction process. Both transfer hydrogenation processes showed very good functional-group tolerance and were successfully applied to access more structurally demanding products bearing other reducible moieties such as chloro, aldehyde or methyl ketone. An easily scalable (up to 1 mmol), low catalyst loading (0.6 mol%) synthetic protocol was realized, providing access to this important scaffold. Under these mild catalytic conditions, the desired products were isolated in good to high yields and with a TON of 130. A library analysis was also performed to demonstrate the usefulness of our synthetic strategy and the physicochemical profile of the derivatives. 相似文献
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Zarganes-Tzitzikas T Neochoritis CG Stephanidou-Stephanatou J Tsoleridis CA 《The Journal of organic chemistry》2011,76(5):1468-1471
A new method for the synthesis of 2-aroyl-, 2-heteroaroyl-, and 2-cinnamoyl-substituted imidazoles in very good yields has been developed. The reaction employs novel nitrogen heterocyclic carbenes (NHCs), namely, N-arylamino-substituted NHCs, formed in situ from the corresponding imidazolium salts, and subsequent reaction with aromatic, heteroaromatic, and cinnamic aldehydes without utilizing transition metals or expensive specialized catalysts. 相似文献
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Markella Konstantinidou Tryfon Zarganes‐Tzitzikas Katarzyna Magiera‐Mularz Prof. Tad A. Holak Prof. Alexander Dömling 《Angewandte Chemie (International ed. in English)》2018,57(18):4840-4848
The PD‐1/PD‐L1 interaction has emerged as a significant target in cancer immunotherapy. Current medications include monoclonal antibodies, which have shown impressive clinical results in the treatment of several types of tumors. The cocrystal structure of human PD‐1 and PD‐L1 is expected to be a valuable starting point for the design of novel inhibitors, along with the recent crystal structures with monoclonal antibodies, small molecules, and macrocycles. 相似文献
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