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1.
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
2.
Fragment‐Based Drug Design Facilitated by Protein‐Templated Click Chemistry: Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin
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Dr. Milon Mondal M. Yagiz Unver Dr. Asish Pal Matthijs Bakker Stephan P. Berrier Prof. Dr. Anna K. H. Hirsch 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(42):14826-14830
There is an urgent need for the development of efficient methodologies that accelerate drug discovery. We demonstrate that the strategic combination of fragment linking/optimization and protein‐templated click chemistry is an efficient and powerful method that accelerates the hit‐identification process for the aspartic protease endothiapepsin. The best binder, which inhibits endothiapepsin with an IC50 value of 43 μm , represents the first example of triazole‐based inhibitors of endothiapepsin. Our strategy could find application on a whole range of drug targets. 相似文献
3.
Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin: Fragment‐Based Drug Design Facilitated by Dynamic Combinatorial Chemistry
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Dr. Milon Mondal Nedyalka Radeva Dr. Hugo Fanlo‐Virgós Prof. Dr. Sijbren Otto Prof. Dr. Gerhard Klebe Prof. Dr. Anna K. H. Hirsch 《Angewandte Chemie (International ed. in English)》2016,55(32):9422-9426
Fragment‐based drug design (FBDD) affords active compounds for biological targets. While there are numerous reports on FBDD by fragment growing/optimization, fragment linking has rarely been reported. Dynamic combinatorial chemistry (DCC) has become a powerful hit‐identification strategy for biological targets. We report the synergistic combination of fragment linking and DCC to identify inhibitors of the aspartic protease endothiapepsin. Based on X‐ray crystal structures of endothiapepsin in complex with fragments, we designed a library of bis‐acylhydrazones and used DCC to identify potent inhibitors. The most potent inhibitor exhibits an IC50 value of 54 nm , which represents a 240‐fold improvement in potency compared to the parent hits. Subsequent X‐ray crystallography validated the predicted binding mode, thus demonstrating the efficiency of the combination of fragment linking and DCC as a hit‐identification strategy. This approach could be applied to a range of biological targets, and holds the potential to facilitate hit‐to‐lead optimization. 相似文献
4.
M. Sc. Manuel G. Ricardo M. Sc. Celia G. Moya Prof. Dr. Carlos S. Pérez Dr. Andrea Porzel Prof. Dr. Ludger A. Wessjohann Prof. Dr. Daniel G. Rivera 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(1):265-269
In contrast to the myriad of methods available to produce α-helices and antiparallel β-sheets in synthetic peptides, just a few are known for the construction of stable, non-cyclic parallel β-sheets. Herein, we report an efficient on-resin approach for the assembly of parallel β-sheet peptides in which the N-alkylated turn moiety enhances the stability and gives access to a variety of functionalizations without modifying the parallel strands. The key synthetic step of this strategy is the multicomponent construction of an N-alkylated turn using the Ugi reaction on varied isocyano-resins. This four-component process assembles the orthogonally protected turn fragment and incorporates handles serving for labeling/conjugation purposes or for reducing peptide aggregation. NMR and circular dichroism analyses confirm the better-structured and more stable parallel β-sheets in the N-alkylated peptides compared to the non-functionalized variants. 相似文献
5.
《印度化学会志》2021,98(8):100106
Multi-drug resistant (MDR) forms of several bacteria, fungi, viruses, and parasites pose a serious challenge to human health and economy. Hence, the rise of antimicrobial resistance (AMR) requires the expedient discovery of novel antimicrobial agents with a unique mode of action. Ugi multicomponent reaction (Ugi-MCR) and its variants have proved to be an important tool in the hand of a medicinal chemist. Traditional Ugi reaction provides one-step access to peptide-like molecules. However, several modifications of Ugi products are now available, enabling the design of diverse molecular scaffolds. This has tremendously expanded the scope of Ugi-MCR in drug discovery. This review focuses on the recently reported application of Ugi reaction in the design of molecules against important pathogenic microbes and parasites. The design, synthesis, and bioactivities of important lead molecules from the literature is discussed. Towards the end, we also provide our perspective highlighting the overall trends in Ugi-MCR enabled antimicrobial drug design and future prospects. 相似文献
6.
Structure‐Based Design of Inhibitors of the Aspartic Protease Endothiapepsin by Exploiting Dynamic Combinatorial Chemistry
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Milon Mondal Nedyalka Radeva Dr. Helene Köster Dr. Ahyoung Park Dr. Constantinos Potamitis Dr. Maria Zervou Prof. Dr. Gerhard Klebe Dr. Anna K. H. Hirsch 《Angewandte Chemie (International ed. in English)》2014,53(12):3259-3263
Structure‐based design (SBD) can be used for the design and/or optimization of new inhibitors for a biological target. Whereas de novo SBD is rarely used, most reports on SBD are dealing with the optimization of an initial hit. Dynamic combinatorial chemistry (DCC) has emerged as a powerful strategy to identify bioactive ligands given that it enables the target to direct the synthesis of its strongest binder. We have designed a library of potential inhibitors (acylhydrazones) generated from five aldehydes and five hydrazides and used DCC to identify the best binder(s). After addition of the aspartic protease endothiapepsin, we characterized the protein‐bound library member(s) by saturation‐transfer difference NMR spectroscopy. Cocrystallization experiments validated the predicted binding mode of the two most potent inhibitors, thus demonstrating that the combination of de novo SBD and DCC constitutes an efficient starting point for hit identification and optimization. 相似文献
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Judith Hoffmann Prof. Dr. Uli Kazmaier 《Angewandte Chemie (International ed. in English)》2014,53(42):11356-11360
The development of a new photolabile protecting group containing an additional allyl functionality allows the synthesis of cyclic photoactivatable natural products. Cyclization occurs between the allyl moiety in the protecting group and a second double bond in the target molecule by means of ring‐closing metathesis. Cyclization should increase the metabolic stability towards proteases. On the other hand, the conformational change should cause diminished biological activity. As illustrated for tubulysin derivatives, cyclic and photoactivatable drug candidates can easily be obtained in only two steps from simple building blocks through Ugi reaction and ring‐closing metathesis. The photolabile protecting group is introduced by means of the isocyanide component during the Ugi reaction. 相似文献
9.
Tracing Binding Modes in Hit‐to‐Lead Optimization: Chameleon‐Like Poses of Aspartic Protease Inhibitors
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Maren Kuhnert Dr. Helene Köster Dr. Ruben Bartholomäus Dr. Ah Young Park Amir Shahim Prof. Dr. Andreas Heine Dr. Holger Steuber Prof. Dr. Gerhard Klebe Prof. Dr. Wibke E. Diederich 《Angewandte Chemie (International ed. in English)》2015,54(9):2849-2853
Successful lead optimization in structure‐based drug discovery depends on the correct deduction and interpretation of the underlying structure–activity relationships (SAR) to facilitate efficient decision‐making on the next candidates to be synthesized. Consequently, the question arises, how frequently a binding mode (re)‐validation is required, to ensure not to be misled by invalid assumptions on the binding geometry. We present an example in which minor chemical modifications within one inhibitor series lead to surprisingly different binding modes. X‐ray structure determination of eight inhibitors derived from one core scaffold resulted in four different binding modes in the aspartic protease endothiapepsin, a well‐established surrogate for e.g. renin and β‐secretase. In addition, we suggest an empirical metrics that might serve as an indicator during lead optimization to qualify compounds as candidates for structural revalidation. 相似文献
10.
Dr. Erich Michel Prof. Andreas Plückthun Prof. Oliver Zerbe 《Angewandte Chemie (International ed. in English)》2018,57(17):4576-4579
Herein, we present the peptide‐guided assembly of complementary fragments of designed armadillo repeat proteins (dArmRPs) to create proteins that bind peptides not only with high affinity but also with good selectivity. We recently demonstrated that complementary N‐ and C‐terminal fragments of dArmRPs form high‐affinity complexes that resemble the structure of the full‐length protein, and that these complexes bind their target peptides. We now demonstrate that dArmRPs can be split such that the fragments assemble only in the presence of a templating peptide, and that fragment mixtures enrich the combination with the highest affinity for this peptide. The enriched fragment combination discriminates single amino acid variations in the target peptide with high specificity. Our results suggest novel opportunities for the generation of new peptide binders by selection from dArmRP fragment mixtures. 相似文献
11.
We functionalized aligned carbon nanotubes (ACNTs) electrode with a new kind of β-cyclodextrin (β-CD) derivative through diazotization reaction. The resulting β-CD/ACNTs electrode was used to detect DNA hybridization in homogeneous solution based on host–guest recognition technology. In the sensing protocol, one special DNA probe was designed with a stem-loop structure and both ends modified, which we called dually labeled DNA probe (DLP). One end of the DLP was labeled with dabcyl as guest molecule for β-CD/ACNTs electrode capture, and the other end was labeled with a CdS nanoparticle as an electrochemical tag to indicate the occurrence of DNA hybridization. In the absence of the target DNA sequence, the DLP maintains its hairpin structure in solution phase and would not be captured and detected by the β-CD/ACNTs electrode. In the presence of the complementary target sequence, the conformational structure of the DLP was altered and a double-stranded DNA (dsDNA) molecule was formed by the hybridization of DLP and complementary DNA sequence. Consequently, the dsDNA was captured by the β-CD/ACNTs electrode owing to guest–host recognition between β-CD and dabcyl. The electrochemical signal from the CdS nanoparticle–dsDNA/β-CD/ACNTs was then measured. Under optimized detection conditions, the proposed method showed high sensitivity and selectivity with a detection limit of 5.0 × 10−13 M for complementary DNA sequence. 相似文献
12.
Development of a stereoselective Ugi reaction starting from an oxanorbornene β-amino acid derivative
Banfi L Basso A Chiappe C De Moliner F Riva R Sonaglia L 《Organic & biomolecular chemistry》2012,10(19):3819-3829
We have synthesised a novel oxanorbornene β-aminoacid derivative and employed it in a stereoselective Ugi reaction. Hypothesis regarding the mechanism taking place during the reaction have been made and validated through the determination of the relative and absolute configuration of the Ugi adducts. Use of the correct choice of solvents can increase stereoselection. The resulting bicyclic peptidomimetics can be used as a novel class of pluripotent substrates to be elaborated according to the synthetic strategies previously elaborated in our laboratories. 相似文献
13.
Valentine G. Nenajdenko Alexander L. Reznichenko Elizabeth S. Balenkova 《Tetrahedron》2007,63(14):3031-3041
The three-component Ugi reaction with chiral 2-(2-formyl-1H-pyrrol-1-yl)acetic acids prepared from natural l-aminoacids was investigated. The reaction opens a new route to chiral substituted pyrroloketopiperazines. One of the first examples of an asymmetric Ugi reaction without chiral amines is described. The reaction proceeds with moderate diastereoselectivity to give the target compounds in good yields. The scope and limitation of the approach are discussed. 相似文献
14.
Nádia R. Aguiam Vânia I. CastroAna I.F. Ribeiro Rui D.V. FernandesCarina M. Carvalho Susana P.G. CostaSílvia M.M.A. Pereira-Lima 《Tetrahedron》2013
The multicomponent Ugi reaction is a straightforward method that can be used for the synthesis of highly hindered C-tetrasubstituted amino acids by reacting an amine, a ketone or aldehyde, a carboxylic acid and an isocyanide. In the present work, the synthesis of several α,α-dialkylglycines (α,α-diethylglycine, Deg; α,α-dipropylglycine, Dpg; 1-amino-1-cyclohexanecarboxylic acid, Ac6c) was achieved by solid phase Ugi reaction using resins functionalized with the isocyanide group. Since no resins with these features were available commercially, the functionalization of an aminomethylated resin started by the use of glycine (Gly), β-alanine (β-Ala) and γ-aminobutyric acid (GABA) as spacers. After spacer N-formylation, followed by dehydration, isocyanide functionalised resins were obtained. The resins were then used in solid phase Ugi reaction, using phenylacetic acid as the acid component, 4-methoxybenzylamine as the amine component and different ketones, to afford the desired N-acylated α,α-dialkylglycines in good overall yields (60–80%), after acidolytic cleavage from the resin, thus proving the feasibility of this approach. 相似文献
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16.
总结了我们课题组应用膦亚胺叶立德的氮杂Wittig反应合成氮杂环的研究工作.我们发展了一种应用α-酯基膦亚胺与异氰酸酯(或二硫化碳)、亲核试剂的连续成环反应,合成咪唑啉酮及唑类杂环的新方法.应用β-酯基膦亚胺与异氰酸酯(或二硫化碳)、亲核试剂的连续成环反应,则可制备(稠合的)喹唑啉酮和嘧啶酮类杂环.而应用β-炔基膦亚胺与异氰酸酯、亲核试剂在银离子催化下的连续成环反应,可得到吲哚类杂环.最近我们课题组又初步将膦亚胺叶立德应用于串联的Ugi和Passerini后修饰反应中,合成了多取代苯并嗪和喹唑啉类杂环化合物. 相似文献
17.
Charlotte Sornay Steve Hessmann Stéphane Erb Dr. Igor Dovgan Anthony Ehkirch Thomas Botzanowski Dr. Sarah Cianférani Dr. Alain Wagner Dr. Guilhem Chaubet 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(61):13797-13805
Site-selective modification of proteins has been the object of intense studies over the past decades, especially in the therapeutic field. Prominent results have been obtained with recombinant proteins, for which site-specific conjugation is made possible by the incorporation of particular amino acid residues or peptide sequences. In parallel, methods for the site-selective and site-specific conjugation of native and natural proteins are starting to thrive, allowing the controlled functionalization of various types of amino acid residues. Pursuing the efforts in this field, we planned to develop a new type of site-selective method, aiming at the simultaneous conjugation of two amino acid residues. We reasoned that this should give higher chances of developing a site-selective strategy compared to the great majority of existing methods that solely target a single residue. We opted for the Ugi four-centre three-component reaction to implement this idea, with the aim of conjugating the side-chain amine and carboxylate groups of two neighbouring lysine and aspartate/glutamate. Herein, we show that this strategy can give access to valuable antibody conjugates bearing several different payloads; furthermore, the approach limits the potential conjugation sites to only six on the model antibody trastuzumab. 相似文献
18.
Efficient Synthesis of Conformationally Restricted Apoptosis Inhibitors Bearing a Triazole Moiety
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Dr. Miriam Corredor Dr. Maria Garrido Dr. Jordi Bujons Dr. Mar Orzáez Prof. Enrique Pérez‐Payá Dr. Ignacio Alfonso Prof. Angel Messeguer 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(40):14122-14128
Apoptosis is a biological process relevant to different human diseases that is regulated through protein–protein interactions and complex formation. Peptidomimetic compounds based on linear peptoids and cyclic analogues with different ring sizes have been previously reported as potent apoptotic inhibitors. Among them, the presence of cis/trans conformers of an exocyclic tertiary amide bond in slow exchange has been characterized. This information encouraged us to perform an isosteric replacement of the amide bond by a 1,2,3‐triazole moiety, in which different substitution patterns would mimic different amide rotamers. The syntheses of these restricted analogues have been carried out through an Ugi multicomponent reaction followed by an intramolecular cyclization. The unexpected formation of a β‐lactam scaffold prompted us to study the course of the intramolecular cyclization of the Ugi adducts. In order to modulate this cyclization, a small library of compounds bearing both heterocyclic scaffolds has been synthesized and their activities as apoptosis inhibitors have been evaluated. 相似文献
19.
The combination of consecutive Isocyanide-based Multicomponent Reactions (IMCRs) allowed the synthesis of a cyclic heptapeptoid in a reduced number of steps. Herein, we describe this efficient approach using four consecutive Ugi reactions, being three Ugi four-center, four-component reactions, and one Ugi four-center, three-component reaction. Our strategy involved eight steps of which seven in a row were microwave-assisted with reaction times of 3–5?min and yields ranging from 88 to 98%. 相似文献
20.
MCC/SNAr methodology. Part 2: Novel three-step solution phase access to libraries of benzodiazepines
New developments in the search for novel pharmacological agents over the last decade have focused on the preparation of chemical libraries as sources for new leads for drug discovery. To aid this search a plethora of personal synthesizers and new automation technologies have emerged to help fuel the lead discovery engines of drug discovery organizations. In fact, multi-step solid-phase syntheses of diverse libraries in excess of 10,000 products are now feasible via split and mix techniques. At the same time, a multitude of more efficient, diversity or target oriented solution phase chemical methodologies have appeared in the chemical literature, which have enabled the relatively facile construction of successful lead generation libraries with low FTE input and little capital expenditure. This communication reveals a further application of N-BOC-α-aminoaldehydes in the Ugi condensation reaction, followed by a secondary SNAr cyclization, accessing arrays of biologically relevant benzodiazepines in good yield and overall purity. 相似文献