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2-Oxo-1,2-ethylenedioxy (2-OED) functionality has been prepared on a soluble MPEG polymer and solid (HM resin and Lanterns) supports as platforms for discovery of drug-like small molecules. The functionality is cleaved either by Yb(OTf)3 or TMSCHN2 in MeOH, or by various amines to release small molecules synthesized on the platform in good yield. Application of these platforms aiming for discovery of potent agonists for growth hormone secretagogue is reported by using the Ugi four-component coupling reaction. 相似文献
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A highly diastereoselective Ugi reaction involving a chiral cyclic imine, two enantiomerically pure isocyanides and various carboxylic acids was employed for the synthesis of polyfunctionalized pyrrolidines. Both chiral substrates have been efficiently prepared by chemoenzymatic methodologies from readily available achiral substrates. This highly convergent approach can find an application in the fragment-based drug discovery process. 相似文献
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Niklas Gangloff Daniel Nahm Lisa Döring Dirk Kuckling Robert Luxenhofer 《Journal of polymer science. Part A, Polymer chemistry》2015,53(14):1680-1686
The highly modular Ugi four‐component reaction (Ugi‐4CR) was used to directly obtain polymers of high molar mass bearing aromatic residues in the backbone. By using at least two bifunctional monomers, the Ugi‐4CR can be employed to synthesize polymers through a polycondensation under mild conditions in the absence of catalysts. This highly versatile approach allows the creation of vast libraries of molecules by a comparably small pool of compounds. We investigated the six different possible types of the Ugi four‐component polymerization (Ugi‐4CP) to generate polyamides using commercially available monomers without further purification. After substantial adjustments of reaction parameters, we were able to obtain a polymer of high molar mass, albeit only for one out of the six types of the Ugi‐4CP. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 1680–1686 相似文献
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This article describes the synthesis of new peptomers through a simple and efficient route using a one-pot Ugi four-component reaction. The synthesis started from either carboxylic acids or protected amino acids, primary amines, aldehydes, and isocyanides in anhydrous methanol and proceeded under stirring at room temperature. The reaction produced several functionalized peptomers in good yields (67–80%). These compounds are versatile multifunctional intermediates that can be further unprotected or functionalized to generate new molecules with numerous applications in the field of biomedicine. 相似文献
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Parul Sahrawat Pawe Kowalczyk Dominik Koszelewski Mateusz Szymczak Karol Kramkowski Aleksandra Wypych Ryszard Ostaszewski 《Molecules (Basel, Switzerland)》2022,27(11)
An efficient method for the synthesis of functionalized peptidomimetics via multicomponent Ugi reaction has been developed. The application of trifluoroethanol (TFE) as a reaction medium provided desired products with good yields. Further, using the developed cyclisation reaction, the obtained peptidomimetics were transformed into the cyclic analogues (diketopiperazines, DKPs). The goal of the performed studies was to revised and compare whether the structure of the obtained structurally flexible acyclic peptidomimetics and their rigid cycling analogue DKPs affect antimicrobial activity. We studied the potential of synthesized peptidomimetics, both cyclic and acyclic, as antimicrobial drugs on model E. coli bacteria strains (k12, R2–R4). The biological assays reveal that DKPs hold more potential as antimicrobial drugs compared to open chain Ugi peptidomimetics. We believe that it can be due to the rigid cyclic structure of DKPs which promotes the membrane penetration in the cell of studied pathogens. The obtained data clearly indicate the high antibiotic potential of synthesized diketopiperazine derivatives over tested antibiotics. 相似文献
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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
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Karell Pérez-Labrada Edwin Flórez-LópezEvelyn Paz-Morales Luis D. Miranda Daniel G. Rivera 《Tetrahedron letters》2011,52(14):1635-1638
A two-step practical synthesis of dehydroalanine derivatives from commercially available starting materials is reported. The approach comprises an Ugi four-component reaction using 2-benzoylacetaldehyde, followed by an elimination process of the benzoate group. This protocol provided access to several dehydroalanine derivatives modified with diverse functional groups, which might be useful for further transformations in the construction of more complex molecules. 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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Tjøstil Vlaar Dr. Eelco Ruijter Prof. Dr. Bert U. W. Maes Prof. Dr. Romano V. A. Orru 《Angewandte Chemie (International ed. in English)》2013,52(28):7084-7097
Isocyanides have been important building blocks in organic synthesis since the discovery of the Ugi reaction and related isocyanide‐based multicomponent reactions. In the past decade isocyanides have found a new application as versatile C1 building blocks in palladium catalysis. Palladium‐catalyzed reactions involving isocyanide insertion offer a vast potential for the synthesis of nitrogen‐containing fine chemicals. This Minireview discusses all the achievements in this emerging field. 相似文献
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A novel ligand-free palladium-catalyzed cascade reaction for the synthesis of highly diverse isoquinolin-1(2H)-one derivatives from isocyanide and amide precursors synthesized by Ugi-MCR has been developed. A broad variety of acids, amines, and isocyanides were used as starting materials for Ugi-MCR leading to various amide precursors, which in turn provided entry into diverse isoquinolin-1(2H)-one derivatives. The reaction proceeds through tandem isocyanide insertion with intramolecular cyclization followed by a Mazurciewitcz-Ganesan type sequence to provide isoquinoline-1(2H)-one derivatives in moderate to good yields. 相似文献
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Dr. Anna Żądło‐Dobrowolska Dr. Szymon Kłossowski Dr. Dominik Koszelewski Daniel Paprocki Prof. Ryszard Ostaszewski 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(46):16684-16689
The application of the Ugi reaction to the construction of new peptide scaffolds is an important goal of organic chemistry. To date, there are no examples of the Ugi reaction being performed with a cyclic imine and amine simultaneously. The application of 2‐substituted cyclic imines in an enzymatic three‐component Ugi‐type reaction provides an elegant and attractive synthesis of substituted pyrrolidine and piperidine derivatives in up to 60 % yield. Results on studies of the selection of an enzyme, amount of water, and solvent used in a novel three‐component Ugi reaction and the limitations thereof are reported herein. The presented methodology exploiting enzyme promiscuity in the multicomponent reaction fulfills the requirements associated with green chemistry. Several methods, such as isotope labeling and enzyme inhibition, were used to probe the possible mechanism of this complex synthesis. This research is the first example of an enzyme‐catalyzed Ugi‐type reaction with an imine, amine, and isocyanide. 相似文献
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Federica Mancini Dr. M. Yagiz Unver Dr. Walid A. M. Elgaher Dr. Varsha R. Jumde Alaa Alhayek Dr. Peer Lukat Dr. Jennifer Herrmann Dr. Martin D. Witte Dr. Matthias Köck Prof. Dr. Wulf Blankenfeldt Prof. Dr. Rolf Müller Prof. Dr. Anna K. H. Hirsch 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(64):14585-14593
Kinetic target-guided synthesis represents an efficient hit-identification strategy, in which the protein assembles its own inhibitors from a pool of complementary building blocks via an irreversible reaction. Herein, we pioneered an in situ Ugi reaction for the identification of novel inhibitors of a model enzyme and binders for an important drug target, namely, the aspartic protease endothiapepsin and the bacterial β-sliding clamp DnaN, respectively. Highly sensitive mass-spectrometry methods enabled monitoring of the protein-templated reaction of four complementary reaction partners, which occurred in a background-free manner for endothiapepsin or with a clear amplification of two binders in the presence of DnaN. The Ugi products we identified show low micromolar activity on endothiapepsin or moderate affinity for the β-sliding clamp. We succeeded in expanding the portfolio of chemical reactions and biological targets and demonstrated the efficiency and sensitivity of this approach, which can find application on any drug target. 相似文献
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Diversity-oriented organic synthesis (DOS) is a key concept for construction of skeletally diverse small molecule libraries to discover drug-like small molecules. Here, we describe a DOS class to transform a complex 7-oxanorbornene skeleton, which is readily accessible by a tandem Ugi/Diels-Alder reaction, into two heterotricycle skeletons selectively by using tandem ROM/CM/RCM reaction. In the present study, the mode of cyclization is pre-encoded by building blocks used in the complexity-generating tandem Ugi/Diels-Alder reaction. Since variable alkenes can be used in the CM reaction, our approach can be extended to construct both skeleton- and appendage-diverse small molecule libraries. 相似文献
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Ting Zhao Katarzyna Kurpiewska Justyna Kalinowska‐Tłuścik Eberhardt Herdtweck Prof. Dr. Alexander Dömling 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(9):3009-3018
The synthesis of all 20 common natural proteinogenic and 4 otherα‐amino acid‐isosteric α‐amino tetrazoles has been accomplished, whereby the carboxyl group is replaced by the isosteric 5‐tetrazolyl group. The short process involves the use of the key Ugi tetrazole reaction followed by deprotection chemistries. The tetrazole group is bioisosteric to the carboxylic acid and is widely used in medicinal chemistry and drug design. Surprisingly, several of the common α‐amino acid‐isosteric α‐amino tetrazoles are unknown up to now. Therefore a rapid synthetic access to this compound class and non‐natural derivatives is of high interest to advance the field. 相似文献
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Jiraborrirak Charoenpattarapreeda Dr. Stephen J. Walsh Prof. Dr. Jason S. Carroll Prof. Dr. David R. Spring 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(51):23245-23250
Hemiasterlin is an antimitotic marine natural product with reported sub-nanomolar potency against several cancer cell lines. Herein, we describe an expeditious total synthesis of hemiasterlin featuring a four-component Ugi reaction (Ugi-4CR) as the key step. The convergent synthetic strategy enabled rapid access to taltobulin (HTI-286), a similarly potent synthetic analogue. This short synthetic sequence enabled investigation of both hemiasterlin and taltobulin as cytotoxic payloads in antibody–drug conjugates (ADCs). These novel ADCs displayed sub-nanomolar cytotoxicity against HER2-expressing cancer cells, while showing no activity against antigen-negative cells. This study demonstrates an improved synthetic route to a highly valuable natural product, facilitating further investigation of hemiasterlin and its analogues as potential payloads in targeted therapeutics. 相似文献
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Zepeng He Zhicheng Le Dr. Yi Shi Dr. Lixin Liu Dr. Zhijia Liu Dr. Yongming Chen 《Angewandte Chemie (International ed. in English)》2023,62(43):e202310401
The development of lipid nanoparticles (LNPs) has enabled a successful clinical application of mRNA vaccines. However, disclosure of design principles for the core component-ionizable lipids (ILs), improving the delivery efficacy and organ targeting of LNPs, remains a formidable challenge. Herein, we report a powerful strategy to modulate ILs in one-step chemistry using the Ugi four-component reaction (Ugi-4CR) under mild conditions. A large IL library of new structures was established simply and efficiently through a multidimensional approach, allowing us to identify the top-performing ILs in delivering mRNA via the formulated LNPs. Adjusting the skeleton of ILs has transformed the organ-specific and robust transfection in mRNA delivery from the liver to the spleen following different administration routes. Of note, a series of isomeric ILs were prepared and we found that the isomers mattered greatly in the performance of LNPs for mRNA delivery. Furthermore, owing to the bis-amide bonds formed in the Ugi-4CR reaction, the ILs within LNPs may form hydrogen bonding intermolecularly, facilitating the colloidal stabilization of LNPs. This work provides clues to the rapid discovery and rational design of IL candidates, assisting the application of mRNA therapeutics. 相似文献
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Yan A 《Combinatorial chemistry & high throughput screening》2006,9(6):473-480
In the computer-aided drug design, in order to find some new leads from a large library of compounds, the pattern recognition study of the diversity and similarity assessment of the chemical compounds is required; meanwhile in the combinatorial library design, more attention is given to design target focusing library along with diversity and drug-likeness criteria. This review presents the current state-of-art applications of Kohonen self-organizing maps (SOM) for studying the compounds pattern recognition, comparing the property of molecular surfaces, distinguishing drug-like and nondrug-like molecules, splitting a dataset into the proper training and test sets before constructing a QSAR (Quantitative Structural-Activity Relationship) model, and also for the combinatorial libraries comparison and the combinatorial library design. The Kohonen self-organizing map will continue to play an important role in drug discovery and library design. 相似文献
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Biocatalysis has become an important method in the pharmaceutical industry for the incorporation of new functionality in small molecules. Currently this method is limited in the types of reactions that can be carried out and no strategy exists to systematically screen for new biocatalyzed reactions. This study involves the development of a medium throughput screen to identify and optimize new reactions using a series of marine-derived bacterial cell lines, which were screened against several (13)C labeled organic substrates. The reactions were analyzed using (13)C NMR as the primary screening tool. We describe the discovery of a bacterial catalyzed indole oxidation reaction in which complete conversion of (13)C labeled N-methyl indole to 3-hydroxyindole was observed. In addition, the sensitivity of this reaction to dO(2) levels can be exploited to oxidize to either 3-hydroxyindole or 2-oxoindole. This new platform sets up an important tool for the discovery of new organic transformations using an extensive library of marine bacteria. 相似文献