New Cytotoxic α-Aminoacylamide and bis-1,5-Disubstituted Tetrazole Adducts From Amino-Diterpene Molecules by Ugi Reaction.

In search for new molecules of diterpene origin with promising anticancer activity, two amino-derivatives (methyl maleopimarate aminoimide and methyl 1ß,13-epoxydihydroquinopimarate C4-hydrazone) were involved in the 4-component Ugi reaction (Ugi-4CR) and pseudo-7-component azido-Ugi condensation (azido-Ugi-7CR) to afford a series of adducts holding α-aminoacylamide and bis-1,5-disubstituted tetrazole substituents. The NCI-60 cancer cell panel screening revealed diterpene-type Ugi adducts 2, 5, and 6 with strong antiproliferative potency with GI50 in range of 1.2-15.4 µM. The high positive correlations with standard anticancer drugs suggest microtubules or progesterone and androgen receptors as possible targets of the synthesized compounds.

Loading Lewis Acid/Base Pair on Metal Nanocluster for Catalytic Ugi Reaction.

Constructing structurally robust and catalytically active metal nanoclusters for catalyzing multi-component reactions is an interesting while challenging task. Inspired by Lewis acid and Lewis base catalysis, we realized the combination of both Lewis acid and Lewis base sites on the surface of a stable gold nanocluster Au35Cd2. The catalytic potential of Au35Cd2 in four-component Ugi reaction was explored, demonstrating high activity and exceptional recyclability. In-depth mechanism studies indicate that the catalytic synergy of the Lewis acid/base pair is crucial for the high efficiency of Au35Cd2-catalyzed Ugi reaction. Bearing the stable structure, multiple activation sites and hierarchical chirality, Au35Cd2 is expected to display further interesting catalytic performance such as asymmetric catalysis.

Derivatization of Abietane Acids by Peptide-like Substituents Leads to Submicromolar Cytotoxicity at NCI-60 Panel.

Natural compounds, including diterpenoids, play a critical role in various biological processes and are recognized as valuable components in cancer treatment. Isocyanides multicomponent reactions (IsMCRs) are one of the effective methods to obtain adducts at the carboxyl group with a peptide-like substituent. In this study, dehydroabietic acid and levopimaric acid diene adducts as the starting scaffolds were modified by the multicomponent Passerini (P-3CR) and Ugi (U-4CR) reactions to afford α-acyloxycarboxamides and α-acylaminocarboxamides. A group of twenty novel diterpene hybrids was subjected to NCI in vitro assessment, and a consistent structure-activity relationship was established. Eleven of the synthesized derivatives inhibited the growth of cancer cells of 4 to 39 cell lines in one dose assay, and the most active were derivatives 3d, 9d, and 10d holding a fragment of 1a,4a-dehydroquinopimaric acid. They were selected for a five-dose analysis and demonstrated a significant antiproliferative effect towards human cancer cell lines. The outstanding cytotoxic activity was observed for the P-3CR product 3d with growth inhibitory at submicromolar and micromolar concentrations (GI50 = 0.42-3 µM) against the most sensitive cell lines. The U-4CR products 9d and 10d showed selective activity against all leukemia cell lines with GI50 in the range of 1-17 µM and selectivity indexes of 5.49 and 4.72, respectively. Matrix COMPARE analysis using the GI50 vector showed a moderate positive correlation of compound 3d with standard anticancer agents that can influence kinase receptors and epidermal growth factor receptors (EGFRs). The ADMET analysis acknowledges the favorable prognosis using compounds as potential anticancer agents. The obtained results indicate that these new hybrids could be useful for the further development of anticancer drugs, and 1a,4a-dehydroquinopimaric acid derivatives could be recommended for in-depth studies and the synthesis of new antitumor analogs on their basis.

Cage-like microstructures via sequential Ugi reactions in aqueous emulsions.

Cage-like microstructures were obtained in two steps by sequential Ugi reactions. At the first stage, submicron colloidal particles based on carboxymethylcellulose and chitosan with a domain structure were obtained in an aqueous suspension. In the second stage, the Ugi reaction was carried out on the surface of the Pickering emulsions with toluene. Removal of toluene and redissolution in water resulted in colloidosomes with large holes on the surface. Varying the cross-link density during the Ugi reaction made it possible to obtain structures with different hole sizes.

Ugi bisamides based on pyrrolyl-ß-chlorovinylaldehyde and their unusual transformations.

By one-pot four- and three-component Ugi reactions involving convertible isocyanides and unexplored pyrrole-containing ß-chlorovinylaldehyde, a small library of 20 bisamides with unusual behavior in post-Ugi transformations was prepared and characterized. Surprisingly, a well-documented approach to obtain peptide-containing carboxylic acids through acid hydrolysis of the convertible isocyanide moiety in the Ugi bisamides proceeded in an unexpected manner in our case, leading to the formation of derivatives of amides of heterylidenepyruvic acid. An optimized synthetic protocol for this transformation was elaborated and a plausible sequence involving the elimination of the 2-chloroacetamide moiety and the conversion of the ß-chlorovinyl fragment into a vinyl one is provided.

Harnessing unprotected deactivated amines and arylglyoxals in the Ugi reaction for the synthesis of fused complex nitrogen heterocycles.

Piperazines and diazepines are examples of nitrogen heterocycles present in many marketed drugs highlighting their importance in the discovery of novel bioactive compounds. However, their synthesis often faces challenges, including complex functionalization and lengthy reaction sequences. Multicomponent reactions, notably the Ugi reaction, have emerged as powerful tools to address these hurdles. Here, we have demonstrated the possibility of using the combination of arylglyoxals and carboxylic acids tethered to nonprotected deactivated amines as a powerful strategy for the synthesis of complex fused heterocycles. The limited nucleophilic character of the amino group of the anthranilic acid, indole-2-carboxylic acid, pyrrole-2-carboxylic acid or N-phenylglycine has allowed the use of these compounds in the Ugi reaction without triggering competitive reactions. The additional functional group present in the resulting Ugi adduct can be leveraged in different post-condensation strategies to easily generate multiple fused nitrogen heterocycles including benzodiazepinone and piperazinone cores.

In vitro screening of chemically synthesized dipeptide-antisense oligonucleotide conjugates to identify ligand molecules enhancing their activity.

Oligonucleotide therapeutics, particularly antisense oligonucleotides (ASOs), have emerged as promising candidates in drug discovery. However, their effective delivery to the target tissues and cells remains a challenge, necessitating the development of suitable drug delivery technologies for ASOs to enable their practical application. In this study, we synthesized a library of chemically modified dipeptide-ASO conjugates using a recent synthetic method based on the Ugi reaction. We then conducted in vitro screening of this library using luciferase-expressing cell lines to identify ligands capable of enhancing ASO activity. Our findings suggest that N-(4-nitrophenoxycarbonyl)glycine may interact with the thiophosphate moiety of the phosphorothioate-modification in ASO. Through our screening efforts, we identified two ligands that modestly reduced luciferase luminescence in a cell type-selective manner. Furthermore, quantification of luciferase mRNA levels revealed that one of these promising dipeptide-ASO conjugates markedly suppressed luciferase RNA levels through its antisense effect in prostate-derived DU-145 cells compared to the ASOs without ligand modification.

Innovative synthesis of drug-like molecules using tetrazole as core building blocks.

Tetrazole is widely utilized as a bioisostere for carboxylic acid in the field of medicinal chemistry and drug development, enhancing the drug-like characteristics of various molecules. Typically, tetrazoles are introduced from their nitrile precursors through late-stage functionalization. In this work, we propose a novel strategy involving the use of diversely protected, unprecedented tetrazole aldehydes as building blocks. This approach facilitates the incorporation of the tetrazole group into multicomponent reactions or other chemistries, aiding in the creation of a variety of complex, drug-like molecules. These innovative tetrazole building blocks are efficiently and directly synthesized using a Passerini three-component reaction (PT-3CR), employing cost-effective and readily available materials. We further showcase the versatility of these new tetrazole building blocks by integrating the tetrazole moiety into various multicomponent reactions (MCRs), which are already significantly employed in drug discovery. This technique represents a unique and complementary method to existing tetrazole synthesis processes. It aims to meet the growing demand for tetrazole-based compound libraries and novel scaffolds, which are challenging to synthesize through other methods.

One-Step Construction of 1,3,4-Oxadiazoles with Anticancer Activity from Tertiary Amines via a Sequential Copper(I)-Catalyzed Oxidative Ugi/aza-Wittig Reaction.

An unparalleled copper(I)-catalyzed synthesis of 1,3,4-oxadiazoles from tertiary amines in one step has been described. The one-pot reactions involving (N-isocyanimine)triphenylphosphorane, tertiary amines, and carboxylic acids resulted in the formation of 1,3,4-oxadiazoles in moderate to good yields through a consecutive oxidative Ugi/aza-Wittig reaction, enabling the direct functionalization of sp3 C-H bonds adjacent to the nitrogen atom. This method offered several notable advantages, including ligands-free, exceptional productivity and a high functional group tolerance. The preliminary biological evaluation demonstrated that compound 4f inhibited hepatoma cells efficiently, suggesting potentially broad applications of the approach for synthesis and medicinal chemistry.

Effective pickering emulsifiers based on submicron carboxymethyl cellulose/chitosan polymer particles.

In this study, cross-linked carboxymethyl cellulose/chitosan submicron particles were employed to facilitate the stabilization of Pickering emulsion. The polymer particles were prepared using the polyelectrolyte self-assembly method in conjunction with isocyanide based multicomponent reactions and the characteristics were obtained using: nuclear magnetic resonance, Fourier-transform infrared spectroscopy and dynamic light scattering. Atomic force microscopy revealed the heterogeneous structure of the resulting submicron particles with domains of 20-30 nm in size. The average diameter was found to be in the range of 229-378 nm and they were found to be suitable for the fabrication of oil/water Pickering emulsion when proceeded via the homogenization method followed by sonication. The results obtained revealed that carboxymethyl cellulose/chitosan particles significantly stabilized the droplets at the oil/water interface. Even at low particle concentrations of 0.3 g/L (which is close to that of low molecular weight surfactants) stable Pickering emulsions have been obtained. Additionally, the resulting emulsions showed a high level of stability with regard to changes in pH, temperature and ionic strength. The natural alkaloid piperine was used as a model compound to load the resulting particles, which possessed encapsulation efficiency of 90.6±0.4%. Furthermore, the in vitro release profile of piperine from the Pickering emulsion revealed a much-controlled release in both acidic and neutral media as compared to the unformulated piperine. Additional findings in this work revealed important information on the application of carboxymethyl cellulose/chitosan submicron particles as Pickering stabilizers for creation of new delivery systems.

Diastereoselective ZnCl2-Mediated Joullié-Ugi Three-Component Reaction for the Preparation of Phosphorylated N-Acylaziridines from 2H-Azirines.

We disclose a direct approach to the diastereoselective synthesis of phosphorus substituted N-acylaziridines based on a one-pot ZnCl2-catalyzed Joullié-Ugi three-component reaction of phosphorylated 2H-azirines, carboxylic acids and isocyanides. Hence, this robust protocol offers rapid access to an array of N-acylaziridines in moderate-to-good yields and up to 98:2 dr for substrates over a wide scope. The relevance of this synthetic methodology was achieved via a gram-scale reaction and the further derivatization of the nitrogen-containing three-membered heterocycle. The diastereo- and regioselective ring expansion of the obtained N-acylaziridines to oxazole derivatives was accomplished in the presence of BF3·OEt2 as an efficient Lewid acid catalyst.

Protein-Templated Ugi Reactions versus In-Situ Ligation Screening: Two Roads to the Identification of SARS-CoV-2 Main Protease Inhibitors.

Protein-templated fragment ligation was established as a method for the rapid identification of high affinity ligands, and multicomponent reactions (MCR) such as the Ugi four-component reaction (Ugi 4CR) have been efficient in the synthesis of drug candidates. Thus, the combination of both strategies should provide a powerful approach to drug discovery. Here, we investigate protein-templated Ugi 4CR quantitatively using a fluorescence-based enzyme assay, HPLC-QTOF mass spectrometry (MS), and native protein MS with SARS-CoV-2 main protease as template. Ugi reactions were analyzed in aqueous buffer at varying pH and fragment concentration. Potent inhibitors of the protease were formed in presence of the protein via Ugi 4CR together with Ugi three-component reaction (Ugi 3CR) products. Binding of inhibitors to the protease was confirmed by native MS and resulted in the dimerization of the protein target. Formation of Ugi products was, however, more efficient in the non-templated reaction, apparently due to interactions of the protein with the isocyanide and imine fragments. Consequently, in-situ ligation screening of Ugi 4CR products was identified as a superior approach to the discovery of SARS-CoV-2 protease inhibitors.

Ugi 5-center-4-component reaction of α-amino aldehydes and its application in synthesis of 2-oxopiperazines.

A synthetic route leading to densely functionalized 2-oxopiperazines is presented. The strategy employs a 5-center-4-component variant of Ugi multicomponent reaction followed by a deprotection/cyclization sequence. N-Boc-α-amino aldehydes were used for the first time as carbonyl components in a key Ugi 5-center-4-component reaction (U-5C-4CR). It is shown that the presented synthetic route can lead to rigid, heterocyclic scaffolds, as demonstrated by the synthesis of tetrahydro-2H-pyrazino[1,2-a]pyrazine-3,6,9(4H)-trione ß-turn mimetic and derivatives of 1,6-dioxooctahydropyrrolo[1,2-a]pyrazine and 3,8-dioxohexahydro-3H-oxazolo[3,4-a]pyrazine.

Recent Advances in the Synthesis of Peptidomimetics via Ugi Reactions.

Peptidomimetics have been extensively explored in many area due to their ability to improve pharmacological qualities and interesting biological activities. Cycles could be incorporated in peptides to reduce their flexibility, often enhancing the affinity for a certain receptor. Many efforts have been made to synthesize various peptidomimetics. Among them, the Ugi reaction is a popular way for the synthesis of peptidomimetics because it provides peptide-like products. The Ugi reaction consists of the condensation of an aldehyde or ketone, a carboxylic acid, an amine, and an isocyanide usually giving a linear peptidomimetic. In order to obtain other linear, cyclic or polycyclic peptidomimetics, the acyclic products have to undergo additional transformations or cyclizations. This review covers the years from 2018-2023, regarding the synthesis of linear, cyclic and polycyclic peptidomimetics, employing Ugi reactions eventually followed by post-Ugi transformations. Organo-catalyzed reactions, base-promoted reactions, and metal-free reactions toward peptidomimetics are highlighted.

Ugi Adducts as Novel Anti-austerity Agents against PANC-1 Human Pancreatic Cancer Cell Line: A Rapid Synthetic Approach.

Pancreatic cancer cells have an inherent tolerance to withstand nutrition starvation, allowing them to survive in hypovascular tumor microenvironments that lack of sufficient nutrients and oxygen. Developing anti-cancer agents that target this tolerance to nutritional starvation is a promising anti-austerity strategy for eradicating pancreatic cancer cells in their microenvironment. In this study, we employed a chemical biology approach using the Ugi reaction to rapidly synthesize new anti-austerity agents and evaluate their structure-activity relationships. Out of seventeen Ugi adducts tested, Ugi adduct 11 exhibited the strongest anti-austerity activity, showing preferential cytotoxicity against PANC-1 pancreatic cancer cells with a PC50 value of 0.5 µM. Further biological investigation of Ugi adduct 11 revealed a dramatic alteration of cellular morphology, leading to PANC-1 cell death within 24 h under nutrient-deprived conditions. Furthermore, the R absolute configuration of 11 was found to significantly contribute to the preferential anti-austerity ability toward PANC-1, with a PC50 value of 0.2 µM. Mechanistically, Ugi adduct (R)-11 was found to inhibit the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway preferentially under nutrition starvation conditions. Consequently, Ugi-adduct (R)-11 could be a promising candidate for drug development targeting pancreatic cancer based on the anti-austerity strategy. Our study also demonstrated that the Ugi reaction-based chemical engineering of natural product extracts can be used as a rapid method for discovering novel anti-austerity agents for combating pancreatic cancer.

Merging the Isonitrile-Tetrazine (4+1) Cycloaddition and the Ugi Four-Component Reaction into a Single Multicomponent Process.

Multicomponent reactions are of utmost importance at generating a unique, wide, and complex chemical space. Herein we describe a novel multicomponent approach based on the combination of the isonitrile-tetrazine (4+1) cycloaddition and the Ugi four-component reaction to generate pyrazole amide derivatives. The scope of the reaction as well as mechanistic insights governing the 4H-pyrazol-4-imine tautomerization are provided. This multicomponent process provides access to a new chemical space of pyrazole amide derivatives and offers a tool for peptide modification and stapling.

Rational Design and Multicomponent Synthesis of Lipid-Peptoid Nanocomposites towards a Customized Drug Delivery System Assembly.

Nanotechnology has assumed a significant role over the last decade in the development of various technologies applied to health sciences. This becomes even more evident with its application in controlled drug delivery systems. In this context, peptoids are a promising class of compounds for application as nanocarriers in drug delivery systems. These compounds can be obtained efficiently and with highly functionalized structural diversity via the Ugi 4-component reaction (U-4CR). Herein, we report the design of the process control strategy for the future development of lipid-peptoid-based customized drug delivery system assemblies. Over 20 lipid-peptoid nanocomposites were synthesized via the U-4CR in good to excellent yields. These products were successfully submitted to the nanoparticle formation by the emulsification-evaporation process from lipophilic solution and analyzed via Dynamic Light Scattering (DLS). Several molecules generated nanoparticles with a size ≤200 nm, making them good candidates for drug delivery systems, such as in cancer treatment.

Transition Metal-Free N-S Bond Cleavage and C-N Bond Activation of Ugi-Adducts for Rapid Preparation of Primary Amides and α-Ketoamides.

A novel method of transition metal-free N-S bond cleavage and subsequent C-N bond activation of Ugi-adducts was developed. Diverse primary amides and α-ketoamides were prepared in a rapid, step-economical and highly efficient manner in two steps. This strategy features excellent chemoselectivity, high yield and functional-group tolerance. Primary amides derived from the pharmaceuticals probenecid and febuxostat were prepared. This method opens a new pathway for the simultaneous synthesis of primary amides and α-ketoamides in an environmentally friendly manner.

Rh(III)-Catalyzed C-2 Alkylation of Indoles followed by a Post-Synthetic Modification via the Ugi Reaction.

Indole derivatives substituted at the C-2 position have shown important biological activities. Due to these properties, several methods have been described for the preparation of structurally diverse indoles. In this work, we have synthesized highly functionalized indole derivatives via Rh(III)-catalyzed C-2 alkylation with nitroolefins. Under the optimized condition, 23 examples were prepared with 39-80 % yield. Moreover, the nitro compounds were reduced and submitted to the Ugi four-component reaction, furnishing a series of new indole-peptidomimetics in moderate to good overall yields.

Synthesis of imidazo[1,2-a]pyridine-containing peptidomimetics by tandem of Groebke-Blackburn-Bienaymé and Ugi reactions.

Peptidomimetics with a substituted imidazo[1,2-a]pyridine fragment were synthesized by a tandem of Groebke-Blackburn-Bienaymé and Ugi reactions. The target products contain substituted imidazo[1,2-a]pyridine and peptidomimetic moieties as pharmacophores with four diversity points introduced from readily available starting materials, including scaffold diversity. A small focused compound library of 20 Ugi products was prepared and screened for antibacterial activity.