Ugi Four-component Reaction Research Articles

Equipping Uridine with Three Dipeptide Motifs for the Inhibition of Radical-Induced DNA Oxidation.

We report the discovery and characterization of antioxidative effects of uridine linked with three dipeptide motifs against DNA oxidation induced by peroxyl radicals. First, the dipeptide motifs are constructed by using the Ugi four-component reaction (Ugi 4CR), in which caffeic, ferulic, sinapic, and syringic acids are used as the carboxylic acid resources, vanillin, benzaldehyde, and p-hydroxybenzaldehyde are used as the aldehyde resources, tyramine- and dopamine-related isocyanides as well as ethyl isocyanoacetate are used as the isocyanide resources, and 2-(p-aminophenyl)ethanol is used as the amine component. We found that the antioxidative effects of the Ugi 4CR products are 1.3-2.8 times higher than those of caffeic, ferulic, sinapic, and syringic acids in the protection of DNA against peroxyl radical-induced oxidation. Moreover, when three Ugi 4CR products are linked with three hydroxyl groups of uridine by using three succinic anhydrides as the linkage, the inhibitory effects of the afforded uridine-dipeptide hybrids against the DNA oxidation increase 4.4-8.9 times (>3 times) compared to that of the Ugi 4CR product. This is due to the hybrid structure consisting of uridine and three motifs of the Ugi 4CR product enabling binding with the DNA strand more efficiently and quenching free radicals more rapidly. Therefore, the hybrid structure constructed by the nucleoside with antioxidative dipeptides offers an additional advantage for protecting DNA against radical-induced oxidation.

Development of peptoid-based heteroaryl-decorated histone deacetylase (HDAC) inhibitors with dual-stage antiplasmodial activity

Dynamics of epigenetic modifications such as acetylation and deacetylation of histone proteins have been shown to be crucial for the life cycle development and survival of Plasmodium falciparum, the deadliest malaria parasite. In this study, we present a novel series of peptoid-based histone deacetylase (HDAC) inhibitors incorporating nitrogen-containing bicyclic heteroaryl residues as a new generation of antiplasmodial peptoid-based HDAC inhibitors. We synthesized the HDAC inhibitors by an efficient multicomponent protocol based on the Ugi four-component reaction. The subsequent screening of 16 compounds from our mini-library identified 6i as the most promising candidate, demonstrating potent activity against asexual blood-stage parasites (IC50Pf3D7 = 30 nM; IC50PfDd2 = 98 nM), low submicromolar activity against liver-stage parasites (IC50PbEEF = 0.25 μM), excellent microsomal stability (t1/2 > 60 min), and low cytotoxicity to HEK293 cells (IC50 = 136 μM).

A versatile gemini amphiphile-based platform with STING-activating properties for efficient gene delivery into dendritic cells

Encouraging results from clinical trials have underscored the potential of gene-pulsed dendritic cell (DC) vaccines as a viable approach for immunotherapy. However, insufficient gene delivery and functional deficiencies in antigen presentation, migratory capacity and cytokine release of DC vaccines limited its broader clinical application. Here, a combinatorial design of cationic gemini amphiphile (GA) molecular library based on the four-component Ugi reaction (Ugi-4CR) has been developed to identify versatile non-viral vectors for gene-engineered DC vaccines. We demonstrated that the leading GA enabled robust transfection of plasmid DNA or mRNA into the DCs through the formation of minimalist binary complexes, which exhibited great advantages of low carrier/gene ratios, high gene loading efficiency and well biocompatibility. The identified GA stimulated strong type I interferon (IFN) expression via the intracellular stimulator of interferon genes (STING) pathway and enhanced DC maturation and activation, which could potentially facilitate strong immunogenicity of DC vaccines. Importantly, DC maturation and activation could be further strengthened by co-delivering maturation stimuli with mRNA/GA complexes, and adoptive transfer of gene-engineered DC vaccines elicited strong T cell responses and thus inhibited tumor growth in vivo. The further studies indicated GAs can be formulated into lipid nanoparticle (LNP)-like quinary complexes that presented 6.9-fold higher mRNA delivery efficiency on the DCs than the commercial Lipofectamine 2000. These results suggest that GA-based molecular library is a powerful platform to develop versatile gene delivery vectors for immune cell engineering.

MIL-88-NH2(Fe) conjugated pectin through a post-modification Ugi four-component reaction: A robust bio-based catalyst for the synthesis of cyclic carbonate via CO2 fixation reaction

The functionalization of materials via multicomponent reactions (MCRs) led to a recent surge in the interest of researchers, owing to the creation of exceptional properties in materials. Herein, a novel robust porous catalyst was prepared via the conjugation of MIL-88-NH2(Fe) and pectin (DAP/MIL-88-NH2(Fe)) through the post-modification Ugi four-component reaction (Ugi-4CR) for the first time. To achieve this aim, pectin was oxidized using sodium periodate as an oxidant agent to produce dialdehyde pectin (DAP). Next, the generated carbonyl functional groups participated in the Ugi-4CR of MIL-88-NH2(Fe), 4-methyl carboxylic acid, and cyclohexyl (c-hex) isocyanide to produce DAP/MIL-88-NH2(Fe) catalyst. The catalytic activity of the prepared bio-based catalyst was examined in producing cyclic carbonates through the chemical fixation of CO2 with epoxides in the presence of TBAB as a co-catalyst. Interestingly, catalytic experiments revealed that the prepared bio-based catalyst could be remarkably active regarding the CO2 fixation reaction and performed it in the shortest reaction time (1 h) via high CO2 adsorbent capacity. The outstanding benefits of the prepared bio-based catalyst include its non-hazardous nature, inexpensive, green and gentle reaction conditions, and ability to be reusable in several runs with slight loss of catalytic activity due to a more durable framework with high chemical and thermal stability.

The Ugi4CR as effective tool to access promising anticancer isatin-based α-acetamide carboxamide oxindole hybrids.

Considering early-stage drug discovery programs, the Ugi four-component reaction is a valuable, flexible, and pivotal tool, facilitating the creation of two new amide bonds in a one-pot fashion to effectively yield the desired α-aminoacylamides. Here, we highlight the reputation of this reaction approach to access number and scaffold diversity of a library of isatin-based α-acetamide carboxamide oxindole hybrids, promising anticancer agents, in a mild and fast sustainable reaction process. The library was tested against six human solid tumor cell lines, among them, non-small cell lung carcinoma, cervical adenocarcinoma, breast cancer and colon adenocarcinoma. The most potent compounds 8d, 8h and 8k showed GI50 values in the range of 1-10 μM.

Preferential HDAC6 inhibitors derived from HPOB exhibit synergistic antileukemia activity in combination with decitabine

Histone deacetylase 6 (HDAC6) is an emerging drug target to treat oncological and non-oncological conditions. Since highly selective HDAC6 inhibitors display limited anticancer activity when used as single agent, they usually require combination therapies with other chemotherapeutics. In this work, we synthesized a mini library of analogues of the preferential HDAC6 inhibitor HPOB in only two steps via an Ugi four-component reaction as the key step. Biochemical HDAC inhibition and cell viability assays led to the identification of 1g (highest antileukemic activity) and 2b (highest HDAC6 inhibition) as hit compounds. In subsequent combination screens, both 1g and especially 2b showed synergy with DNA methyltransferase inhibitor decitabine in acute myeloid leukemia (AML). Our findings highlight the potential of combining HDAC6 inhibitors with DNA methyltransferase inhibitors as a strategy to improve AML treatment outcomes.

Four component Ugi reaction based small-molecule probes for integrated phenotypic screening

Quorum-sensing (QS) is a cell density-dependent signaling pathway regulated by gene expression for intra- and interspecies communication. We have targeted QS activity in Pseudomonas aeruginosa, an opportunistic human pathogen that causes disease in immunocompromised patients, with a set of probes containing a variety of functional groups, including photoreactive (diazirine) and affinity (alkyne) moieties, that were synthesized using a four-component Ugi reaction (Ugi-4CR).

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 four-multicomponent reaction based synthesis, in vitro, and in silico enzymatic evaluations of new pyrazino[1,2-a]indole-1,4-dione-indole-2-phenylacetamides as potent inhibitors against α-glucosidase and α-amylase.

In this work, synthesis and evaluation of pyrazino[1,2-a]indole-1,4-dione-indole-2-phenylacetamides 6 a-k as new synthetic anti-diabetes agents were presented. These compounds were synthesized by a four-component Ugi reaction without metal catalyst. All synthesized compounds were evaluated against α-glucosidase and α-amylase as two important targets in the treatment of diabetes. Approximately, all new compounds 6 a-k were more potent than positive control acarbose against these studied enzymes. The obtained potent compounds against the target enzymes were docked in the active site of the related enzyme. Docking study showed that our new potent compounds as well interacted with key residues of the target enzyme.

A Facile Ugi/Ullmann Cascade Reaction to Access Fused Indazolo-Quinoxaline Derivatives with Potent Anticancer Activity.

A facile methodology for the construction of a complex heterocycle indazolo-fused quinoxalinone has been developed via an Ugi four-component reaction (U-4CR) followed by an intramolecular Ullmann reaction. The expeditious process features an operationally simple approach, time efficiency, and a broad substrate scope. Biological activity was evaluated and demonstrated that compound 6e inhibits human colon cancer cell HCT116 proliferation with an IC50 of 2.1 μM, suggesting potential applications for developing a drug lead in medicinal chemistry.

The Ugi Four-Component Reaction: Application in the synthesis of bis-hydantoins

Three new bis 1,3,5-trisubstituted hydantoins were synthesized by combining an Ugi four-component condensation reaction with a base induced cyclization. In the two-step sequence, first three new bis Ugi compounds were synthesized by the Ugi four-component condensation reaction, and then bis 1,3,5-trisubstituted hydantoins were obtained by intramolecular cyclization reaction.

A stereodivergent multicomponent approach for the synthesis of C-N atropisomeric peptide analogues.

A four-component Ugi reaction is described for the stereoselective synthesis of novel C-N atropisomeric peptide analogues. Using this approach, a combination of simple, readily available starting materials (ortho-substituted anilines, aldehydes, carboxylic acids and isocyanides) could be combined to access complex products possessing both central and axial chirality in up to 92% yield and >95 : 5 d.r. Variation of the reaction temperature enabled the development of stereodivergent reactions capable of selectively targeting either diastereoisomer of a desired product from a single set of starting materials with high levels of stereocontrol. Detailed experimental and computational studies have been performed to probe the reaction mechanism and stereochemical outcome of these reactions. Preliminary studies show that novel atropisomeric scaffolds prepared using this method display inhibitory activity against M. tuberculosis with a significant difference in activity observed between different atropisomers.

Saccharide branched cellulose with controllable molecular structure and excellent water retention ability

In this work, saccharide branched cellulose (saccharide b-Cel) was synthesized by combining reducing saccharides with cellulose molecules using Ugi four-component reaction (Ugi-4CR). First, the carboxyl groups required for Ugi-4CR are obtained by carboxymethylating cellulose molecules. Then, saccharide b-Cel with a controlled molecular structure is formed when the terminal aldehyde group of reducing saccharides combines with the carboxyl group and auxiliary functional group. The types of saccharides, the degree of substitution of carboxymethyl groups, and the degree of branching all affect the molecular structure of saccharide b-Cel. Through molecular structural regulation, the relationship between the branching structure and water retention ability of saccharide b-Cel was examined in detail. This work not only provides new insights into the synthesis of cellulose derivatives, but it also provides a template for the synthesis of other biomass derivatives.

Design, molecular docking and synthesis of pyrazino[1,2-a] indole derivatives via tandem Ugi-4CR/intramolecular cyclization as potential urease inhibitor agents

In the present paper, a novel series of pyrazino[1,2-a]indole derivatives 6(a-k) were synthesized by Ugi four-component reaction (U-4CR), followed by an intramolecular cyclization of the Ugi products in the presence of DBU as a catalyst, Subsequently, we assessed their inhibitory activity against Jack bean's urease enzyme in vitro, and some of these derivatives exhibited potent urease inhibition. Notably, compounds 6e (IC50 = 3.55 ± 1.11 µM), 6g (IC50 = 3.18 ± 0.42 µM), and 6j (IC50 = 3.80 ± 0.65 µM) demonstrated urease inhibitory effects comparable to the reference compound, thiourea. Additionally, our docking study corroborated these experimental results, confirming that the pyrazino[1,2-a]indole derivatives (6a-k) effectively interacted with the urease enzyme's active site, exhibiting proper binding energies and modes.

Merging the Isonitrile-Tetrazine (4+1) Cycloaddition and the Ugi Four-ComponentReaction 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 novel tool for peptide modification and stapling.

A Multidimensional Approach to Modulating Ionizable Lipids for High-Performing and Organ-Selective mRNA Delivery.

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.

An Efficient Synthesis of Benzimidazole‐pyrazines via the Sequential Ugi/Hydroamination/Cyclization Reactions

AbstractThis study reported an efficient two‐step method based on the sequential post‐Ugi hydroamination reaction for synthesizing a novel class of benzimidazole‐pyrazines with high yields. First, a Ugi fourcomponent reaction (Ugi‐4CR) is carried out using readily available starting materials, i. e., 1H‐benzo[d]imidazole‐2‐carboxylic acid, aldehydes, propargylamine, and isocyanides, in methanol at ambient temperature. Afterward, the Ugi products undergoes a sequential intramolecular hydroamination/cyclization reaction between a nitrogen of imidazole and alkyne functional group in aqua media in the presence of AuCl3 as a catalyst to obtain benzimidazole‐pyrazine products. These heterocyclic compounds may have a potential to be utilized in designing modern drugs with desirable features.

Synthesis of Novel Diterpenic Peptides via the Ugi Reaction and Their Anticancer Activities

Novel diterpenic peptide derivatives were synthesized via the Ugi four-component reaction at ambient temperature. The protocol employed a reaction between formaldehyde, benzyl amine, the corresponding diterpene acid, and ethyl 2-isocyanoacetate. The anticancer properties of the compounds were studied in vitro.

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.

Exploring the Effect of Amphiphile Architecture on Intracellular Protein Delivery Capacity: Dimeric versus Trimeric Amphiphiles.

Carrier-mediated intracellular protein delivery holds tremendous application potential in biology and medicine. The ideal carrier should be well-controlled and cost-effective and able to facilitate robust delivery of diverse types of proteins into the target cells, thus ensuring efficacy in different application scenarios. Here, we describe a modular chemistry approach for generating a small-molecule amphiphile molecular library based on the Ugi four-component reaction under one-pot and mild conditions. Then, two different types of amphiphiles with the dimeric or trimeric architecture were obtained for intracellular protein delivery through in vitro screening test. Depending on the precise adjustment of the hydrophobic tails of amphiphiles, the optimized trimeric amphiphile (TA) exhibited more superior protein loading performance and a higher efficiency of delivering proteins into cells through the endocytosis pathway and subsequent endosomal escape. Furthermore, we demonstrated that the TA could be a universal delivery carrier capable of transporting broad-spectrum proteins, especially for the hard-to-deliver native antibodies, into the cytosol. Overall, we describe a robust amphiphile platform with a well-defined and cost-effective design to improve the cytosolic protein delivery capacity, exhibiting great promise for developing intracellular protein-based therapeutics.