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Researchers explore the potential of click chemistry for drug development and diverse chemical-biology applications. Click chemistry is a newer approach to the synthesis of drug-like molecules that can accelerate the drug discovery process by utilizing a few practical and reliable reactions. Researchers have defined the click reaction as wide in sc...
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... compounds were screened for α-glucosidase inhibitory activity using yeast maltase (MAL12) as a model enzyme. Methyl-2,3-Oisopropylidene-β-D-ribofuranosides, such as the 4-(1-cyclohexenyl)-1,2,3-triazole derivative (compound 89, Figure 16), were among the most active compounds, showing up to 25-fold higher inhibitory potency than the complex oligosaccharide acarbose with IC 50 = 3.8 ± 0.5 μM. 108 New N-alkylaminocyclitols bearing a 1,2,3-triazole system at different positions of the alkyl chain were prepared as potential glucocerebrosidase pharmacological chaperones using click chemistry approaches. ...
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... New N-alkylaminocyclitols bearing a 1,2,3-triazole system at different positions of the alkyl chain were prepared as potential glucocerebrosidase pharmacological chaperones using click chemistry approaches. Among them, compound 90a ( Figure 16) (K i = 0.06 μM), with the shorter spacer (n = 1) between the alkyltriazolyl system and the aminocyclitol core, was the most active as glucocerebrosidase inhibitor, revealing a determinant effect of the location of the triazole ring on the activity. 109 Recently, the same research group developed new glucocerebrosidase inhibitors by diversity of N-substituted aminocyclitols using click chemistry and in situ screening. ...
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... members with IC 50 values below 3.5 μM were individually synthesized and tested as glucocerebrosidase inhibitors and also for their ability to induce enzyme thermal stabilization, an in vitro indication of their potential as pharmacological chaperones. Compounds 90b (K i = 0.05 μM) and 90c (K i = 0.06 μM) ( Figure 16) with a linear aliphatic side chain showed the highest enzyme stabilization ratios and were promising candidates for further development. 110 Linhardt and his co-workers reported that a small library of 1,2,3-triazole-linked sialic acid derivatives was synthesized using click chemistry. ...
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... novel sialic acid derivatives were then evaluated as potential neuraminidase inhibitors using a 96-well plate fluorescence assay. Compound 91 ( Figure 16) showed potent inhibition activity against Neuraminidase with an IC 50 value of 17 μM. 111 Gouin and his co-workers recently developed an efficient click procedure to tether hydrophobic substituents to Nazidopropyl-1-deoxynojirimycin. ...
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... activity of the whole set of synthetic compounds was also explored in mutant Gaucher cells. The most active compound (92a, Figure 16) gave a nearly 2-fold increase in enzyme activity at 20 μM, a value significantly higher than the 1.33-fold recorded for the reference compound N-nonyl-1-deoxynojirimycin (N-nonyl-DNJ). 112 Compound 92a showed K i = 9 μM against beta glucosidase (bovine liver), K i = 1 μM against beta glucosidase (almond), K i = 57 μM against alpha glucosidase, and K i = 16 μM against amyloglucosidase. ...
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... et al. reported the synthesis of multivalent iminosugars from a click chemistry reaction between oligoethylene scaffolds and N-substituted DNJ derivatives. 113 These series of compounds screened against glycosidase inhibitory activities and resultant compounds (92b, 93, and 94, Figure 16) showed good inhibition against glycosidase. 114 Compound 92b showed a K i value of 47 ± 2 μM against beta glucosidase when n = 1 ( Figure 16) and K i = 95 ± 5 μM against alpha glactosidase when n = 4 ( Figure 16). ...
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... These series of compounds screened against glycosidase inhibitory activities and resultant compounds (92b, 93, and 94, Figure 16) showed good inhibition against glycosidase. 114 Compound 92b showed a K i value of 47 ± 2 μM against beta glucosidase when n = 1 ( Figure 16) and K i = 95 ± 5 μM against alpha glactosidase when n = 4 ( Figure 16). The dimer version of compound 93 showed K i = 17 ± 1 μM against amyloglactosidase when n = 1in Figure 16 and K i = 55 ± 2 μM against niringinase when n = 4 in Figure 16. ...
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... These series of compounds screened against glycosidase inhibitory activities and resultant compounds (92b, 93, and 94, Figure 16) showed good inhibition against glycosidase. 114 Compound 92b showed a K i value of 47 ± 2 μM against beta glucosidase when n = 1 ( Figure 16) and K i = 95 ± 5 μM against alpha glactosidase when n = 4 ( Figure 16). The dimer version of compound 93 showed K i = 17 ± 1 μM against amyloglactosidase when n = 1in Figure 16 and K i = 55 ± 2 μM against niringinase when n = 4 in Figure 16. ...
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... Compound 92b showed a K i value of 47 ± 2 μM against beta glucosidase when n = 1 ( Figure 16) and K i = 95 ± 5 μM against alpha glactosidase when n = 4 ( Figure 16). The dimer version of compound 93 showed K i = 17 ± 1 μM against amyloglactosidase when n = 1in Figure 16 and K i = 55 ± 2 μM against niringinase when n = 4 in Figure 16. Trimer version of compound 94 showed K i = 35 ± 2 μM against alpha mannosidase. ...
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... Compound 92b showed a K i value of 47 ± 2 μM against beta glucosidase when n = 1 ( Figure 16) and K i = 95 ± 5 μM against alpha glactosidase when n = 4 ( Figure 16). The dimer version of compound 93 showed K i = 17 ± 1 μM against amyloglactosidase when n = 1in Figure 16 and K i = 55 ± 2 μM against niringinase when n = 4 in Figure 16. Trimer version of compound 94 showed K i = 35 ± 2 μM against alpha mannosidase. ...
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... activity of the whole set of synthetic compounds was also explored in mutant Gaucher cells. The most active compound (94, Figure 16) gave a nearly 2-fold increase in enzyme activity at 20 μM, a significantly higher value than the 1.33-fold recorded for the reference compound N-nonyl-1-deoxynojirimycin (N-nonyl-DNJ) with K i = 35 ± 2 μM. 114 ...
Citations
... [20] Current synthetic procedures are based on "protection-deprotection" steps, difficult chromatographic purifications, and low isolated yields, hampering further clinical development of these probes. Biorthogonal chemistry was exploited to overcome these synthetic problems in a DOTA-based probe containing 4 symmetrical substitutions using either CuAAC [21] or SPAAC chemistries. [22] However, biorthogonal strategies to access heteromultifunctional DOTA scaffolds remain largely uncharted. ...
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal malignancy with extremely poor patient survival rates. A key reason for the poor prognosis is the lack of effective diagnostic tools to detect the disease at curable, premetastatic stages. Tumor surgical resection is PDAC's first‐line treatment, however distinguishing between cancerous and healthy tissue with current imaging tools remains a challenge. In this work, we report a DOTA‐based fluorescent probe targeting plectin‐1 for imaging PDAC with high specificity. To enable heterogeneous functionalization of the DOTA‐core with multiple targeting peptide units and the fluorophore, a novel, fully clickable synthetic route that proceeds in one pot was developed. Extensive validation of the probe set the stage for PDAC detection in mice and human tissue. Altogether, these findings may pave the way for improved clinical understanding and early detection of PDAC progression as well as more accurate resection criteria.
... Therefore, developing efficient organic synthesis strategies to cope with this situation is very necessary. By exploring a series of reliable synthetic methods, it is possible to efficiently construct the structurally complex molecular frameworks found in natural products and biologically active compounds, including carbocyclic and heterocyclic structures, thereby facilitating the discovery of potential new drugs and pesticides [7][8][9][10][11][12]. Among the numerous reported synthetic strategies, domino reactions have a racted considerable a ention due to their potential to conserve resources, reduce waste generation during the synthesis process, and align with the principles of green chemistry [13][14][15][16]. ...
Quinone imines are important derivatives of quinones with a wide range of applications in organic synthesis and the pharmaceutical industry. The attack of nucleophilic reagents on quinone imines tends to lead to aromatization of the quinone skeleton, resulting in both the high reactivity and the unique reactivity of quinone imines. The extreme value of quinone imines in the construction of nitrogen- or oxygen-containing heterocycles has attracted widespread attention, and remarkable advances have been reported recently. This review provides an overview of the application of quinone imines in the synthesis of cyclic compounds via the domino annulation reaction.
... [27] These compounds have shown promise as anticancer, antibacterial, and antituberculosis agents. [69] Notably, 1,2,3-triazoles, when fused with both the biocompatible carbo-and heterocycles, have demonstrated therapeutic potential in addressing conditions such as HIV, cancer, and Alzheimer disease. [69][70][71] In this discussion, we explore the synthesis of a broad spectrum of fused heterocycles utilizing the 'MCR Click Chemistry'. ...
... [69] Notably, 1,2,3-triazoles, when fused with both the biocompatible carbo-and heterocycles, have demonstrated therapeutic potential in addressing conditions such as HIV, cancer, and Alzheimer disease. [69][70][71] In this discussion, we explore the synthesis of a broad spectrum of fused heterocycles utilizing the 'MCR Click Chemistry'. MCR reaction of nitromethane, aromatic aldehydes, and NaN 3 in the presence of a catalytic amount of CuFe 2 O 4 afforded a high yield of respective aryl-1H-1,2,3-triazoles. [72] An RTIL-based Cu(II) catalyst obtained by combining of 1-(1-carboxymethyl)-3-methylimidazolium tetrafluoroborate and Cu(OAc) 2 was used to deliver 1,2,3-triazole under MW irradiation in aqueous media for 20 min. ...
... Exclusively, functionalized 5-amino-1,2,3-triazoles were produced in the case of nonenolizable α-CF3 esters, which may allow for the post-functionalization of complex bioactive molecules (Scheme 18). [86] Based on a literature study, [69][70][71] the mechanistic route stated that primarily, gem-difluoro vinyl ketone I is shaped via baseassisted dehydro-fluorination of α-CF 3 ketone 68, and it then after successive nucleophilic addition-elimination produces intermediate II. Two possible reaction routes are recommended, both of which are grounded on the active intermediate II. ...
Multicomponent reactions are operationally simple and display a significant role in diverse chemical modification by reducing reaction times as well as additional steps involved. In this review, we highlighted the impact of multi‐component reactions in assistance with modular Click chemistry to develop a library of triazole‐appended scaffolds including 1,2,3‐triazole‐fused heterocycles, glycoconjugates, macrocycles as well as in the combinatorial synthesis of differently functionalized triazoles along with mechanistic insights with a diverse range of applications in the field of medicinal chemistry.
... 1-3 Five-membered aromatic 1,2,3-triazoles illustrate such heterocyclic moieties, which have the ability to imitate peptide bonds and oligosaccharides, enabling them to behave as antidotes against cancers, tumors, STDs and tuberculosis. [4][5][6][7][8][9][10] For instance, triazole-bearing medicinal hybrids, such as cefatrizine and tazobactam, have been approved as beta-lactam antibiotics against bacterial infections caused by drug-resistant ESKAPE pathogens. 11 A 1,4-disubstituted triazole, namely 3-(4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl)benzo [d]isoxazole (PTB), works as an antiproliferative agent by restricting tubulin acetylation and thereby ceasing the proliferation of cancer cells in acute myeloid leukemia. ...
In this study, a sustainable and eco-friendly copper-free protocol has been developed for the regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles using a zinc-based heterogeneous catalyst. This water-driven procedure links 1,4-disubstituted 1,2,3-triazoles in an azide–alkyne reaction via a one-pot multicomponent pathway without any base or reducing agents and ligands. The sonochemically prepared CTAB-stabilized ZnO particles with a nanorod-like architecture were quite robust and economical as a catalyst and could generate several 1,4-isomeric triazoles by tolerating different substituted azides and alkynes. Moreover, this catalyst was also applied for constructing pharmaceutically active N-unsubstituted 1,2,3-triazoles and 1,4,5-trisubstituted 1,2,3-triazoles with excellent yields. The catalyst was recovered and reused four times to synthesize 1,4-disubstituted and N-unsubstituted 1,2,3-triazoles. In addition, the successful two-gram-scale syntheses also confirm the efficiency of the catalyst. The catalytic protocol was designed considering green chemistry principles, and the eco-friendliness of this methodology was verified by its high eco-score and low E-factor values. This is the first report on using ZnO nanoparticles as a catalyst for regioselective triazole synthesis, and they are far better in terms of catalytic efficiency than many reported zinc-based catalysts.
... [1] In addition, triazoles have been demonstrated to be effective bioisosteres of common functions, such as the amide or ester. [2] These properties have positioned the triazole ring as a key pharmacophore in medicinal chemistry, but its applications extend to other fields, including chemical biology, [3] supramolecular chemistry, [4] polymer, [5] and materials sciences. [6] First, attention was given to the synthesis of 1,4-disubstituted 1,2,3-triazole compounds but 1,4,5-trisubstituted 1,2,3-triazoles then emerged as valuable molecules due to the possibility to expand the structural modularity ( Figure 1). ...
1,2,3‐triazole is an important building block in organic chemistry. It is now well known as a bioisostere for various functions, such as the amide or the ester bond, positioning it as a key pharmacophore in medicinal chemistry and it has found applications in various fields including life sciences. Attention was first focused on the synthesis of 1,4‐disubstituted 1,2,3‐triazole molecules however 1,4,5‐trisubstituted 1,2,3‐triazoles have now emerged as valuable molecules due to the possibility to expand the structural modularity. In the last decade, methods mainly derived from the copper(I)‐catalyzed azide‐alkyne cycloaddition (CuAAC) reaction have been developed to access halo‐triazole compounds and have been applied to nucleosides, carbohydrates, peptides and proteins. In addition, late‐stage modification of halo‐triazole derivatives by metal‐mediated cross‐coupling or halo‐exchange reactions offer the possibility to access highly functionalized molecules that can be used as tools for chemical biology. This review summarizes the synthesis, the functionalization, and the applications of 1,4,5‐trisubstituted halo‐1,2,3‐triazoles in biologically relevant molecules.
... The small triazole linkage is identical in size and polarity to the peptide linkage, minimizing disruption of the biological function of the conjugate (Valverde et al., 2012;Birts et al., 2014). However, there is a significant drawback in using CuAAC reactions for bioconjugations related to the presence of Cu, which generates reactive oxygen species (Thirumurugan et al., 2013). Because of the oxidation of Cu(I) to Cu(II), it is often necessary to carry out the reaction under inert gas or to use reducing agents such as ascorbic acid or sodium ascorbate (Rostovtsev et al., 2002). ...
A revolution in chemical biology occurred with the introduction of click chemistry. Click chemistry plays an important role in protein chemistry modifications, providing specific, sensitive, rapid, and easy-to-handle methods. Under physiological conditions, click chemistry often overlaps with bioorthogonal chemistry, defined as reactions that occur rapidly and selectively without interfering with biological processes. Click chemistry is used for the posttranslational modification of proteins based on covalent bond formations. With the contribution of click reactions, selective modification of proteins would be developed, representing an alternative to other technologies in preparing new proteins or enzymes for studying specific protein functions in different biological processes. Click-modified proteins have potential in diverse applications such as imaging, labeling, sensing, drug design, and enzyme technology. Due to the promising role of proteins in disease diagnosis and therapy, this review aims to highlight the growing applications of click strategies in protein chemistry over the last two decades, with a special emphasis on medicinal applications.
... [26] Additionally, it finds extensive applications in the field of medicinal chemistry. [27] The most common methods for producing substituted 1,2,3-triazoles are organocatalytic azidealdehyde/ketone 1,3-dipolar cycloaddition processes or copper catalytic azidealkyne click (CuAAC) reactions. [28] Recently, the CuAAC reaction has proven to be a highly effective tool for synthesizing 1,4-disubstituted 1,2,3-triazoles. ...
An efficient and practical method for the N‐alkynylation of 7‐azaindoles has been established by using CuI/DMAP catalytic system at room temperature and in open air. This simple protocol has been successfully employed in the synthesis of a wide range of N‐alkynylated 7‐azaindoles with good yields. Also, this approach is well‐suited for large‐scale N‐alkynylation reactions. The designed N‐alkynylated 7‐azaindoles were further subjected to Cu‐/Ir‐catalyzed alkyne–azide cycloaddition (CuAAC/IrAAC) or “click” reaction for the rapid synthesis of 1,4‐/1,5 disubstituted 1,2,3‐triazole decorated 7‐azaindoles. A mechanistic study based on density functional theory (DFT) calculations and ultraviolet–visible (UV) spectroscopic studies revealed that the CuI and DMAP combination formed a [CuII(DMAP)2I2] species, which acts as an active catalyst. The DFT method was used to assess the energetic viability of an organometallic in the C−N bond formation pathway originating from the [CuII(DMAP)2I2] complex. We expect that the newly designed Cu/DMAP/alkyne system will offer valuable insights into the field of Cu‐catalyzed transformations.
... Moreover, various series of 1H-1,2,3triazoles with a-glucosidase inhibitory potential have been identified (Fallah et al., 2022). The 1H-1,2,3-triazole was chosen because of its well-known medicinal properties and wide variety of applications in biochemical, pharmaceutical, biomedical, and materials sciences (Thirumurugan et al., 2013). Based upon our findings and the medicinal significance of these derivatives, we have gained insights into an approach that may be employed in the treatment of type 2 diabetes. ...
... Organic azides are a group of universal reagents that play an important role in chemistry, biochemistry, materials science, and the development of new drugs [1][2][3][4][5]. The widespread use of the concept of the azide-alkyne click reaction has led to an explosive increase in breakthrough work in which organyl azides play the role of key synthons and building blocks [2,6]. ...
Using X-ray diffraction, IR spectroscopy, and quantum chemistry [B3LYP/6–311 + + G**, AIM], the molecular and supramolecular structures and association of 5-phenyl-1H-pyrrole-2-carbonyl azide were studied in detail. The motives for the formation of supramolecular and crystal structures have been established. A topological analysis of non-valent interactions in the crystal was carried out. A probable reason has been established for the relatively low sensitivity of 5-phenyl-1H-pyrrole-2-carbonyl azide to ionizing ultraviolet and X-ray radiation compared to other pyrrole-2-carbonyl azides. Indeed, the relative stability of the new pyrrolazide lies in the organization of associative dimeric structures, in the formation of which the nitrogen atoms of the azide fragment participate through hydrogen bonds.
... Additionally, this approach confers more flexibility and diversification opportunities. For more detailed information about 'click chemistry', also including CuAAC, in drug development and for medicinal applications, the reviews of Thirumurugan et al. [274] and Addonizion et al. [275] are recommended. ...
Targeted cancer treatment should avoid side effects and damage to healthy cells commonly encountered during traditional chemotherapy. By combining small molecule or peptidic ligands as homing devices with cytotoxic drugs connected by a cleav-able or non-cleavable linker in peptide-drug conjugates (PDCs) or small molecule-drug conjugates (SMDCs), cancer cells and tumours can be selectively targeted. The development of highly affine, selective peptides and small molecules in recent years has allowed PDCs and SMDCs to increasingly compete with antibody-drug conjugates (ADCs). Integrins represent an excellent target for conjugates because they are overexpressed by most cancer cells and because of the broad knowledge about native binding partners as well as the multitude of small-molecule and peptidic ligands that have been developed over the last 30 years. In particular, integrin α V β 3 has been addressed using a variety of different PDCs and SMDCs over the last two decades, following various strategies. This review summarises and describes integrin-addressing PDCs and SMDCs while highlighting points of great interest.
