CuAAC Reaction Research Articles

Synthesis and thermoresponsive behavior of double hydrophilic graft copolymer based on poly(2-methyl-2-oxazoline) and poly(2-ethyl-2-oxazoline)

A recent challenge in polymer self-assembly is the utilization of double hydrophilic graft copolymers (DHGC) in view of biomedical applications. Here we describe, for the first time, a platform of biocompatible DHGC fully based on poly(2-alkyl-2-oxazoline) leading to stimuli-responsive self-assemblies. This original DHGC platform was composed of backbone poly(2-methyl-2-oxazoline-co-2-pentyl-2-oxazoline) (P(MeOx-co-PentOx)) and poly(2-ethyl-2-oxazoline) (PEtOx) grafts. A “grafting onto” approach based on the combination of cationic ring-opening polymerization (CROP) technique and “click chemistry” CuAAc reaction, was successfully used to synthesize poly(2-methyl-2-oxazoline-co-2-pentyl-2-oxazoline)-g-poly(2-ethyl-2-oxazoline) (P(MeOx-co-PentOx)-g-PEtOx) copolymer conjugates of varying backbone and side chain lengths. These purely hydrophilic copolymers demonstrated self-assembling behavior in aqueous solution, showing a characteristic double hydrophilic behavior originating from building blocks immiscibilities. Self-associated structures with spherical morphologies have been evidenced by DLS and cryo-TEM. The sizes and the efficiency of self-association were mainly controlled by the concentration of the graft copolymer and by the molar ratio of the different hydrophilic compounds. In addition, thermoresponsive properties of these copolymers were studied by turbidimetry and DLS. From purely hydrophilic at low temperature, the copolymers showed amphiphilic characters at temperatures close to the cloud points (CP). Interestingly, cloud points were not controlled by the PEtOx graft length as it has been reported for PEtOx homopolymers but it depended mainly upon the PEtOx content of the copolymer, with a critical value around 75 PEtOx wt%. Addition of a kosmotropic salt (Na2SO4) allowed to trigger CPs from 80 °C till 26 °C. The self-assembling properties of this family of hydrophilic and biocompatible copolymers may offer promising prospect in the field of biomedical applications as bioreactors.

Response to Comment on “Following Molecular Mobility during Chemical Reactions: No Evidence for Active Propulsion” and “Molecular Diffusivity of Click Reaction Components: The Diffusion Enhancement Question”

In their Comment (DOI: 10.1021/jacs.2c02965) on two related publications by our group (J. Am. Chem. Soc.2022, 144, 1380–1388; DOI: 10.1021/jacs.1c11754) and another (J. Am. Chem. Soc.2021, 143, 20884–20890; DOI: 10.1021/jacs.1c09455), Huang and Granick refer to the diffusion NMR measurements of molecules during a copper-catalyzed azide–alkyne cycloaddition (CuAAC) “click” reaction. Here we respond to their comments and maintain that no measurable diffusion enhancement was observed during the reaction. We expand on the physical arguments presented in our original JACS Article regarding the appropriate reference state for the diffusion coefficient and present new data showing that the use of other reference states, as suggested by Huang and Granick, will still support our conclusion that the two reactants and one product of the CuAAC reaction do not exhibit boosted mobility during the reaction.

Response to Comment on "Following Molecular Mobility during Chemical Reactions: No Evidence for Active Propulsion" and "Molecular Diffusivity of Click Reaction Components: The Diffusion Enhancement Question".

In their Comment (DOI: 10.1021/jacs.2c02965) on two related publications by our groups (J. Am. Chem. Soc. 2021, 143, 20884-20890; DOI: 10.1021/jacs.1c09455) and another (J. Am. Chem. Soc. 2022, 144, 1380-1388; DOI: 10.1021/jacs.1c11754), Huang and Granick discuss the diffusion NMR measurements of molecules during a copper-catalyzed azide-alkyne cycloaddition (CuAAC) "click" reaction. Here we respond to these comments and maintain that no diffusion enhancement was observed for any species during the reaction. We show that the relaxation agent does not interfere with the CuAAC reaction kinetics nor the diffusion of the molecules involved. Similarly, the gradient pulse length and diffusion time do not affect the diffusion coefficients. Peak overlap was completely removed in our study with the use of hydrazine as the reducing agent. The steady-state assumption does not hold for these diffusion measurements that take several minutes, which is the reason monotonic gradient orders are not suitable. Finally, we discuss the other reactions where similar changes in diffusion have been claimed. Our conclusions are fully supported by the results represented in our original JACS Article and the corresponding Supporting Information.

Application of the Functionality Transfer Oligodeoxynucleotide for the Site-Selective Modification of RNA with a Divers Molecule.

Due to the importance of the RNA chemical modifications, methods for the selective chemical modification at a predetermined site of the internal position of RNA have attracted much attention. We have developed functional artificial nucleic acids that modify a specific site of RNA in a site- and base-selective manner. In addition, the copper-catalyzed azide-alkyne cycloaddition (CuAAC) has been shown to introduce additional molecules on the alkynes attached to the pyridine ring. However, it was found that some azide compounds produced the cycloadduct in lower yields. Therefore, in this study, we synthesized the pyridinyl transfer group with the alkyne attached via a polyethylene glycol (PEG) linker with a different length and optimized its structure for both the transfer and CuAAC reaction. Three new transfer groups were synthesized by introducing an alkyne group at the end of the triethylene (11), tetraethylene (12) or pentaethylen glycol linker (13) at the 5-position of the pyridine ring of (E)-3-iodo-1-(pyridin-2-yl)prop-2-en-1-one. These transfer groups were introduced to the 6-thioguanine base in the oligodeoxynucleotide (ODN) in high yields. The transfer groups 11 and 12 more efficiently underwent the cytosine modification. For the CuAAC reaction, although 7 showed low adduct yields with the anionic azide compound, the new transfer groups, especially 12 and 13, significantly improved the yields. In conclusion, the transfer groups 12 and 13 were determined to be promising compounds for the modification of long RNAs.

N-Acetylenethio phthalimides: Sequential linkage for compositional click reaction

Click chemistry has become a useful tool for diverse molecular linkage and modification, and the development of new click strategy that enable reversibility and multifunctionality is of high demand for the multifunction and drug release. Herein, compositionally clicking combined regioselective iridium-catalyzed azide-alkynthio cycloaddition (Ir-AAC) and disulfuration has been developed for the sequential linkage from N -acetylenethio phthalimides, naturally occurring thiols and readily available azides. This method has been successfully applied to the construction of drug hybrids, peptide modification and glycosylation. Furthermore, by the design of diacetylenethio phthalimide as a platform molecule, trifunctional conjugants were sequentially linked through independent Ir-AAC, disulfuration and Cu-AAC reaction for hydrophobic tagging ternary PROTACs. An iridium-catalyzed azide-alkynthio phthalimides cycloaddition has been developed for the regioselective construction of diverse N -triazolylthio phthalimides, and the developed compositional cycloaddition and disulfuration click was applied for the reversibly sequential linkage of drug hybrids, peptide modification and glycosylation.

Combining CuAAC reaction enables sialylated Bi- and triantennary pseudo mannose N-glycans for investigating Siglec-7 interactions

Naturally occurring N-glycans display much diversity in modifications, linkages, and peripheral presentation of the oligosaccharide chain. Despite continued advancements in oligosaccharide synthesis, synthetic access to these natural glycans remains challenging. Biologically relevant complex N-glycan mimetics with various natural and unnatural modifications are an alternate way for investigating glycan–protein interactions. Further supporting this pattern, we report here a new class of sialylated bi- and triantennary pseudo mannose N-glycans reproducing orientation of the underlying glycan chain and branching patterns and replacing the two inner mannopyranosyl units with 1,2,3-triazole rings. Such mimetics are straightforwardly generated by implementing multiple intermolecular Cu(I)-catalyzed azide–alkyne cycloaddition between chemoenzymatically synthesized azido sialosides and rationally designed C-3 and C-6 di-O- or C-2, C-3, and C-6 tri-O-alkynylated mannoside. Human recombinant Siglec-7-Fc fusion protein recognizes almost all sialylated pseudo mannose N-glycans in the microarray. However, a differential Sia-binding pattern was also observed. Given the library size, comparison of pairwise mannose N-glycan combinations showed that biantennary linear α(2,3)α(2,8)- and α(2,6)α(2,8)- or branched α(2,3)α(2,6)-, and triantennary branched α(2,3)α(2,6)-sialyl pseudo N-glycans possess similar binding capabilities and affinity to recombinant Siglec-7-Fc. While the full range of topological mannose arms remain elusive, the bi- and triantennary mimics are simpler structures for interrogating Siglec interactions.

A Copper Iodide Cluster‐Based Metal–Organic Polyhedra for Photocatalytic Click Chemistry

Light-Induced CuAAC Reaction In article number 2100155 by Guo-Hong Ning, Dan Li, Xuanfeng Jiang, and co-workers, a novel copper-iodide cluster-based metal–organic polyhedra (MOP) with half-truncated cube topology is prepared through conformation-adaptive self-assembly strategy. This MOP containing unprecedent Cu3I3 cluster node highly exhibits photo-catalytic activity towards CuAAC reaction under the WLED irradiation in water.

Novel octanuclear copper(I) clusters [Cu8{(N)-(μ4-S)}4(μ3-I)2I2(PPh3)2] produced via reductive S-S bond cleavage of disulfide Schiff base ligands and their use as efficient heterogeneous catalysts in CuAAC click reaction

Thiol/disulfide interconversion, catalyzed by metal ions and enzymes, is a fundamental transformation and plays important roles in biological systems. The thiolates, produced in these reactions, are particularly versatile sulfur-containing ligands that can bind to metals or group of metals via a variety of modes and this versatility can lead to the formation of polymeric chains and metal clusters with high nuclearity. Herein, we report the facile one pot synthesis of novel octanuclear copper(I) complexes, [Cu8{(N)-(μ4-S)}4(μ3-I)2I2(PPh3)2] (1–5), by the reaction of copper(I) iodide and disulfide Schiff base molecules (R-CHN˗Ph˗S˗S˗Ph-NCH-R, RMePh = 4-MePh (SB1), RMeOPh = 4-MeOPh (SB2), RMeSPh = 4-MeSPh (SB3), RBrPh = 4-BrPh (SB4), and RFur = 2-furan (SB5)) in the presence of PPh3 in dichloromethane-acetonitrile or chloroform-acetonitrile solution under ambient conditions. Single-crystal X-ray structure analyses of these clusters confirm the presence of Cu8S4I4 core stabilized by the chelating Schiff base thiolate fragment R-CHN˗Ph˗Sˉ produced by the reductive cleavage of disulfide bond, Iˉ, and PPh3. DFT calculations have been performed to describe a speculative mechanism of cluster formation. The octanuclear clusters [Cu8{(N)-(μ4-S)}4(μ3-I)2I2(PPh3)2] (1–5) have been exploited as efficient heterogeneous catalysts for the green synthesis of 1,2,3-triazoles from NaN3, alkyl halides, and alkyne derivatives (CuAAC reaction) under mild conditions.

Concerted Cycloaddition Mechanism in the CuAAC Reaction Catalyzed by 1,8-Naphthyridine Dicopper Complexes

Copper-catalyzed azide-alkyne cycloaddition (CuAAC) is one of the most versatile reactions in the “click chemistry” toolbox, and its development has made the synthesis of 1,4-triazole derivatives robust and efficient. In this work, we present a density functional theory (DFT) study on the mechanism of the CuAAC reaction catalyzed by a dicopper complex supported by a nonsymmetric 1,8-naphtyridine ligand bearing two different metal-coordinating substituents (i.e., −P(tBu)2 and −C(Me)(Py)2). The calculations showed that the cycloaddition of the azide to the alkyne occurs in a single concerted step, in contrast with the two-step mechanism proposed in the literature. The energies predicted for this step indicated that the 1,4-triazole isomer of the product is formed in a selective manner, in agreement with experiments. Further, the DFT results showed that there is a subtle and complex interplay between several variables, including the relative orientation of the two substrates, the position of the counter-anion, and the partial decoordination of the 1,8-naphtyridine ligand. A series of 90 transition state calculations showed that, on average, the impact of these variables is strong on the structures but soft on the energy barriers, highlighting the flexible nature of the bonding within the coordination sphere of the bimetallic core of the catalyst. The insight provided by this study will be valuable for the further development of dicopper catalysts for the CuAAC reaction.

Highly efficient catalytic performance on CuAAC reaction by polymer‐like supramolecular self‐assemblies‐Cu(I) in aqueous solution

A series of AA/BB types of cyclodextrin‐based supramolecular polymers (CD‐SP 1, 2, 3, and 4) have been constructed and characterized, which employed as ligands to accelerate the copper(I)‐catalyzed azide alkyne cycloaddition (CuAAC) using the conventional Sharpless–Fokin catalyst (CuSO4 + Na ascorbate) for the first time. Among them, the bridged‐maleic‐2‐β‐CD (CD = cyclodextrin)@bridged‐maleic‐2‐Ada (Ada = adamantane) (CD‐SP 4) self‐assembly shows more effective catalytic activity for CuAAC of azide and acetylene at 40 mol ppm of Cu(I) in water with excellent yields and remarkable TON (turnover number) values (up to 23,750). CD‐SP 4 can be fully recycled, and the catalyst can be reused efficiently for 10 times with negligible loss of catalyst activity. Therefore, it may extend the potential applications of cyclodextrin‐based supramolecular polymers in green chemical synthesis.

Synthesis, spectroscopic characterization of novel phthalimides derivatives bearing a 1,2,3-triazole unit and examination as potential SARS-CoV-2 inhibitors via in silico studies

In the present study, novel phthalimide derivatives 8(a-f) and 9(a-f) bearing a 1,2,3-triazole subunit were synthesized via CuAAC reactions and characterized by 1H, 13C NMR, HR-MS, and FT-IR analyses. To support the fight against SARS-CoV-2, in silico molecular docking studies were carried out to examine their interactions with the proteins of SARS-CoV-2 (Mpro and PLpro) and the protein-protein interactions (PPI) between the ACE2-spike (S1) in comparison with various inhibitors reported to be active by in vitro experiments. The ligand-protein stabilities of compounds 8a-Mpro, 8b-PLpro, and 9a-‘ACE2-S1’ showing the best binding energy and predicted inhibition constant values (Ki) were examined by molecular dynamics simulation studies. Finally, in silico ADMET properties of the target compounds were investigated using the Swiss ADME and ProTox-II web tools. According to in silico results, all phthalimide analogs may block the PPI between S1 and ACE2. The compounds may also inhibit the progression of the Mpro, and PLpro proteins of SARS-CoV-2. Additionally, it has been estimated that the compounds are suitable for oral administration and exhibit low levels of toxicity.

Retraction of “Pristine Graphene–Copper(II) Oxide Nanocatalyst: A Novel and Green Approach in CuAAC Reactions”

ADVERTISEMENT RETURN TO ISSUEPREVRetractionNEXTORIGINAL ARTICLEThis notice is a retraction.Retraction of “Pristine Graphene–Copper(II) Oxide Nanocatalyst: A Novel and Green Approach in CuAAC Reactions”Tripti VatsTripti VatsMore by Tripti Vats, Rituporn GogoiRituporn GogoiMore by Rituporn Gogoi, Pankaj GaurPankaj GaurMore by Pankaj Gaur, Anuradha SharmaAnuradha SharmaMore by Anuradha Sharma, Subrata Ghosh*Subrata GhoshMore by Subrata Ghosh, and Prem Felix Siril*Prem Felix SirilMore by Prem Felix SirilCite this: ACS Sustainable Chem. Eng. 2022, 10, 12, 4040Publication Date (Web):March 17, 2022Publication History Received14 February 2022Published online17 March 2022Published inissue 28 March 2022https://doi.org/10.1021/acssuschemeng.2c00895Copyright © 2022 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views499Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (459 KB) Get e-Alerts Get e-Alerts

Copper-catalyzed three-component synthesis of pyrrole-substituted 1,2-dihydroisoquinolines

A general approach to the synthesis of 1,3-disubstituted-1,2-dihydroisoquinolines was achieved with pyrrole and various electron withdrawing groups as substituents. CuAAC reaction on enynes yielded the resulting 1,2,3-triazole which spontaneously decomposed to the corresponding ketenimine. Nucleophilic attack by pyrrole and subsequent intramolecular Aza-Michael cyclization generated 1,2-dihydroisoquinolines in moderate to good yields. The optimized conditions allow for a range of substituents with excellent reproducibility.

N‐Functionalization of 4‐amino‐2‐(trifluoromethyl)‐1H‐pyrroles: Synthesis of N‐alkyl derivatives and 1,2,3‐triazol‐4‐yl‐pyrrole scaffolds

AbstractThe N‐functionalization of 4‐amino‐2‐trifluoromethyl‐1H‐pyrroles using alkyl halides is reported. The selectivity of the alkylation reaction was highly dependent on the nature of the alkyl halide and the reaction conditions applied, that is, methyl iodide may furnish N‐methyl or N,N‐dimethyl pyrroles, while allyl bromide furnishes N‐allyl or N,C‐diallyl analogs and propargyl bromide furnishes exclusively N‐propargyl pyrroles. The alkylated products were obtained between 65%–90% yields and were subjected to CuAAC reactions, which furnished conjugated 1,2,3‐triazoles in good yields (72%–91%). The structures of the obtained compounds were unambiguously determined via 2D‐NMR experiments.

Recent Advances in Copper-Based Solid Heterogeneous Catalysts for Azide-Alkyne Cycloaddition Reactions.

The copper(I)-catalyzed azide−alkyne cycloaddition (CuAAC) reaction is considered to be the most representative ligation process within the context of the “click chemistry” concept. This CuAAC reaction, which yields compounds containing a 1,2,3-triazole core, has become relevant in the construction of biologically complex systems, bioconjugation strategies, and supramolecular and material sciences. Although many CuAAC reactions are performed under homogenous conditions, heterogenous copper-based catalytic systems are gaining exponential interest, relying on the easy removal, recovery, and reusability of catalytically copper species. The present review covers the most recently developed copper-containing heterogenous solid catalytic systems that use solid inorganic/organic hybrid supports, and which have been used in promoting CuAAC reactions. Due to the demand for 1,2,3-triazoles as non-classical bioisosteres and as framework-based drugs, the CuAAC reaction promoted by solid heterogenous catalysts has greatly improved the recovery and removal of copper species, usually by simple filtration. In so doing, the solving of the toxicity issue regarding copper particles in compounds of biological interest has been achieved. This protocol is also expected to produce a practical chemical process for accessing such compounds on an industrial scale.

Copper-Containing Catalysts for Azide–Alkyne Cycloaddition in Supercritical CO2

Background: Chemical industry has increased the investment into and innovation capacity to supply chemicals from safe and sustainable sources, which will be essential to offering new solutions and supporting the green transition of the global economy and society. In this sense, the use of green solvents and reusable heterogeneous catalysts has emerged as a promising sustainable process strategy for engineering, chemistry and the environment. In this work, different homogeneous (copper bromide, CuBr and copper(II) acetate, Cu (CH3COO)2·H2O) and heterogeneous (Cu Wire, Cu Plate, Cu/β-SiC, pre-treated Cu Wire and pre-treated Cu Plate) copper catalysts were tested for the copper(I)-catalyzed alkyne–azide cycloaddition (CuAAC) reaction. In addition, the influence of different reaction media was analyzed, comparing the use of an organic solvent such as toluene and a green solvent such as supercritical CO2 (scCO2). Methods: Characterization of the catalysts includes by X-ray diffraction (XRD), Scan Electron Microscopy (SEM), Atomic absorption spectrophotometry (AA) and Temperature Programmed Reduction (TPR). Parameters such as catalyst loading, reaction time, reusability and leaching of the catalysts were studied to obtain more information on the CuAAC reaction in scCO2. Results: The pre-treated copper plate achieved a 57% increase in reaction yield compared to the non pre-treated copper plate. However, the recovery and reuse of the pre-treated copper plate showed a severe deterioration and a considerable change in its surface. Cu Wire (without pre-treatment) achieved yields of up to 94.2% after reusing it for five cycles. Conclusions: These results suggest the possibility to exploit the combination of heterogeneous catalysts and scCO2 and justify further research to highlight green solvents and simultaneously address the challenges of reaction, purification and recycling.

New 1,2,3-Triazoles from (R)-Carvone: Synthesis, DFT Mechanistic Study and In Vitro Cytotoxic Evaluation.

Aseries of novel 1,4-disubstituted 1,2,3-triazoles were synthesized from an (R)-carvone terminal alkyne derivative via a Cu (I)-catalyzed azide–alkyne cycloaddition reaction using CuSO4,5H2O as the copper (II) source and sodium ascorbate as a reducing agent which reduces Cu (II) into Cu (I). All the newly synthesized 1,2,3-triazoles 9a–h were fully identified on the basis of their HRMS and NMR spectral data and then evaluated for their cell growth inhibition potential by MTS assay against HT-1080 fibrosarcoma, A-549 lung carcinoma, and two breast adenocarcinoma (MCF-7 and MDA-MB-231) cell lines. Compound 9d showed notable cytotoxic effects against the HT-1080 and MCF-7 cells with IC50 values of 25.77 and 27.89 µM, respectively, while compound 9c displayed significant activity against MCF-7 cells with an IC50 value of 25.03 µM. Density functional calculations at the B3LYP/6-31G* level of theory were used to confirm the high reactivity of the terminal alkyne as a dipolarophile. Quantum calculations were also used to investigate the mechanism of both the uncatalyzed and copper (I)-catalyzed azide–alkyne cycloaddition reaction (CuAAC). The catalyzed reaction gives complete regioselectivity via a stepwise mechanism streamlining experimental observations. The calculated free-energy barriers 4.33 kcal/mol and 29.35 kcal/mol for the 1,4- and 1,5-regioisomers, respectively, explain the marked regioselectivity of the CuAAC reaction.

Untargeted Identification of Alkyne-Containing Natural Products Using Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reactions Coupled to LC-MS/MS.

Alkyne-containing natural products have been identified from plants, insects, algae, fungi, and bacteria. This class of natural products has been characterized as having a variety of biological activities. Polyynes are a subclass of acetylenic natural products that contain conjugated alkynes and are underrepresented in natural product databases due to the fact that they decompose during purification. Here we report a workflow that utilizes alkyne azide cycloaddition (AAC) reactions followed by LC-MS/MS analysis to identify acetylenic natural products. In this report, we demonstrate that alkyne azide cycloaddition reactions with p-bromobenzyl azide result in p-bromobenzyl-substituted triazole products that fragment to a common brominated tropylium ion. We were able to identify a synthetic alkyne spiked into the extract of Anabaena sp. PCC 7120 at a concentration of 10 μg/mL after optimization of MS/MS conditions. We then successfully identified the known natural product fischerellin A in the extract of Fischerella muscicola PCC 9339. Lastly, we identified the recently identified natural products protegenins A and C from Pseudomonas protegens Pf-5 through a combination of genome mining and RuAAC reactions. This is the first report of RuAAC reactions to detect acetylenic natural products. We also compare CuAAC and RuAAC reactions and find that CuAAC reactions produce fewer byproducts compared to RuAAC but is limited to terminal-alkyne-containing compounds. In contrast, RuAAC is capable of identification of both terminal and internal acetylenic natural products, but byproducts need to be eliminated from analysis by creation of an exclusion list. We believe that both CuAAC and RuAAC reactions coupled to LC-MS/MS represent a method for the untargeted identification of acetylenic natural products, but each method has strengths and weaknesses.

Synthesis and antiproliferative activity of 3-aryl-5-{[(1-aryl-1h-tetrazol-5-yl)thio]methyl}-1,2,4-oxadiazoles

Derivatives of 5-mercapto- 1H -tetrazole have long attracted the attention of researchers as promising groups for introduction into drug-like molecules within the concept of fragment-oriented drug design. One of the first drugs to contain this fragment was the beta-lactam antibiotic Cefamandole, which has been used for over 40 years to treat various infections caused by susceptible strains of bacteria, including lower respiratory tract infections, urinary tract infections, skin infections, bones and joints. Subsequently, a number of antibiotics containing the 5-mercapto-1H-tetrazole fragment were obtained. Recently, a series of new derivatives of 5-(1,2,3-triazolylmethylsulfanyl)tetrazole was synthesized by the CuAAC reaction, their antimicrobial activity showed moderate or good results compared to standard drugs. Moreover, 2-[(1-(naphthalen-1-yl)- 1H -tetrazol-5-yl)thio]- N -(2-nitrophenyl)acetamide is discovered for HIV treatment as a potent non-nucleoside nanomolar inhibitor of reverse transcriptase activity. A convenient route for the synthesis of such compounds is the preparation of 5-mercapto- 1H -tetrazole from various isothiocyanates by the reaction of 1,3-dipolar cycloaddition with sodium azide, trimethylsilyl azide or their synthetic equivalent, and subsequent alkylation of the thiol group. Given the availability of methods for the synthesis of these compounds and their valuable properties, the study aims to obtain a number of compounds and evaluate their antiproliferative properties. The starting 5-mercapto- 1H -tetrazoles were obtained from commercially available anilines. First, the anilines were converted to the corresponding isothiocyanates by the Kaluza method. The next reaction of isothiocyanates 2 with sodium azide in water synthesized the target 5-mercapto- 1H -tetrazoles 3 with approximately quantitative yield. At the same time, 5-(chloromethyl)-3-aryl-1,2,4-oxadiazoles were obtained by us earlier. The reaction of 5-mercapto- 1H -tetrazoles 3 with 5-(chloromethyl)-3-aryl-1,2,4-oxadiazoles 4 synthesized the target compounds, which were tested for antiproliferative activity. The synthesized compounds 5a-d were submitted and evaluated at a concentration of 10 -5 M on a panel of approximately 60 cancer cell lines. Human tumor cell lines have been derived from nine different types of cancer: leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, kidney, prostate, and breast cancer. Primary anti-cancer assays were performed according to the US NCI protocol (http://dtp.nci.nih.gov). The results for each compound are presented as the percentage of cell growth (GP, %). Unfortunately, the selected representatives of this molecular scaffold did not show high activity. Compound 5d showed the highest activity. In particular, this compound inhibited the growth of 44 % (GP = 66.01 %) of UO-31 kidney cancer cells. It should be noted that compounds 5b and 5c were also active against UO-31 cells, inhibiting their growth by almost 30 % (GP = 73.35 and 72.53 %), respectively. In addition, compound 5d was most active against T-47D breast cancer cells (GP = 75.69 %) and a number of leukemia cell lines (CCRF-CEM, K-562, MOLT-4, RPMI-8226, SR). In general, leukemia cells were the most sensitive to compounds 5 , while ovarian and prostate cancer panels were resistant. By convenient synthetic transformations we obtained representatives of the new molecular framework, which were investigated for antitumor activity. The compounds were found to have low activity, but have some selective effect on UO-31 kidney cancer cells. The obtained results indicate the need for significant modification of the molecular scaffold to discover more active compounds. Keywords: tetrazoles, 1,2,4-oxadiazoles, antiproliferative activity, cancer.

Development of sustainable synthesis of glucuronic acid glycodendrimers using ball milling and microwave-assisted CuAAC reaction

Two green strategies for CuAAC reaction based on two activation pathways, solvent free mechanochemistry and microwave irradiation using a recycable biosolvent, are reported for the synthesis of glucuronic acid glycodendrimers with good conversión.