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The Click Reaction: A Powerful and Widely Used Tool in Drug Discovery, Bioconjugation, and Materials Science

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Organic Chemistry".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 37099

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Dr. Joice Thomas

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The Bridge@USC and Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles, CA 90089, USA
Interests: medicinal chemistry; heterocycles; supramolecular chemistry; multicomponent reactions; macrocyclic chemistry; click chemistry; fluorine chemistry; sulfur(vi) fluoride exchange (sufex) chemistry

Dr. Nithya Joseph

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Guest Editor

KU Leuven, ku leuven Leuven Chemistry, Catalysis and Chemical Technology Research Centre, Leuven, Belgium
Interests: polymer membrane; nanofiltrations; separation science and technology; supramolecular polymers; thermoresponsive polymers; hyperbranched polymers

Dr. Dmitry Eremin

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The Bridge@USC, University of Southern California, Los Angeles, CA, USA
Interests: reactive intermediates in organic chemistry; mass spectrometry insight into catalysis; “on-water” transformations; covalent protein modification; combination of instrumental methods (NMR, MS, IR, x-Ray, EM) for synthetic tasks; computational approaches in modern chemistry

Special Issue Information

Dear Colleagues,

“Click” chemistry is a chemical philosophy introduced by Sharpless, Finn and Fokin in early 21st century and describes a methodology of neat tailoring of substances by joining small units together. “Click” chemistry has made an extensive contribution to many areas of modern chemistry from small molecule synthesis to drug discovery to materials science. Reactions united by the “click” family have a strong energy driving force that ensures starting compounds to react promptly, efficiently, and with no undesired byproducts even under physiological conditions, which make these transformations perfect models of biorthogonality. Examples of “click”-reactions include Copper-Catalyzed Azide-Alkyne Cycloaddition (CuAAC) Reaction, Strain-Promoted Azide-Alkyne Cycloaddition (SPAAC) Reaction, Strain-Promoted Alkyne-Nitrone Cycloaddition (SPANC) Reaction, Alkene and Tetrazine Inverse-Demand Diels-Alder Reaction, Alkene and Tetrazole Photoclick Reaction, Thiol–ene “click” reaction, Sulfur Fluorine Exchange (SuFEx) reaction etc.

Research papers, as well as reviews, will be considered for publication. This Special issue aims to focus on the applications of click chemistry in drug discovery, bioconjugation, and materials science. Resent advancement in methodology and mechanistic studies in the field of “click”-chemistry will be also covered in the Special issue.

Dr. Joice Thomas
Dr. Nithya Joseph
Dr. Dmitry Eremin
Guest Editors

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

CuAAC
SuFEx
Reactions of strained alkenes and alkynes
Thiol–ene “click” reaction
Multicomponent reaction
Mechanistic studies
Supramolecular chemistry
Macrocyclic chemistry
Biodegradable and clickable polymers
Polymer membranes
Polymer-based drug delivery systems
Functionalization of nanoparticles
Drug discovery
In situ click chemistry
Bioconjugate chemistry

Published Papers (10 papers)

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Research

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14 pages, 3143 KiB

Open AccessArticle

The Impact of a 1,2,3-Triazole Motif on the Photophysical Behavior of Non-K Tetrasubstituted Pyrene with a Substitution Pattern Providing the Long Axial Symmetry

by Dawid Zych and Aneta Slodek

Molecules 2022, 27(13), 4314; https://doi.org/10.3390/molecules27134314 - 05 Jul 2022

Cited by 4 | Viewed by 1445

Abstract

1,3,6,8-Tetrasubstituted pyrene derivatives with two types of substituents (4-(2,2-dimethylpropyloxy)pyridine, 1-decyl-1,2,3-triazole, 1-benzyl-1,2,3-triazole, and pyrazole), substituted in such a way that provides the long axial symmetry, are prepared and characterized in the present study. To the best of our knowledge, the pyrene derivative containing the same heteroaryl motif (triazole) but substituted by two various alkyls, straight decyl and benzyl-based side chains (C), is reported for the first time. For comparison, compounds with one kind of triazole motif and substituted pyridine or pyrazole groups were prepared (A and B). The photophysical properties of all molecules were evaluated by thermogravimetric analysis (TGA) and UV-Vis spectroscopy (absorption and emission spectra, quantum yields, and fluorescence lifetimes). The obtained results were compared to analogues substituted at the 1,3,6,8 positions by one kind of substituent and also with all the 1,3,6,8-tetrasubstituted pyrenes reported in the literature substituted by two kinds of substituents with a substitution pattern that provides long axial symmetry. In addition, theoretical studies based on DFT and TD-DFT were performed that supported the interpretation of the experimental results. The photophysical properties of tetrasubstituted pyrene derivatives having triazole units at the 1,8-positions, respectively, and other identical substituents at the 3,6 positions show the dominance of triazole units in the pyrene framework; the dominance is even higher in the case of the substitution of 1,3,6,8 positions by triazoles, but containing two various alkyls. Full article

(This article belongs to the Special Issue The Click Reaction: A Powerful and Widely Used Tool in Drug Discovery, Bioconjugation, and Materials Science)

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17 pages, 1869 KiB

Open AccessArticle

Design and Synthesis of Novel Podophyllotoxins Hybrids and the Effects of Different Functional Groups on Cytotoxicity

by Zhongtao Yang, Zitong Zhou, Xiai Luo, Xiaoling Luo, Hui Luo, Lianxiang Luo and Weiguang Yang

Molecules 2022, 27(1), 220; https://doi.org/10.3390/molecules27010220 - 30 Dec 2021

Cited by 5 | Viewed by 1575

Abstract

Development of novel anticancer therapeutic candidates is one of the key challenges in medicinal chemistry. Podophyllotoxin and its derivatives, as a potent cytotoxic agent, have been at the center of extensive chemical amendment and pharmacological investigation. Herein, a new series of podophyllotoxin-N-sulfonyl amidine hybrids (4a–4v, 5a–5f) were synthesized by a CuAAC/ring-opening procedure. All the synthesized podophyllotoxins derivatives were evaluated for in vitro cytotoxic activity against a panel of human lung (A-549) cancer cell lines. Different substituents’, or functional groups’ antiproliferative activities were discussed. The –CF₃ group performed best (IC₅₀: 1.65 μM) and exhibited more potent activity than etoposide. Furthermore, molecular docking and dynamics studies were also conducted for active compounds and the results were in good agreement with the observed IC₅₀ values. Full article

(This article belongs to the Special Issue The Click Reaction: A Powerful and Widely Used Tool in Drug Discovery, Bioconjugation, and Materials Science)

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15 pages, 2059 KiB

Open AccessArticle

Terminal and Internal Alkyne Complexes and Azide-Alkyne Cycloaddition Chemistry of Copper(I) Supported by a Fluorinated Bis(pyrazolyl)borate

by Anurag Noonikara-Poyil, Alvaro Muñoz-Castro and H. V. Rasika Dias

Molecules 2022, 27(1), 16; https://doi.org/10.3390/molecules27010016 - 21 Dec 2021

Cited by 2 | Viewed by 2979

Abstract

Copper plays an important role in alkyne coordination chemistry and transformations. This report describes the isolation and full characterization of a thermally stable, copper(I) acetylene complex using a highly fluorinated bis(pyrazolyl)borate ligand support. Details of the related copper(I) complex of HC≡CSiMe₃ are also reported. They are three-coordinate copper complexes featuring η²-bound alkynes. Raman data show significant red-shifts in C≡C stretch of [H₂B(3,5-(CF₃)₂Pz)₂]Cu(HC≡CH) and [H₂B(3,5-(CF₃)₂Pz)₂]Cu(HC≡CSiMe₃) relative to those of the corresponding alkynes. Computational analysis using DFT indicates that the Cu(I) alkyne interaction in these molecules is primarily of the electrostatic character. The π-backbonding is the larger component of the orbital contribution to the interaction. The dinuclear complexes such as Cu₂(μ-[3,5-(CF₃)₂Pz])₂(HC≡CH)₂ display similar Cu-alkyne bonding features. The mononuclear [H₂B(3,5-(CF₃)₂Pz)₂]Cu(NCMe) complex catalyzes [3 + 2] cycloadditions between tolyl azide and a variety of alkynes including acetylene. It is comparatively less effective than the related trinuclear copper catalyst {μ-[3,5-(CF₃)₂Pz]Cu}₃ involving bridging pyrazolates. Full article

(This article belongs to the Special Issue The Click Reaction: A Powerful and Widely Used Tool in Drug Discovery, Bioconjugation, and Materials Science)

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18 pages, 8706 KiB

Open AccessCommunication

Halomethyl-Triazoles for Rapid, Site-Selective Protein Modification

by Richard C. Brewster and Alison N. Hulme

Molecules 2021, 26(18), 5461; https://doi.org/10.3390/molecules26185461 - 08 Sep 2021

Viewed by 2163

Abstract

Post-translational modifications (PTMs) are used by organisms to control protein structure and function after protein translation, but their study is complicated and their roles are not often well understood as PTMs are difficult to introduce onto proteins selectively. Designing reagents that are both good mimics of PTMs, but also only modify select amino acid residues in proteins is challenging. Frequently, both a chemical warhead and linker are used, creating a product that is a misrepresentation of the natural modification. We have previously shown that biotin-chloromethyl-triazole is an effective reagent for cysteine modification to give S-Lys derivatives where the triazole is a good mimic of natural lysine acylation. Here, we demonstrate both how the reactivity of the alkylating reagents can be increased and how the range of triazole PTM mimics can be expanded. These new iodomethyl-triazole reagents are able to modify a cysteine residue on a histone protein with excellent selectivity in 30 min to give PTM mimics of acylated lysine side-chains. Studies on the more complicated, folded protein SCP-2L showed promising reactivity, but also suggested the halomethyl-triazoles are potent alkylators of methionine residues. Full article

(This article belongs to the Special Issue The Click Reaction: A Powerful and Widely Used Tool in Drug Discovery, Bioconjugation, and Materials Science)

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11 pages, 1740 KiB

Open AccessArticle

Copper-Catalyzed One-Pot Synthesis of N-Sulfonyl Amidines from Sulfonyl Hydrazine, Terminal Alkynes and Sulfonyl Azides

by Yu Zhao, Zitong Zhou, Man Chen and Weiguang Yang

Molecules 2021, 26(12), 3700; https://doi.org/10.3390/molecules26123700 - 17 Jun 2021

Cited by 4 | Viewed by 2308

Abstract

N-Sulfonyl amidines are developed from a Cu-catalyzed three-component reaction from sulfonyl hydrazines, terminal alkynes and sulfonyl azides in toluene at room temperature. Particularly, the intermediate N-sulfonylketenimines was generated via a CuAAC/ring-opening procedure and took a nucleophilic addition with the weak nucleophile [...] Read more.

(This article belongs to the Special Issue The Click Reaction: A Powerful and Widely Used Tool in Drug Discovery, Bioconjugation, and Materials Science)

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9 pages, 1533 KiB

Open AccessArticle

ESI-MS Analysis of Thiol-yne Click Reaction in Petroleum Medium

by Evgeniya S. Degtyareva, Julia V. Burykina and Valentine P. Ananikov

Molecules 2021, 26(10), 2896; https://doi.org/10.3390/molecules26102896 - 13 May 2021

Cited by 4 | Viewed by 2372

Abstract

Petroleum contains a large number of heteroatomic compounds, but today, most of them are not efficiently utilized. The constant development of the sustainability concept recalls for rethinking the usage of fossil resources with improved chemical utility. In order to initiate research aimed at involving active petroleum compounds in chemical transformations, a new analytical method for product detection is needed. Here, we study the click reaction of thiols with alkynes, leading to the formation of α-vinyl sulfides directly in the petroleum environment. The reaction was carried out using an (IMes)Pd(acac)Cl catalyst, which demonstrated tolerance to petroleum components. In this study, the concentration of thiols ranged from 1 M to 0.01 M (from 8% to 0.1%). To detect products at low concentrations, a special alkyne labeled with an imidazole moiety was used. This approach made it possible to observe the formation of vinyl sulfides by electrospray ionization mass spectrometry (ESI-MS), which provides an opportunity for further optimization of the reaction conditions and future developments for the direct involvement of oil components in chemical reactions. Full article

(This article belongs to the Special Issue The Click Reaction: A Powerful and Widely Used Tool in Drug Discovery, Bioconjugation, and Materials Science)

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16 pages, 9093 KiB

Open AccessArticle

New 1,2,3-Triazole-Containing Hybrids as Antitumor Candidates: Design, Click Reaction Synthesis, DFT Calculations, and Molecular Docking Study

by Islam H. El Azab, Hamdy S. El-Sheshtawy, Rania B. Bakr and Nadia A. A. Elkanzi

Molecules 2021, 26(3), 708; https://doi.org/10.3390/molecules26030708 - 29 Jan 2021

Cited by 30 | Viewed by 3652

Abstract

In an effort to improve and achieve biologically active anticancer agents, a novel series of 1,2,3-triazole-containing hybrids were designed and efficiently synthesized via the Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction of substituted-arylazides with alkyne-functionalized pyrazole-[1,2,4]-triazole hybrids. The structure geometry of these new clicked 1,2,3-triazoles was explored by density functional theory (DFT) using the B3LYP/6-311++G(d,p) level; also, the potential activity of the compounds for light absorption was simulated by time-dependent DFT calculations (TD-DFT). The antitumor impacts of the newly synthesized compounds were in vitro estimated to be towards the human liver cancer cell line (HepG-2), the human colon cancer cell line (HCT-116), and human breast adenocarcinoma (MCF-7). Among the tested compounds, conjugate 7 was the most potent cytotoxic candidate towards HepG-2, HCT-116, and MCF-7, with IC₅₀ = 12.22, 14.16, and 14.64 µM, respectively, in comparison to that exhibited by the standard drug doxorubicin (IC₅₀ = 11.21, 12.46, and 13.45 µM). Finally, a molecular docking study was conducted within the epidermal growth factor receptor (EGFR) active site to suggest possible binding modes. Hence, it could conceivably be hypothesized that analogies 7, 6, and 5 could be considered as decent lead candidate compounds for anticancer agents. Full article

(This article belongs to the Special Issue The Click Reaction: A Powerful and Widely Used Tool in Drug Discovery, Bioconjugation, and Materials Science)

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Review

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17 pages, 3929 KiB

Open AccessReview

Recent Advances about the Applications of Click Reaction in Chemical Proteomics

by Tingting Yao, Xiaowei Xu and Rong Huang

Molecules 2021, 26(17), 5368; https://doi.org/10.3390/molecules26175368 - 03 Sep 2021

Cited by 8 | Viewed by 6663

Abstract

Despite significant advances in biological and analytical approaches, a comprehensive portrait of the proteome and its dynamic interactions and modifications remains a challenging goal. Chemical proteomics is a growing area of chemical biology that seeks to design small molecule probes to elucidate protein composition, distribution, and relevant physiological and pharmacological functions. Click chemistry focuses on the development of new combinatorial chemical methods for carbon heteroatom bond (C-X-C) synthesis, which have been utilized extensively in the field of chemical proteomics. Click reactions have various advantages including high yield, harmless by-products, and simple reaction conditions, upon which the molecular diversity can be easily and effectively obtained. This paper reviews the application of click chemistry in proteomics from four aspects: (1) activity-based protein profiling, (2) enzyme-inhibitors screening, (3) protein labeling and modifications, and (4) hybrid monolithic column in proteomic analysis. Full article

(This article belongs to the Special Issue The Click Reaction: A Powerful and Widely Used Tool in Drug Discovery, Bioconjugation, and Materials Science)

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19 pages, 4175 KiB

Open AccessReview

IEDDA: An Attractive Bioorthogonal Reaction for Biomedical Applications

by Maryana Handula, Kuo-Ting Chen and Yann Seimbille

Molecules 2021, 26(15), 4640; https://doi.org/10.3390/molecules26154640 - 30 Jul 2021

Cited by 26 | Viewed by 5733

Abstract

The pretargeting strategy has recently emerged in order to overcome the limitations of direct targeting, mainly in the field of radioimmunotherapy (RIT). This strategy is directly dependent on chemical reactions, namely bioorthogonal reactions, which have been developed for their ability to occur under physiological conditions. The Staudinger ligation, the copper catalyzed azide-alkyne cycloaddition (CuAAC) and the strain-promoted [3 + 2] azide–alkyne cycloaddition (SPAAC) were the first bioorthogonal reactions introduced in the literature. However, due to their incomplete biocompatibility and slow kinetics, the inverse-electron demand Diels-Alder (IEDDA) reaction was advanced in 2008 by Blackman et al. as an optimal bioorthogonal reaction. The IEDDA is the fastest bioorthogonal reaction known so far. Its biocompatibility and ideal kinetics are very appealing for pretargeting applications. The use of a trans-cyclooctene (TCO) and a tetrazine (Tz) in the reaction encouraged researchers to study them deeply. It was found that both reagents are sensitive to acidic or basic conditions. Furthermore, TCO is photosensitive and can be isomerized to its cis-conformation via a radical catalyzed reaction. Unfortunately, the cis-conformer is significantly less reactive toward tetrazine than the trans-conformation. Therefore, extensive research has been carried out to optimize both click reagents and to employ the IEDDA bioorthogonal reaction in biomedical applications. Full article

(This article belongs to the Special Issue The Click Reaction: A Powerful and Widely Used Tool in Drug Discovery, Bioconjugation, and Materials Science)

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27 pages, 6187 KiB

Open AccessReview

Modified Nucleosides, Nucleotides and Nucleic Acids via Click Azide-Alkyne Cycloaddition for Pharmacological Applications

by Daniela Perrone, Elena Marchesi, Lorenzo Preti and Maria Luisa Navacchia

Molecules 2021, 26(11), 3100; https://doi.org/10.3390/molecules26113100 - 22 May 2021

Cited by 12 | Viewed by 4555

Abstract

The click azide = alkyne 1,3-dipolar cycloaddition (click chemistry) has become the approach of choice for bioconjugations in medicinal chemistry, providing facile reaction conditions amenable to both small and biological molecules. Many nucleoside analogs are known for their marked impact in cancer therapy and for the treatment of virus diseases and new targeted oligonucleotides have been developed for different purposes. The click chemistry allowing the tolerated union between units with a wide diversity of functional groups represents a robust means of designing new hybrid compounds with an extraordinary diversity of applications. This review provides an overview of the most recent works related to the use of click chemistry methodology in the field of nucleosides, nucleotides and nucleic acids for pharmacological applications. Full article

(This article belongs to the Special Issue The Click Reaction: A Powerful and Widely Used Tool in Drug Discovery, Bioconjugation, and Materials Science)

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