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Pharmaceuticals
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Click Reactions in Medicinal Chemistry
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Click Reactions in Medicinal Chemistry

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 October 2022) | Viewed by 15198

Special Issue Editor

Dr. Damien Bosc

E-Mail Website
Guest Editor
Inserm—Institut Pasteur de Lille, U1177—Drugs and Molecules for Living Systems, Université de Lille, 59006 Lille, France
Interests: click chemistry; macrocycles; drug design; metalloproteases; KTGS; medicinal chemistry; chemical probes; chemical space; new modalities.
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Since the term “click chemistry” was coined by K. B. Sharpless 20 years ago, click reactions have offered their wide range of assets to medicinal chemists. These reactions share many features such as high yield, modularity, large scope, and stereospecificity, which meet the requirements of drug discovery. This field is indeed in constant search of methodologies allowing a fast and easy access to large libraries of compounds. The ability to carry out click reactions in biological media is of great interest to medicinal chemists who wish to perform chemistry with biological macromolecules.

The flagship of click chemistry reactions, copper-catalyzed azide-alkyne cycloaddition (CuAAC), has all of these advantages. Moreover, the resulting 1,4-disubstituted 1,2,3-triazoles exhibit favorable physicochemical properties that are particularly appealing for medicinal chemists. In addition to CuAAC, other click reactions are exploited for drug discovery such as cycloadditions involving various reactants (e.g., mesoionics, isocyanides, alkenes), nucleophilic substitutions on three-membered heterocycles (epoxides, aziridines), and addition reactions to carbon–carbon multiple bonds or sulfur-fluoride exchange (SuFEx).

The applications of click reactions in medicinal chemistry are numerous. Almost all facets of drug discovery are involved. For example, bioorthogonal click reactions are convenient for designing chemical probes for target validation and proteomics. Hits can then be identified by screening large libraries stemming from diversity-oriented click synthesis or by in situ protein-templated click chemistry. Click reactions are also useful for lead optimization with considerations of bioisosterism, pharmacophore, linking, and ADME.

For this Special Issue of Pharmaceuticals, comprehensive reviews, original research articles, and short communications highlighting the potential of click reactions in medicinal chemistry and focusing on, but not limited to, the synthesis of privileged scaffolds, the design and optimization of small molecules, or new modalities (macrocycles, PROTACs) for therapeutic applications and proteomics are welcome.

Dr. Damien Bosc
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 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

  • click chemistry
  • drug discovery
  • chemical probes
  • bioorthogonal reactions
  • protein-templated reactions
  • bioisosteres
  • bioconjugation
  • cycloaddition
  • 1,2,3-triazole
  • chemical space

Published Papers (6 papers)

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Editorial

Jump to: Research, Review

2 pages, 185 KiB  
Editorial
Click Reactions in Medicinal Chemistry
by Damien Bosc
Pharmaceuticals 2023, 16(10), 1361; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16101361 - 27 Sep 2023
Viewed by 574
Abstract
Two decades after K [...] Full article
(This article belongs to the Special Issue Click Reactions in Medicinal Chemistry)

Research

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13 pages, 2098 KiB  
Article
Synthesis and Anti-Tumor Effects of Novel Pomalidomide Derivatives Containing Urea Moieties
by Yajie Guo, Xi Wang, Zhenzhen Wang, Longfei Mao, Jiahao Wang, Lizeng Peng and Guiqing Xu
Pharmaceuticals 2022, 15(12), 1479; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15121479 - 27 Nov 2022
Cited by 2 | Viewed by 1945
Abstract
In order to explore novel immunomodulatory agents as anti-tumor drugs, we designed and synthesized a series of new pomalidomide derivatives containing urea moieties. Interestingly, in vitro biological experiments performed in several cancer cell lines showed that some of them displayed potent anti-tumor ability. [...] Read more.
In order to explore novel immunomodulatory agents as anti-tumor drugs, we designed and synthesized a series of new pomalidomide derivatives containing urea moieties. Interestingly, in vitro biological experiments performed in several cancer cell lines showed that some of them displayed potent anti-tumor ability. These novel compounds 5a–5e and 6a–6e demonstrated the best cell growth inhibitive activity in human breast cancer cell lines MCF-7, but weaker inhibitive activity in human hepatocellular carcinoma cell lines Huh7. Moreover, compound 5d had the most powerful effects in this study, with an IC50 value of 20.2 μM in MCF-7. Further study indicated that compound 5d could inhibit cell growth and induce cell death in a concentration-dependent manner. Besides, compound 5d increased cellular ROS levels and induced DNA damage, thereby potentially leading to cell apoptosis. These observations suggest that the novel pomalidomide derivatives containing urea moieties may be worth further investigation to generate potential anti-tumor drugs. Full article
(This article belongs to the Special Issue Click Reactions in Medicinal Chemistry)
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12 pages, 2601 KiB  
Article
Discovery of Novel 1,2,3-triazole Derivatives as IDO1 Inhibitors
by Xixi Hou, Xiaoqing Gong, Longfei Mao, Jie Zhao and Jianxue Yang
Pharmaceuticals 2022, 15(11), 1316; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15111316 - 25 Oct 2022
Cited by 3 | Viewed by 1441
Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) has received much attention as an immunomodulatory enzyme in the field of cancer immunotherapy. While several IDO1 inhibitors have entered clinical trials, there are currently no IDO1 inhibitor drugs on the market. To explore potential IDO1 inhibitors, we designed [...] Read more.
Indoleamine 2,3-dioxygenase 1 (IDO1) has received much attention as an immunomodulatory enzyme in the field of cancer immunotherapy. While several IDO1 inhibitors have entered clinical trials, there are currently no IDO1 inhibitor drugs on the market. To explore potential IDO1 inhibitors, we designed a series of compounds with urea and 1,2,3-triazole structures. Organic synthesis and IDO1 enzymatic activity experiments verified the molecular-level activities of the designed compounds, and the IC50 value of compound 3a was 0.75 μM. Molecular docking and quantum mechanical studies further explained the binding mode and reaction potential of compound 3a with IDO1. Our research has resulted in a series of novel IDO1 inhibitors, which is beneficial to the development of drugs targeting IDO1 in numerous cancer diseases. Full article
(This article belongs to the Special Issue Click Reactions in Medicinal Chemistry)
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15 pages, 3948 KiB  
Article
Pretargeted Imaging beyond the Blood–Brain Barrier—Utopia or Feasible?
by Sara Lopes van den Broek, Vladimir Shalgunov, Rocío García Vázquez, Natalie Beschorner, Natasha S. R. Bidesi, Maiken Nedergaard, Gitte M. Knudsen, Dag Sehlin, Stina Syvänen and Matthias M. Herth
Pharmaceuticals 2022, 15(10), 1191; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15101191 - 27 Sep 2022
Cited by 8 | Viewed by 2062
Abstract
Pretargeting is a promising nuclear imaging technique that allows for the usage of antibodies (Abs) with enhanced imaging contrast and reduced patient radiation burden. It is based on bioorthogonal chemistry with the tetrazine ligation—a reaction between trans-cyclooctenes (TCOs) and tetrazines (Tzs)—currently being [...] Read more.
Pretargeting is a promising nuclear imaging technique that allows for the usage of antibodies (Abs) with enhanced imaging contrast and reduced patient radiation burden. It is based on bioorthogonal chemistry with the tetrazine ligation—a reaction between trans-cyclooctenes (TCOs) and tetrazines (Tzs)—currently being the most popular reaction due to its high selectivity and reactivity. As Abs can be designed to bind specifically to currently ‘undruggable’ targets such as protein isoforms or oligomers, which play a crucial role in neurodegenerative diseases, pretargeted imaging beyond the BBB is highly sought after, but has not been achieved yet. A challenge in this respect is that large molecules such as Abs show poor brain uptake. Uptake can be increased by receptor mediated transcytosis; however, it is largely unknown if the achieved brain concentrations are sufficient for pretargeted imaging. In this study, we investigated whether the required concentrations are feasible to reach. As a model Ab, we used the bispecific anti-amyloid beta (Aβ) anti-transferrin receptor (TfR) Ab 3D6scFv8D3 and conjugated it to a different amount of TCOs per Ab and tested different concentrations in vitro. With this model in hand, we estimated the minimum required TCO concentration to achieve a suitable contrast between the high and low binding regions. The estimation was carried out using pretargeted autoradiography on brain sections of an Alzheimer’s disease mouse model. Biodistribution studies in wild-type (WT) mice were used to correlate how different TCO/Ab ratios alter the brain uptake. Pretargeted autoradiography showed that increasing the number of TCOs as well as increasing the TCO-Ab concentration increased the imaging contrast. A minimum brain concentration of TCOs for pretargeting purposes was determined to be 10.7 pmol/g in vitro. Biodistribution studies in WT mice showed a brain uptake of 1.1% ID/g using TCO-3D6scFv8D3 with 6.8 TCO/Ab. According to our estimations using the optimal parameters, pretargeted imaging beyond the BBB is not a utopia. Necessary brain TCO concentrations can be reached and are in the same order of magnitude as required to achieve sufficient contrast. This work gives a first estimate that pretargeted imaging is indeed possible with antibodies. This could allow the imaging of currently ‘undruggable’ targets and therefore be crucial to monitor (e.g., therapies for intractable neurodegenerative diseases). Full article
(This article belongs to the Special Issue Click Reactions in Medicinal Chemistry)
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32 pages, 6428 KiB  
Article
The Design and Synthesis of a New Series of 1,2,3-Triazole-Cored Structures Tethering Aryl Urea and Their Highly Selective Cytotoxicity toward HepG2
by Sittisak Oekchuae, Jitnapa Sirirak, Purin Charoensuksai, Pawaris Wongprayoon, Natthaya Chuaypen, Jutatip Boonsombat, Somsak Ruchirawat, Pisit Tangkijvanich, Apichart Suksamrarn and Panupun Limpachayaporn
Pharmaceuticals 2022, 15(5), 504; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15050504 - 20 Apr 2022
Cited by 5 | Viewed by 2989
Abstract
Target cancer drug therapy is an alternative treatment for advanced hepatocellular carcinoma (HCC) patients. However, the treatment using approved targeted drugs has encountered a number of limitations, including the poor pharmacological properties of drugs, therapy efficiency, adverse effects, and drug resistance. As a [...] Read more.
Target cancer drug therapy is an alternative treatment for advanced hepatocellular carcinoma (HCC) patients. However, the treatment using approved targeted drugs has encountered a number of limitations, including the poor pharmacological properties of drugs, therapy efficiency, adverse effects, and drug resistance. As a consequence, the discovery and development of anti-HCC drug structures are therefore still in high demand. Herein, we designed and synthesized a new series of 1,2,3-triazole-cored structures incorporating aryl urea as anti-HepG2 agents. Forty-nine analogs were prepared via nucleophilic addition and copper-catalyzed azide-alkyne cycloaddition (CuAAC) with excellent yields. Significantly, almost all triazole-cored analogs exhibited less cytotoxicity toward normal cells, human embryonal lung fibroblast cell MRC-5, compared to Sorafenib and Doxorubicin. Among them, 2m’ and 2e exhibited the highest selectivity indexes (SI = 14.7 and 12.2), which were ca. 4.4- and 3.7-fold superior to that of Sorafenib (SI = 3.30) and ca. 3.8- and 3.2-fold superior to that of Doxorubicin (SI = 3.83), respectively. Additionally, excellent inhibitory activity against hepatocellular carcinoma HepG2, comparable to Sorafenib, was still maintained. A cell-cycle analysis and apoptosis induction study suggested that 2m’ and 2e likely share a similar mechanism of action to Sorafenib. Furthermore, compounds 2m’ and 2e exhibit appropriate drug-likeness, analyzed by SwissADME. With their excellent anti-HepG2 activity, improved selectivity indexes, and appropriate druggability, the triazole-cored analogs 2m’ and 2e are suggested to be promising candidates for development as targeted cancer agents and drugs used in combination therapy for the treatment of HCC. Full article
(This article belongs to the Special Issue Click Reactions in Medicinal Chemistry)
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Review

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25 pages, 7419 KiB  
Review
Recent Advances in the Development of Tetrazine Ligation Tools for Pretargeted Nuclear Imaging
by Rocío García-Vázquez, Umberto Maria Battisti and Matthias M. Herth
Pharmaceuticals 2022, 15(6), 685; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15060685 - 30 May 2022
Cited by 10 | Viewed by 5178
Abstract
Tetrazine ligation has gained interest as a bio-orthogonal chemistry tool within the last decade. In nuclear medicine, tetrazine ligation is currently being explored for pretargeted approaches, which have the potential to revolutionize state-of-the-art theranostic strategies. Pretargeting has been shown to increase target-to-background ratios [...] Read more.
Tetrazine ligation has gained interest as a bio-orthogonal chemistry tool within the last decade. In nuclear medicine, tetrazine ligation is currently being explored for pretargeted approaches, which have the potential to revolutionize state-of-the-art theranostic strategies. Pretargeting has been shown to increase target-to-background ratios for radiopharmaceuticals based on nanomedicines, especially within early timeframes. This allows the use of radionuclides with short half-lives which are more suited for clinical applications. Pretargeting bears the potential to increase the therapeutic dose delivered to the target as well as reduce the respective dose to healthy tissue. Combined with the possibility to be applied for diagnostic imaging, pretargeting could be optimal for theranostic approaches. In this review, we highlight efforts that have been made to radiolabel tetrazines with an emphasis on imaging. Full article
(This article belongs to the Special Issue Click Reactions in Medicinal Chemistry)
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