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Pharmaceuticals
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Fluorine-Containing Pharmaceuticals
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Fluorine-Containing Pharmaceuticals

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

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 20704

Special Issue Editor

Prof. Dr. Chung-Shan Yu

E-Mail Website
Guest Editor
Faculty of Biomedical Engineering & Environmental Sciences, National Tsing Hua University, 101, sec. 2 Guang-Fu Rd., Hsinchu 30013, Taiwan
Interests: medicinal chemistry; organic synthesis; radiopharmaceuticals; nuclear medicine; boron neutron capture therapy

Special Issue Information

Dear Colleagues,

Fluorine-containing pharmaceuticals, also known as fluoro-pharmaceuticals, have been attracting attention for more than half a century. Presently, about 20% of the commercial pharmaceuticals are fluoro-pharmaceuticals. Notably, 17 fluoro-pharmaceuticals were approved by the U.S. Food and Drug Administration (FDA) in 2018, equivalent to 45% of 38 small-molecule pharmaceuticals approved in 2018. An impressive rate of 41% (13/32) in 2019 is also noted. The special nature of fluorine includes high electronegativity; small size and van der Waals radius; and different chemical reactivity with respect to hydrogen. Isosteres such as F, CF3, and C=CHF are used to replace H (or OH), CH3CH2, and peptide bond, respectively. The judicious introduction of fluorine into a molecule can productively influence conformation, pKa, intrinsic potency, selectivity, toxicity, membrane permeability, and pharmacokinetic properties (i.e., absorption, distribution, metabolism, excretion (ADME)). In addition, 18F has been established as a useful positron-emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development. One of the most important examples, [18F]fluorodeoxyglucose, has been widely used to treat brain tumors, lung cancer, hepatocellular carcinoma, prostate lesions, and bladder cancer. In this Special Issue, we wish to present our readers with updated works addressing the development of fluorine-containing pharmaceuticals and their application in drug discovery. Topics include: bioorganic chemistry of fluoro-compounds, positron emission tomography imaging-directed fluoro-compounds and binding study, metabolism study, and nuclear medicine of fluoro-pharmaceuticals. Both reviews and original articles are welcomed. The collection of manuscripts will be published as a Special Issue of Pharmaceuticals.

Prof. Dr. Chung-Shan Yu
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

  • fluoro-organics
  • ligands
  • transmitters
  • receptors
  • central nervous system (CNS)
  • gliomas
  • molecular imaging
  • “real time” monitoring
  • PET

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Published Papers (5 papers)

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Research

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12 pages, 5222 KiB  
Communication
Facile Entry to Pharmaceutically Important 3-Difluoromethyl-quinoxalin-2-ones Enabled by Visible-Light-Driven Difluoromethylation of Quinoxalin-2-ones
by Kai-Zhong Fu, Xu-Xin Chen, Ya-Shi Zhao, Yuan-Qing Gu and Guo-Kai Liu
Pharmaceuticals 2022, 15(12), 1552; https://doi.org/10.3390/ph15121552 - 13 Dec 2022
Cited by 5 | Viewed by 1744
Abstract
CF2H moiety has a significant potential utility in drug design and discovery, and the incorporation of CF2H into biologically active molecules represents an important and efficient strategy for seeking lead compounds and drug candidates. On the other hand, quinoxalin-2-one [...] Read more.
CF2H moiety has a significant potential utility in drug design and discovery, and the incorporation of CF2H into biologically active molecules represents an important and efficient strategy for seeking lead compounds and drug candidates. On the other hand, quinoxalin-2-one is of great interest to pharmaceutical chemists as a common skeleton frequently occurring in plenty of natural products and bioactive compounds. Herein, we reported a practical and efficient protocol for the synthesis of 3-CF2H-quinoxalin-2-ones. Thus, in the presence of 3 mol% of photocatalyst and S-(difluoromethyl)sulfonium salt as difluoromethyl radical sources, a wide range of quinoxalin-2-ones readily underwent a visible-light redox-catalyzed difluoromethylation reaction, to deliver structurally diverse 3-difluoromethyl-quinoxalin-2-ones. We believe that this would facilitate increasing chances and possibilities for seeking potential lead compounds and drug candidates and further boost the development of fluorine-containing pharmaceuticals. Full article
(This article belongs to the Special Issue Fluorine-Containing Pharmaceuticals)
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16 pages, 2735 KiB  
Article
Development of a Promising 18F-Radiotracer for PET Imaging Legumain Activity In Vivo
by Chunmei Lu, Xiuting Wang, Qiqi Wang, Lixia Zhang, Jianguo Lin and Ling Qiu
Pharmaceuticals 2022, 15(5), 543; https://doi.org/10.3390/ph15050543 - 27 Apr 2022
Cited by 7 | Viewed by 2357
Abstract
Legumain has been found overexpressed in several cancers, which serves as an important biomarker for cancer diagnosis. In this research, a novel fluorine-18 labeled radioactive tracer [18F]SF-AAN targeting legumain was designed and synthesized for positron emission tomography (PET) imaging. Nonradioactive [...] Read more.
Legumain has been found overexpressed in several cancers, which serves as an important biomarker for cancer diagnosis. In this research, a novel fluorine-18 labeled radioactive tracer [18F]SF-AAN targeting legumain was designed and synthesized for positron emission tomography (PET) imaging. Nonradioactive probe [19F]SF-AAN was obtained through chemical and solid phase peptide synthesis. After a simple one-step 18F labeling, the radiotracer [18F]SF-AAN was obtained with a high radiochemical conversion rate (>85%) and radiochemical purity (99%) as well as high molar activity (12.77 ± 0.50 MBq/nmol). The targeting specificity of [18F]SF-AAN for detecting legumain activity was investigated systematically in vitro and in vivo. In vitro cellular uptake assay showed that the uptake of [18F]SF-AAN in legumain-positive MDA-MB-468 cells was twice as much as that in legumain-negative PC-3 cells at 4 h. In vivo PET imaging revealed that the tumor uptake of [18F]SF-AAN in MDA-MB-468 tumor-bearing mice was about 2.7 times of that in PC-3 tumor-bearing mice at 10 min post injection. The experimental results indicated that [18F]SF-AAN could serve as a promising PET tracer for detecting the legumain expression sensitively and specifically, which would be beneficial for the diagnosis of legumain-related diseases. Full article
(This article belongs to the Special Issue Fluorine-Containing Pharmaceuticals)
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Review

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12 pages, 1915 KiB  
Review
Recent Development of Radiofluorination of Boron Agents for Boron Neutron Capture Therapy of Tumor: Creation of 18F-Labeled C-F and B-F Linkages
by Jin-Pei Deng and Chung-Shan Yu
Pharmaceuticals 2023, 16(1), 93; https://doi.org/10.3390/ph16010093 - 9 Jan 2023
Cited by 6 | Viewed by 3090
Abstract
Boron neutron capture therapy (BNCT) is a binary therapeutic technique employing a boron agent to be delivered to the tumor site followed by the irradiation of neutrons. Biofunctional molecules/nanoparticles labeled with F-18 can provide an initial pharmacokinetic profile of patients to guide the [...] Read more.
Boron neutron capture therapy (BNCT) is a binary therapeutic technique employing a boron agent to be delivered to the tumor site followed by the irradiation of neutrons. Biofunctional molecules/nanoparticles labeled with F-18 can provide an initial pharmacokinetic profile of patients to guide the subsequent treatment planning procedure of BNCT. Borono phenylalanine (BPA), recognized by the l-type amino acid transporter, can cross the blood-brain barrier and be accumulated in gliomas. The radiofluoro BNCT agents are reviewed by considering (1) less cytotoxicity, (2) diagnosing and therapeutic purposes, (3) aqueous solubility and extraction route, as well as (4), the trifluoroborate effect. A trifluoroborate-containing amino acid such as fluoroboronotyrosine (FBY) represents an example with both functionalities of imaging and therapeutics. Comparing with the insignificant cytotoxicity of clinical BPA with IC50 > 500 μM, FBY also shows minute toxicity with IC50 > 500 μM. [18F]FBY is a potential diagnostic agent for its tumor to normal accumulation (T/N) ratio, which ranges from 2.3 to 24.5 from positron emission tomography, whereas the T/N ratio of FBPA is greater than 2.5. Additionally, in serving as a BNCT therapeutic agent, the boron concentration of FBY accumulated in gliomas remains uncertain. The solubility of 3-BPA is better than that of BPA, as evidenced by the cerebral dose of 3.4%ID/g vs. 2.2%ID/g, respectively. While the extraction route of d-BPA differs from that of BPA, an impressive T/N ratio of 6.9 vs. 1.5 is noted. [18F]FBPA, the most common clinical boron agent, facilitates the application of BPA in clinical BNCT. In addition to [18F]FBY, [18F] trifluoroborated nucleoside analog obtained through 1,3-dipolar cycloaddition shows marked tumoral uptake of 1.5%ID/g. Other examples using electrophilic and nucleophilic fluorination on the boron compounds are also reviewed, including diboronopinacolone phenylalanine and nonsteroidal anti-inflammatory agents. Full article
(This article belongs to the Special Issue Fluorine-Containing Pharmaceuticals)
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37 pages, 6092 KiB  
Review
Fluorinated Protein and Peptide Materials for Biomedical Applications
by Julia M. Monkovic, Halle Gibson, Jonathan W. Sun and Jin Kim Montclare
Pharmaceuticals 2022, 15(10), 1201; https://doi.org/10.3390/ph15101201 - 28 Sep 2022
Cited by 13 | Viewed by 4234
Abstract
Fluorination represents one of the most powerful modern design strategies to impart biomacromolecules with unique functionality, empowering them for widespread application in the biomedical realm. However, the properties of fluorinated protein materials remain unpredictable due to the heavy context-dependency of the surrounding atoms [...] Read more.
Fluorination represents one of the most powerful modern design strategies to impart biomacromolecules with unique functionality, empowering them for widespread application in the biomedical realm. However, the properties of fluorinated protein materials remain unpredictable due to the heavy context-dependency of the surrounding atoms influenced by fluorine’s strong electron-withdrawing tendencies. This review aims to discern patterns and elucidate design principles governing the biochemical synthesis and rational installation of fluorine into protein and peptide sequences for diverse biomedical applications. Several case studies are presented to deconvolute the overgeneralized fluorous stabilization effect and critically examine the duplicitous nature of the resultant enhanced chemical and thermostability as it applies to use as biomimetic therapeutics, drug delivery vehicles, and bioimaging modalities. Full article
(This article belongs to the Special Issue Fluorine-Containing Pharmaceuticals)
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25 pages, 4133 KiB  
Review
The Latest FDA-Approved Pharmaceuticals Containing Fragments of Tailor-Made Amino Acids and Fluorine
by Qian Wang, Jianlin Han, Alexander Sorochinsky, Aitor Landa, Greg Butler and Vadim A. Soloshonok
Pharmaceuticals 2022, 15(8), 999; https://doi.org/10.3390/ph15080999 - 14 Aug 2022
Cited by 34 | Viewed by 7580
Abstract
Nowadays, the selective introduction of fluorine into bioactive compounds is a mature strategy in the design of drugs allowing to increase efficiency, biological half-life and bio-absorption. On the other hand, amino acids (AAs) represent one of the most ubiquitious classes of naturally occurring [...] Read more.
Nowadays, the selective introduction of fluorine into bioactive compounds is a mature strategy in the design of drugs allowing to increase efficiency, biological half-life and bio-absorption. On the other hand, amino acids (AAs) represent one of the most ubiquitious classes of naturally occurring organic compounds, which are found in over 40% of newly marked small-molecule pharmaceutical drugs and medical formulations. The primary goal of this work is to underscore two major trends in the design of modern pharmaceuticals. The first is dealing with the unique structural characteristics provided by the structure of amino acids featuring an abundance of functionality and the presence of a stereogenic center, all of which bodes well for the successful development of targeted bioactivity. The second is related to fine-tuning the desired activity and pharmacokinetics by selective introduction of fluorine. Historically, both trends were developed separately as innovative and prolific approaches in modern drug design. However, in recent decades, these approaches are clearly converging leading to an ever-increasing number of newly approved pharmaceuticals containing both structural features of amino acids and fluorine. Full article
(This article belongs to the Special Issue Fluorine-Containing Pharmaceuticals)
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