2-Deoxy-D-Glucose: Chemistry and Biology E-Book
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- Sprache: Englisch
2-Deoxy-D-Glucose: Chemistry and Biology extensively examine 2-deoxy-D-glucose (2DG), a glucose analog with profound biomedical and therapeutic potential. This detailed resource covers 2DG's chemical structure, methods of synthesis, and its pivotal roles in diagnostics and therapeutics. This book provides a comprehensive overview of the compound’s multifaceted uses, from antiviral applications to its emerging role in cancer treatment.
Key Features:
- Comprehensive coverage of 2DG synthesis, structure, and characterization.
- Insights into 2DG’s diagnostic and therapeutic potential, including cancer and antiviral applications.
- Exploration of its role in the Warburg effect and glycosylation inhibition.
- Discussion on 2DG’s clinical applications, including COVID-19 treatments.
Readership: Organic and medicinal chemists, oncologists, virologists, pharmaceutical researchers, and graduate students.
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Seitenzahl: 440
Veröffentlichungsjahr: 2024
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FOREWORD
It is with great pleasure that I compose the Foreword for this timely and insightful publication on the ‘Chemistry and Biology of 2-Deoxy-D-Glucose (2-DG)’. As comprehensively outlined throughout the chapters, 2-DG is emerging as a versatile molecule with vast therapeutic potential in the fields of antiviral, anti-cancer, and neurological research.
This publication provides an exceptional overview of the medicinal chemistry that underlies 2-DG, encompassing its structure, synthesis, analytical characterization, and pharmacological actions along with its role in diagnostics and therapeutics. The chapters delve into the various synthetic pathways for producing 2-DG, elucidating the advantages and limitations of each method. Additionally, the text thoroughly discusses spectroscopic, chromatographic, and optical techniques for the analysis of 2-DG. These sections offer invaluable insights into optimizing the production and analysis of this crucial pharmaceutical intermediate.
Of particular interest are the mechanistic investigations into the biological effects of 2-DG. As explained, 2-DG acts as a glycolytic inhibitor and glycosylation modulator, selectively disrupting pathological metabolism in viruses, cancers, and seizures. The publication compiles compelling evidence from preclinical and clinical studies that highlight the therapeutic potential of 2-DG in these disease contexts. Furthermore, ongoing research on enhancing the delivery and efficacy of 2-DG through medicinal chemistry approaches is also prominently featured.
In conclusion, this publication provides a comprehensive and well-rounded overview of an exciting molecule that bridges the realms of chemistry and biomedicine. The chapters draw upon essential perspectives from synthetic organic chemistry, analytical methods, pharmacology, and molecular medicine to shed light on the diverse aspects of 2-DG research and applications, including prospects for cancer diagnosis, treatment, and surveillance. This interdisciplinary knowledge equips readers with a solid foundation to advance the potential of 2-DG and related compounds as diagnostic and therapeutic agents.
I commend the editors and authors for creating an outstanding reference that will educate, inspire, and guide future interdisciplinary endeavors in this medically relevant field.
PREFACE
2-Deoxy-D-glucose (2-DG) is a modified molecule of glucose that has garnered significant interest in research in recent years due to its potential for therapy in various diseases. As outlined in this book, 2-DG and its derivatives have shown promise as agents against viruses, cancer, seizures, and COVID-19.
The book provides a comprehensive overview of the chemistry and biology of 2-DG. It delves into the structure, properties, and methods of synthesis of 2-DG, providing important insight into this pharmaceutical intermediate. Analytical techniques for characterizing and establishing the purity of 2-DG are also discussed.
A key highlight of the book is the exploration of the mechanisms and applications of 2-DG in biomedicine. As an inhibitor of glycolysis, 2-DG displays broad antiviral activity by disrupting the supply of energy and replication of viruses. Chapters outline evidence for the effectiveness of 2-DG against herpes simplex virus, influenza, Ebola, and SARS-CoV-2. The book also extensively covers the use of 2-DG and its analogs in cancer therapy, given their ability to selectively target tumor metabolism.
Beyond its roles in antiviral and anticancer applications, the book examines the emerging potential of 2-DG in the management of seizures and neurological conditions. Contradictory effects as anticonvulsant and proconvulsant are elucidated across different models. Therapeutic possibilities in Alzheimer's, aging, and stroke are discussed.
The book emphasizes how the unique properties of 2-DG and its derivatives enable their dual application in medical diagnostics and therapy. Radio-labeled 2-DG offers enhanced imaging, while functionalized analogs may improve drug delivery. This integrated approach can pave the way for more precise and personalized medicine.
Overall, this book provides a comprehensive reference on the chemistry and biology of 2-DG. It compiles essential insights from interdisciplinary research to offer a well-rounded perspective on this versatile molecule. The collective knowledge presented here will equip readers to further explore the therapeutic applications of 2-DG and related compounds. I hope this book serves as a valuable addition to the scientific literature, inspiring further advancement in this medically relevant field.
List of Contributors
2-Deoxy-D-Glucose: Chemical Structure and Properties
Raman Singh1,Kuldeep Singh1,*Abstract
2-Deoxy-D-glucose (2DG) is a variant of glucose lacking the 2-hydroxyl group. This minor alteration has significant biological and pharmacological implications, enhancing its therapeutic value and necessitating evaluations of its safety and efficacy in clinical environments. This chapter delves into the chemical composition of different deoxy-D-glucose molecules, focusing on the structure and characteristics of 2DG.
1. INTRODUCTION
Deoxy sugars are sugars in which a hydroxyl group (-OH) on the carbon ring is substituted with a hydrogen atom. Deoxyribose, a prominent deoxy sugar, constitutes the sugar-phosphate backbone of DNA, bearing the molecular formula C5H10O4. Other notable deoxy sugars are detailed in Table 1. Sugars undergoing the replacement of two hydroxyl groups with hydrogen are classified as dideoxy sugars, with colitose and abequose being instances [1].
1.2. Nomenclature
Traditionally, many deoxy sugars were given trivial or common names. However, a systematic nomenclature system has been developed to name these compounds more precisely. This system uses the prefix 'deoxy' followed by the position number indicating which carbon atom has the hydroxyl group replaced by a hydrogen. The stem name of the parent sugar is then included, along with any necessary configurational prefixes to specify the stereochemistry at the remaining chiral centers of the deoxy sugar molecule.
2. DEOXY-GLUCOSE
When a hydroxyl group in D-glucose is substituted with a hydrogen atom, the result is deoxy-D-glucose, a molecule that possesses one less oxygen atom than D-glucose. Various deoxy-D-glucose types can be produced based on which carbon's attached oxygen is eliminated. Illustrations of these molecular structures are provided in Fig. (1) and Table 2.
Fig. (1)) Various deoxy sugars originating from D-Glucose.2-Deoxy-D-glucose (2DG) is the most common but other deoxy positions and substitutions can alter potency, metabolism, and effects. 2DG has become an important research tool and leads to potential therapeutic applications.
3. 2-DEOXY-D-GLUCOSE (2DG)
2DG is a synthetic compound [9], however, α and β D-glucopyranose forms (2-deoxy-α-D-arabino-hexopyranose, and 2-deoxy-β-D-arabino-hexopyranose) were extracted from the carbohydrate fraction of the solid-state fermentation product of Actinosynnema pretiosum ssp. auranticum ATCC 31565 [10, 11]. 2DG, has been assigned with the CAS registry number 154-17-6, and its structure has been depicted in Fig. (2). This compound is also known by the synonyms 2-deoxy-D-arabino-hexose and D-arabino-2-deoxyhexose. The α-pyranose form of the reducing aldose 2-deoxy-D-arabino-hexose (2-deoxy-D-arabino-hexopyranose) adopts a 4C1 conformation, where the anomeric hydroxyl group is positioned axially, and the remaining substituents align equatorially. In the crystalline state, the four hydroxyl groups participate in an intricate three-dimensional hydrogen-bonding network, each acting as an intermolecular hydrogen-bond donor [12].
4. PHYSICAL PROPERTIES
2-Deoxy-D-glucose (2DG) exists as a crystalline solid with a white to off-white appearance [13]. Its melting point has been reported as 146°C [13]. However, when recrystallized from methanol, it forms colorless needle-like crystals with a melting range of 151-154°C and a specific optical rotation value of +43.0° (c=1.0, H2O, 15°C) [11]. Under different conditions, such as in a 0.13 concentration aqueous solution, the specific rotation value for 2DG has been documented as +48.8° at 23°c [4]. These physical properties, including the melting behavior and optical activity, can aid in characterizing and identifying the 2DG compound.
Fig. (2)) Structure of 2-deoxy-D-Glucose.5. ANALYTICAL CHARACTERIZATION
Analytical characterization and confirmation of the precise compound identity and purity of 2DG is crucial for both basic research studies and therapeutic development efforts. Spectroscopic techniques like nuclear magnetic resonance (NMR) spectroscopy [8, 14-16], infra-red (IR) spectroscopy [17], and mass spectrometry are used to confirm the core compound structure and distinguish it from similar glucose derivatives [18]. Techniques including capillary electrophoresis (CE), high-performance liquid chromatography (HPLC), and gas chromatography (GC), when linked with appropriate detection systems, are utilized for measuring the relative amounts of 2DG and assessing its purity [19].
5.1. Spectral Characterization
5.1.1. UV-VIS Spectrum
The 2DG molecule shows an absorption maxima at 279 nm in water and 277 nm in DMSO [20].
5.1.2. Mass Spectrum
Mass spectrometric analysis of 2-deoxy-D-glucose (2DG) reveals a prominent fragmentation pathway involving the initial loss of a water molecule, resulting in the formation of an ion with m/z of 119. Concurrently, an alternative decomposition route emerges, characterized by the formal loss of hydrogen peroxide, which proceeds through the sequential elimination of two hydroxyl groups. Notably, this latter pathway precludes the formation of the ion species typically observed at m/z 107, suggesting a compete inhibition of that particular fragmentation channel [21].
5.1.3. IR and Raman Spectrum
The 2-deoxy-D-glucose molecule is composed of 23 atoms and exhibits 63 normal vibrational modes. Venkatesh and colleagues conducted a comprehensive study on the vibrational assignments of the fundamental modes in 2-DG, including calculated (scaled) infrared (IR) and Raman bands, as well as descriptions of the corresponding normal modes [20]. The IR spectrum of 2DG displays a characteristic carbonyl band at 1722 cm-1 and an enediol band at 1658 cm-1 [22]. These distinct vibrational features provide valuable insights into the structural and bonding characteristics of the 2-DG molecule.
5.1.4. NMR
Table 3 lists 1H-NMR peaks. 13C NMR shows signals at δ 93.61, 95.73 (C-1), 74.31, 73.50, 78.31, 73.17, 72.77, 70.26, 63.27, 63.02, (C-3,4,5,6), 41.77, 39.53 (C-2) [24]. 1H and 13C spectra of 2-deoxy-β-D-glucose were recently captured using a 600 MHz instrument in C5D5N (Table 3) [23]. Fig. (3) depicts anomeric sugar signals (600 MHz 1H-NMR; 2 M D2SO4/D2O; 30 °C) [8] for D-glucose, D-mannose and 2DG.
6. ANALYSIS OF 2-DEOXY-D-GLUCOSE
2DG exhibits reducing properties, as evidenced by its ability to reduce Fehling's solution [11] and yields a positive result in the Keller-Kiliani reaction [11], which is a test for identifying reducing sugars. The concentration and purity of 2DG in crystalline or liquid samples can be accurately and precisely determined using high-performance liquid chromatography (HPLC) analysis, a technique suitable for the analysis of active pharmaceutical ingredients and drug products [25]. This method is applicable for the standardization and quality control of 2DG-based active pharmaceutical ingredients and drug formulations. Ultraviolet (UV) detection at 195 nm, coupled with HPLC using μBondapak 10 μm NH2 or Varian Micropak 10 μm NH2 columns, has been employed for the detection and quantification of 2DG, with a typical retention time of around four minutes when using an 85% acetonitrile/water mobile phase. Additionally, polymer-based amino columns (e.g., HILICpak VG-50 4E) and Shodex SUGAR SC1011 columns have been utilized for the separation of 2DG and glucose [26]. In pharmacokinetic studies involving 2DG, the estimation of 2-deoxyglucose in plasma is crucial. To facilitate this, a precolumn fluorescent derivatization technique has been developed, which involves reductive amination of 2DG using sodium cyanoborohydride and 2-aminobenzoic acid [27].
7. DRUGABILITY OF 2DG
2DG exerts its effects by inhibiting various enzymes involved in the glycolytic pathway, ultimately leading to cell death. 2DG is also a mannose-mimetic that interferes with protein glycosylation. This molecule has a molecular weight of 164.158 Daltons, a calculated logP value of -1.525, five hydrogen bond acceptors (HBA), and four hydrogen bond donors (HBD). Consequently, it satisfies four out of the five Lipinski rules for drug-likeness. Additionally, 2DG has a polar surface area (PSA) of 90.15 Å2 and a single rotatable bond (RotB), thereby meeting two of the Veber criteria. The approval of 2DG for emergency use in Indian hospitals to treat COVID-19 patients requiring supplemental oxygen has highlighted the potential of this compound and ignited hope for the development of a safe drug to combat the current pandemic [28]. Viral mutations, which can render existing drugs and monoclonal vaccines ineffective, are a significant concern. Targeting the glycolytic pathway, a process essential for energy production in infected cells, represents a promising strategy as it is less susceptible to viral mutations [29-32]. Various studies have explored the use of varying doses of 2DG, with the maximum tolerable dose reported to be 250 mg/kg body weight [33].
8. TOXICOLOGY AND HANDLING OF 2DG
2-Deoxyglucose (2DG) is a toxic glucose analog that operates through a pleiotropic mechanism [34-36]. Its molecular structure bears resemblance to both glucose and mannose. Due to its similarity with mannose, 2DG significantly disrupts the N-linked glycosylation process [34], leading to the inhibition of protein synthesis and inducing endoplasmic reticulum (ER) stress within cells [34, 37]. Reports indicate that 2DG can stimulate autophagy, increase oxidative stress levels, and impair the N-linked glycosylation pathway [38]. Following a ketogenic diet has been shown to enhance tolerance to glycolysis inhibitors [39]. When handling 2DG, proper safety precautions should be taken, including wearing hand protection and a mask, as well as avoiding exposure to moisture [40].
CONCLUSION
2-Deoxy-D-glucose, a molecule that resembles D-glucose and D-mannose, complies with Lipinski's rule of five, indicative of promising drug-like characteristics. It demonstrates a range of activities, such as an inhibitor of glycolysis, impacting metabolic pathways, signaling pathways like AMPK and mTORC1, biosynthesis processes such as lipid and protein-N-glycosylation and its use as a tracer compound. Its potential application in treating COVID-19 has sparked heightened interest, potentially paving the way for novel antiviral medications and therapeutic approaches for individuals experiencing hyper- glycemia.
LIST OF ABBREVIATIONS
2DG2-Deoxy-D-GlucoseBWBody WeightEREndoplasmic ReticulumHBAHydrogen Bond AcceptorsHBDHydrogen Bond DonorsPSAPolar Surface AreaRotBRotatable BondACKNOWLEDGEMENTS
The authors extend their heartfelt gratitude to the management of Amity University Madhya Pradesh, Gwalior, Madhya Pradesh, India, for offering the necessary facilities that enabled the writing and submission of the book chapter for publication.
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Sci.,2023, 2023, 1-15.[http://dx.doi.org/10.1155/2023/9993386] [PMID: 36911357]Methods and Procedures for the Synthesis of 2-Deoxy-D-Glucose
Raman Singh1,Vidushi Gupta2,Kuldeep Singh1,*Abstract
Many synthetic procedures for preparing 2-deoxy-D-glucose (2DG) are available in the literature. The synthesis of 2DG involves the modification of glucose at 2-position. Several methods to synthesize 2DG include glucose nitrosation and reductive amination of 2-deoxy-D-arabinose. These methods are highly efficient and produce high yields of 2DG. This chapter discusses various methods for synthesizing 2DG and their advantages and disadvantages. This chapter describes the different approaches for synthesizing 2DG and how the choice of method affects its purity, yield, and properties.
