2-Deoxy-D-Glucose: Chemistry and Biology

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.

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.

2-Deoxy-D-glucose is an important pharmaceutical intermediate, and its analytical characterization is critical for establishing its purity and quality. This chapter summarizes spectroscopic techniques, including UV, IR, NMR, and mass spectrometry, along with HPLC and GC studies used for the complete structural elucidation and purity analysis of 2-Deoxy-D-glucose. The UV spectrum of 2-DeoxyD-Glucose showed no distinct peaks. The IR spectrum displayed characteristic bands for the O-H and C-H functional groups. 1H, 13C, APT, DEPT NMR, HSQC, and HMBC experiments confirmed the nominally proposed structure. ESI-MS revealed an [M+Na]+ ion at m/z 187. Specific optical rotation was measured in water. HPLC studies estimated the related substances and assay to be 1.2% and 99.8%, on an anhydrous basis, respectively. The residual solvents, such as methanol, isopropyl alcohol, ethyl acetate, and toluene, were determined by GC headspace and found to be within the limits. The collective analytical evidence confirmed that the test sample met the quality specifications for 2-Deoxy-D-glucose.

 2-[18F]fluoro-D-glucose ([18F]FDG) is a versatile molecule in nuclear medicine that has evolved into a vital radiotracer in medical imaging applications via positron emission tomography (PET) [18F]FDG is derived from its derivative, 2-deoxyD-glucose (2-DG), where the triflate group is attached to carbon-2 [18F]FDG serves as a crucial non-invasive diagnostic tool and is prominently utilized in non-invasive imaging of various metastatic diseases, particularly cancer imaging. Its importance as a tracer has been further enhanced by its unexpected attribute of generating a low body background through excretion, leading to its effective application in PET/CT for highly-sensitive and specific tumor detection. This chapter provides insight into the synthesis of [18F]FDG, employing various reaction protocols such as electrophilic and nucleophilic processes. This chapter also summarized the purification and their quality assurance methods and highlighted the distinct challenges associated with each. The nucleophilic technique produces [18F]FDG with a higher yield and purity than the electrophilic method for routine manufacture. Commercially devoted automated modules for FDG production use this method, demonstrating its widespread use in clinical imaging. Nucleophilic reactions of [18F]fluoride ions attacking the C-2 position of mannose triflate to produce FDG are routine in clinical imaging. The final [18F]FDG product satisfies safety, purity, and efficacy standards through rigorous quality control and assurance. The trajectory from glucose discovery to the development of [18F]FDG exemplifies the continuing advancement of medical imaging methods. FDG's accomplishment shows how biology, chemistry, and medical technology are interrelated, providing a better understanding and treatment of complicated diseases like cancer.

The evolution of viral infections has pushed researchers constantly to find new approaches to disseminate these infections. One such promising finding in this aspect is 2-deoxy-D-glucose (2-DG), a glucose analogue that gained attention for its potential as an antiviral agent effective against a variety of viral infections. The antiviral properties of 2-DG are due to its ability to interfere with viral replication within host cells, hence reducing the severity of infections. 2-DG is easily taken up by cells as it mimics glucose-like structure but interferes with glycolysis and other metabolic pathways. It also acts as a glycosylation inhibitor that helps in the disruption of viral assembly. Viruses are obligate and utilize the host cell machinery for proliferation. 2-DG mechanistically disrupts the energy supply by inhibiting the glycolysis cycle and providing an unfavourable environment for viral replication. 2-DG elicits broad-spectrum antiviral activity as it was found to be very effective against different families of viruses. By interfering with this process, 2-DG not only interferes with viral replication but also with the ability of the virus to enter host cells and evade the immune system. Although 2-DG has shown some promising antiviral potential, it also possesses some side effects as well. All the attributes related to the antiviral potential of 2-DG have been discussed in this chapter.

This chapter delves into the multifaceted applications of 2-Deoxy-d-Glucose (2-DG) and its derivatives as versatile tools in diagnostics and therapeutics. Highlighting their dual role in the medical landscape, this chapter provides a comprehensive overview of the diverse functions and mechanisms by which these compounds contribute to both diagnostic assessments and therapeutic interventions. The first section examines the use of 2-DG and its derivatives in diagnostics, detailing their efficacy in various imaging techniques, diagnostic assays, and investigative procedures. Their unique properties and specific interactions in these contexts were explored to elucidate their significance in the accurate detection and visualization of specific physiological conditions or anomalies. The subsequent segment shifts the focus towards the therapeutic realm, where the book chapter investigates the potential and current applications of 2-DG and its derivatives in treating a spectrum of diseases and conditions. From their roles in cancer therapy to neurological disorders and severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) treatment, the chapter outlines the mechanisms and clinical advancements where these compounds show promise as therapeutic agents. Throughout this discussion, the chapter emphasizes the evolving landscape of 2-DG and its derivatives, touching upon ongoing research, challenges, and future prospects in harnessing their dual attributes for enhanced healthcare outcomes. The exploration of these compounds in both diagnostic and therapeutic realms not only illuminates their versatility but also underlines the potential for innovative and integrated medical approaches.

The search for effective therapeutics has been unyielding in the relentless battle against the COVID-19 pandemic. A potential drug candidate is 2-deoxyD-glucose (2-DG), which has been evaluated as a polypharmacological agent for antiviral therapy due to its influence on the glycolytic pathway. This chapter delves into the promising role of 2-deoxy-D-glucose (2-DG) as a potential anti-viral drug. With a focus on the biochemical and pharmacological aspects, this chapter explores how 2-DG may disrupt the viral life cycle and modulate host immune responses. An in-depth analysis of the current scientific evidence, including preclinical studies and clinical trials, will be highlighted to shed light on the drug's efficacy, safety, and potential as a treatment option. Furthermore, the challenges and prospects of 2-DG in the context of COVID-19 management will be elaborated. The COVID-19 pandemic has posed unprecedented challenges to global healthcare systems, demanding swift and innovative approaches to combat the virus. Amid this backdrop, the utilization of 2- deoxy-D-glucose (2-DG) as an anti-COVID-19 drug has emerged as a promising avenue for research and therapeutic development. This chapter offers an exhaustive exploration of the potential of 2-DG in the context of COVID-19 treatment. Additionally, action mechanisms and safety concerns associated with administering 2- DG in treating COVID-19 will be reviewed. This chapter aims to equip readers with a comprehensive understanding of 2-DG's role in the fight against COVID-19 and its place in the evolving the landscape of antiviral therapeutics.

Positron Emission Tomography (PET), a noninvasive technique, is most suitable for quantitative evaluation of in vivo tumor biology. Based on its metabolic activity, the accumulation of F-18 fluorodeoxyglucose ([18F]FDG), a positron emitter radionuclide, is most explored indicative of tumor features. Quantitative evaluation of FDG uptake is frequently used for treatment monitoring following chemotherapy or chemoradiotherapy. Several investigations showed that FDG PET, which measures metabolic change, was a more sensitive marker than CT or MRI, which measures morphological change. [18F]FDG is now frequently used to assess tumor metabolism as well as to track the effectiveness of immunotherapy, which is a useful treatment for several malignancies. With the use of in vivo whole-body CD8+ T cell and PD-L1 expression imaging, for instance, radiopharmaceuticals that are novel in nature offer the rare chance to characterize the immunological tumor microenvironment (TME) and more accurately forecast which patients may react to therapy. Longitudinal molecular imaging may also aid in clarifying potent changes, especially in instances of resistance that occurred during immunotherapy, and aid in guiding a more individualized therapeutic strategy. To categorize, forecast, and track treatment response and molecular dynamics in areas of therapeutic need, this review focuses on new and existing uses of [18F]FDG for imaging.

Cancer cells have a unique property of uncontrolled growth and thus they require a constant supply of energy. Warburg observed that tumor cells prefer glycolysis even under oxygenic conditions and the process is known as aerobic glycolysis. Hence, cancerous cells show an enhanced glucose-to-lactate conversion rate. As cancerous growth is accompanied by enhanced glucose uptake, this feature is best suited for the management of unwanted cell proliferation by blocking the glucose metabolism of cancer cells. 2-deoxy-D-glucose (2DG), a glucose antimetabolite is considered a competitive inhibitor of glucose transport and glucose phosphorylation. It inhibits the glycolytic pathway primarily due to the inhibition of phosphohexose isomerase by 2-deoxy-D-glucose-6-phosphate (2DG- 6P). Its chemical resemblance to 2-deoxymannose causes interruption in the initial steps of N-linked glycosylation leading to the misfolding of proteins resulting in endoplasmic reticulum stress. In addition to the two properties of 2DG namely, the prevention of glycolysis and selective storage in the tumor cells, there are several other attributes of 2DG apart from the ones mentioned above that make it an attractive target for use as an antitumor agent. Some properties include the capability of inducing autophagy in tumor cells, inhibiting genomic replication as well as mRNA expression of viral genes responsible for Omit the induction of oncogenesis, blocking pathological angiogenesis while being cautious towards established endothelial tubes and prominent anti-metastatic effect. In the present chapter, various aspects of the use of 2DG in cancer management have been discussed.

Cancer involves abnormal and rapid cell growth, which requires an increased energy supply for proliferating cells. As the demand for glucose rises in cancer cells, the expression and activity of glucose transporters (GLUTs) also increase to facilitate higher cellular glucose uptake. Cancer cells tend to shift their glucose metabolic pathway from mitochondrial oxidative phosphorylation towards aerobic glycolysis. 2-Deoxy-D-glucose competes with glucose and involves aerobic glycolysis. It leads to the inhibition of HK and PGI, diminishes ATP production, and induces apoptosis. Further, the increase in the AMP/ATP ratio promotes the AMPK signaling, downregulating VEGF, and leading to angiogenesis inhibition and autophagy. As the structural mimic of mannose, 2-DG interferes with the N-linked glycosylation, leading to ER stress, and triggering the mitochondrial apoptotic pathway. 2-DG has been employed as an antiproliferative, antiangiogenic, and antimetastatic drug by being involved in the energy metabolic pathway. Combination therapy shows improved results and reduces chemotherapeutic drug resistance. In this chapter, we will discuss the Warburg effect, the role of 2-DG in the inhibition of aerobic glycolysis, and how 2- DG inhibits the various other cancer hallmarks in energy metabolic pathway. Also, reports on cancer treatment as well as cancer cell-imaging and risks associated with chronic exposure are discussed.

 2-Deoxy-D-glucose (2-DG) is a glucose analog that inhibits glycolysis. Conflicting evidence exists regarding the effects of 2-DG on seizure activity. The effects of 2-deoxy-D-glucose (2-DG) on seizures and epileptogenesis have been a subject of interest in the field of neuroscience and epilepsy research. In the 6-Hz seizure threshold test, 2-DG significantly increased the seizure threshold, indicating anticonvulsant properties. However, in other models, such as the mouse electroshock seizure threshold test, intravenous pentylenetetrazol test, and intravenous kainic acid test, 2-DG decreased the seizure threshold and exhibited proconvulsant effects. Similarly, the related compound 3-methylglucose reduced seizure threshold when administered intravenously with pentylenetetrazol. In contrast, 2-DG administered chronically retarded the progression of kindled seizures in rats, suggesting antiepileptic effects. The anticonvulsant actions of 2-DG may be mediated through the inhibition of glycolysis and diversion of glucose metabolism towards the pentose phosphate pathway. Meanwhile, its acute proconvulsant effects are likely due to reduced glucose uptake. In summary, 2-DG displays both anticonvulsant and proconvulsant actions on seizures, which depend on the model system and mechanisms involved, including glycolytic inhibition and decreased glucose uptake. Further study is needed to fully elucidate the contradictory effects of 2-DG on seizure activity in different experimental models. 

Christopher A. Lipinski formulated a rule based on his observation that most drugs administered orally are relatively small and moderately lipophilic molecules. This rule serves as a guideline to determine whether a molecule with specific pharmacological or biological activity possesses properties that would make it a viable orally active drug in humans. Lipinski's Rule of Five functions as a powerful screening tool in the initial phases of drug discovery, enabling researchers to pick molecules with ideal attributes for subsequent development and testing.