d-Glucose- and d-mannose-based antimetabolites. Part 4: Facile synthesis of mono- and di-acetates of 2-deoxy-d-glucose prodrugs as potentially useful antimetabolites

• Published in: Carbohydrate research Vol. 531; p. 108861
• Main Authors: Fokt, Izabela, Cybulski, Marcin, Skora, Stanisław, Pająk, Beata, Ziemniak, Marcin, Woźniak, Krzysztof, Zielinski, Rafal, Priebe, Waldemar
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.09.2023
• Subjects: 2-Deoxy-d-glucose; 2-DG diacetates; 2-DG monoacetates; 2-DG prodrugs; Antimetabolites; Antiviral Agents - pharmacology; Deoxyglucose - chemistry; Glucose - chemistry; Mannose - chemistry; Prodrugs; WP1122; 2-Deoxy-d-glucose; WP1122; 2-DG monoacetates; 2-DG prodrugs; 2-DG diacetates
• ISSN: 0008-6215; 1873-426X
• DOI: 10.1016/j.carres.2023.108861

2-Deoxy-d-glucose (2-DG), a compound known to interfere with d-glucose and d-mannose metabolism, has been tested as a potential anticancer and antiviral agent. Preclinical and clinical studies focused on 2-DG have highlighted several limitations related to 2-DG drug-like properties, such as poor pharmacokinetic properties. To overcome this problem, we proposed design and synthesis of novel 2-DG prodrugs that subsequently could be tested using a variety of biochemical and molecular methods. We narrowed here our focus to esters of 2-DG as potential prodrugs based on the hypothesis that ubiquitous esterases will regenerate 2-DG, leading to increased circulation time of drug and adequate organ and tumor penetration. Testing this hypothesis in vitro and, especially, in vivo requires significant amounts of respective pure mono- and previously unknown di-acetylated water-soluble derivatives of 2-DG. Development of their efficient and practical method of synthesis was imperative. We describe novel facile and scalable syntheses of seven selectively acetylated water-soluble derivatives of 2-DG and present a detailed 1H and 13C NMR analysis of all final products. X-ray diffraction analysis has been performed for compound WP1122 that was selected for detailed preclinical and subsequent clinical evaluation as potential anticancer or antiviral agent. [Display omitted] •2-Deoxy-d-glucose (2-DG) prodrugs, WP1122, 2-DG monoacetates, 2-DG diacetates.