d-Glucose and d-mannose-based metabolic probes. Part 3: Synthesis of specifically deuterated d-glucose, d-mannose, and 2-deoxy-d-glucose

Abstract

Altered carbohydrate metabolism in cancer cells was first noted by Otto Warburg more than 80 years ago. Upregulation of genes controlling the glycolytic pathway under normoxia, known as the Warburg effect, clearly differentiates malignant from non-malignant cells. The resurgence of interest in cancer metabolism aims at a better understanding of the metabolic differences between malignant and non-malignant cells and the creation of novel therapeutic and diagnostic agents exploiting these differences. Modified d-glucose and d-mannose analogs were shown to interfere with the metabolism of their respective monosaccharide parent molecules and are potentially clinically useful anticancer and diagnostic agents. One such agent, 2-deoxy-d-glucose (2-DG), has been extensively studied in vitro and in vivo and also clinically evaluated. Studies clearly indicate that 2-DG has a pleiotropic mechanism of action. In addition to effectively inhibiting glycolysis, 2-DG has also been shown to affect protein glycosylation. In order to better understand its molecular mechanism of action, we have designed and synthesized deuterated molecular probes to study 2-DG interference with d-glucose and d-mannose metabolism using mass spectrometry. We present here the synthesis of all desired probes: 2-deutero-d-glucose, 2-deutero-d-mannose, 6-deutero-d-glucose, 6-deutero-d-mannose, and 2-deutero-2-deoxy-d-glucose as well as their complete chemical characterization.

1,2‐Annulated Sugars: Synthesis of Polyhydroxylated 2,10‐Dioxadecalins with β‐manno Configuration

“…For that purpose, tetra-O-acetylglucosyl bromide 4 was readily converted into allyl glucoside 5 in 5 steps by the intermediate formation of the methyl orthoester as reported by Draghetti et al [21] Recently, Fokt et al reported on the synthesis of a benzyl 2uloside by Dess-Martin oxidation, [22] and we first attempted the reaction of 5 under similar conditions. For that purpose, tetra-O-acetylglucosyl bromide 4 was readily converted into allyl glucoside 5 in 5 steps by the intermediate formation of the methyl orthoester as reported by Draghetti et al [21] Recently, Fokt et al reported on the synthesis of a benzyl 2uloside by Dess-Martin oxidation, [22] and we first attempted the reaction of 5 under similar conditions.…”

Carbohydrate‐Derived 3,2‐Enolones in the Base‐Catalyzed Rearrangement to Highly Functionalized C4‐Quaternary 4‐Hydroxy‐2‐cyclopentenones

“…For this purpose, benzyl β‐glucoside 1a , allyl β‐glucoside 1b and methyl β‐glucoside 1c were first transformed into the corresponding 2‐ulosides 2a ,, [1b] 2b [1a] and 2c via Dess–Martin oxidation (Scheme ), which we found to be the method of choice in this case. Allyl 2‐uloside 2b was found to be more sensitive towards premature elimination, and therefore crude 2b was directly subjected to the following transformation due to increased decomposition upon chromatographic purification.…”

“…Benzyl 3,6‐Di‐ O ‐benzyl‐4‐deoxy‐β‐ d ‐ glycero ‐hex‐3‐enopyranoside‐2‐ulose (3a): Benzyl 3,4,6‐Tri‐ O ‐benzyl‐β‐ d ‐ arabino ‐hexopyranoside‐2‐ulose 2a [1b], (0.97 g; 1.80 mmol) was dissolved in toluene (38 mL) and water (2.6 mL). Next, K 2 CO 3 (0.50 g; 3.62 mmol) was added, and the suspension was stirred at 95 °C.…”

2-C-Alkynyl and 2-C-cis-Alkenyl β-Mannosides with Acetal Protected γ-Aldehyde Functionality via 2-Uloside Alkynylation and Lindlar Hydrogenation

“…Previously, Fokt et al [8] described the synthesis of 2 via glycosylation reactions with a 2-ulosyl bromide. However, based on our previously encountered difficulties with comparable glycosylation reactions [5] (i.e., low yields and the formation of side products) we anticipated our approach via Dess-Martin oxidation of 1 to be more efficient.…”

“…The carbohydrate system was found to comprise a distorted 4 Our synthetic sequence started by subjecting benzyl β-glucoside 1 [7] to Dess-Martin oxidation to afford the corresponding perbenzylated 2-uloside 2 (Scheme 1). Previously, Fokt et al [8] described the synthesis of 2 via glycosylation reactions with a 2-ulosyl bromide. However, based on our previously encountered difficulties with comparable glycosylation reactions [5] (i.e., low yields and the formation of side products) we anticipated our approach via Dess-Martin oxidation of 1 to be more efficient.…”