Synthesis of glycosyl derivatives as dopamine prodrugs: interaction with glucose carrier GLUT-1Electronic supplementary information (ESI) available: experimental details for the preparation of all derivatives and biological assays. See http://www.rsc.org/suppdata/ob/b2/b212066f/

Abstract

Glucosyl dopamine (DA) derivatives may represent a new class of DA prodrugs that would interact with glucose transporter GLUT-1, present in the blood-brain barrier, and generate DA in the brain. Therefore, compounds bearing the sugar moiety linked to either the amino group or the catechol ring of DA through amide, ester, carbamate, peptide or glycosidic bonds were synthesized. The behavior of the compounds as prodrugs was monitored in different media and the affinity of the glycoconjugates for the glucose carrier GLUT-1 using human erythrocytes was also studied. Most of the compounds were markedly stable in buffer and plasma, and several compounds released DA when incubated with brain extracts and the rate was related to the bond linking DA with glucose. The new glucosyl conjugates substituted at the C-6 position of the sugar were more potent inhibitors of glucose transport when compared to C-1 and C-3 substituted derivatives. This work provides structure-activity information about the interaction of substituted glucose with the GLUT-1 transporter.

The stress response factor daf-16/FOXO is required for multiple compound families to prolong the function of neurons with Huntington’s disease

“…Among the most active hits are four quercetin analogs carrying a glucoside group. Interestingly, glycosyl derivatives have brain prodrug delivery potential 42 . We focused our attention on isoquercitrin (quercetin-3-O-glucoside) as this compound shows a better Rmax and EC50 compared to resveratrol and as the Rmax of isoquercitrin is very close to the maximally-achievable level of neuroprotection in the touch response assay (Fig.…”

“…Furthermore, flavonoid-glucosides have brain prodrug delivery potential. The interaction of the glycosyl with GLUT-1, a glucose transporter highly expressed in the BBB, may indeed help generate active compound concentrations in the brain 42 . Although some flavonoids such as quercetins might act promiscuously 68 , flavonol analogs such as isoquercitrin may constitute bona fide compounds that engage the stress response machinery ( e.g .…”

Application of Mono‐ and Disaccharides in Drug Targeting and Efficacy

“…[9][10][11][12] Such hexoses are attractive targeting agents for the delivery of drug molecules to destination proteins. Dopamine, [13][14][15][16][17] compounds such as arginine, [18][19][20] and other drugs that act on the brain [21,22] have been conjugated to d-galactose or d-glucose to cross the BBB and enter into the central nervous system( CNS) by specific carrier-mediated transport. More importantly,t hese glycoconjugates have been found to show minimal cardiovascular side effects and better permeability and bioavailability,e mphasizing the importance of the targeting and specificity properties of d-glucose and d-galactose in improving the efficacy of the parent compounds.…”

“…[12] This was further confirmed by research into the mechanism of action, that NAGAL can bind GLUT3 and induce the activity of nonspecific nitric oxide synthase( NOS). [18] The therapeutic effects of glucosylateda nd galactosylated dopamine against Parkinson's disease have been demonstrated; [14][15][16][17] however,d opaminel inked to the C6 or C1(b)p osition of glucose and galactose through asuccinyl linker (compounds 7-9)o rtheC 1p osition of glucosea ttached to the phenolic groups of dopamine( compounds 10 and 11)t hrough ag lycosidic bond ( Figure 2) revealed only modeste ffects, and was not significant enough to exhibit antiparkinsonian properties. [13] This exception mayb ea scribed to the mode of linkage or position of attachment to glucosea nd galactose, ultimately affecting the affinity for the transport protein and thus the amount taken up by nerve cells.…”

p-Nitrophenyl carbonate promoted ring-opening reactions of DBU and DBN affording lactam carbamates

“…Very recently, Hotha et al utilized 1-ethynylcyclohexyl p -nitrophenyl carbonate to synthesize alkynyl glycosyl carbonate donors from hemiacetals [19]. Also, glycocarbamates [20] obtained from glycosyl p -nitrophenyl carbonates [21–24], were explored in studies of carbohydrate–protein interactions [25], ligation and surfactant properties [26–27]. Although p -nitrophenyl carbonates were extensively utilized in these reactions, the nucleophilicity of amidine bases towards these carbonates was not encountered so far.…”