Synthesis and biological studies of glycosyl dopamine derivatives as potential antiparkinsonian agents

Fernández, Cristina; Nieto, Ofelia; Rivas, Emilia; Montenegro, Gisela; Fontenla, J. A.; Fernández-Mayoralas, Alfonso

doi:10.1016/s0008-6215(00)00073-2

Cited by 70 publications

(50 citation statements)

References 15 publications

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“…Accordingly, different glyco-and galacto-conjugated drugs capable of breaching the BBB by virtue of their specific carrier-mediated transport have been synthesized [5][6][7]. In particular, the hydroxyl group at the carbon 6'-position of the sugar is the most potential functional group to which the drug molecule attaches in order to maintain the affinity for the GLUT-1 transporter [8]. For instance, drugs as 7-chlorokynurenic acid [9], nipecotic acid [10] and dopamine [11][12] that have been conjugated with D-galactose have revealed enhanced activities in the CNS.…”

Section: Brainmentioning

confidence: 99%

D-Galactose as a Vector for Prodrug Design

Melisi¹,

Curcio²,

Luongo³

et al. 2011

CTMC

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D-galactose is a simple and natural compound that has mainly been exploited in prodrug strategies. Galactosyl prodrugs can be considered a good approach to reach different goals in clinical drug application, especially when traditional drugs are likely to fail therapeutically owing to reasons such as the lack of site specificity, toxicity, and chemical instability. Indeed, of paramount importance is their ability to increase the selectivity of the parent compound, a phenomenon that helps to reduce the incidence of adverse effects, while preserving intact the pharmacodynamic features of the parent drug. Study results have varied according to the type of linkage between the drug and the hydroxyl group exploited. By working with these parameters, researchers have been able not only to generate selective pharmacological targeting of brain, liver, and cancerous cells, but also to improve cellular permeability as well as the pharmacokinetic profile of parent drugs. This review describes the broad spectrum of possibilities for exploiting D-galactose as a vector for prodrug design and the synthetic strategies that allow its realization.

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Section: Brainmentioning

confidence: 99%

D-Galactose as a Vector for Prodrug Design

Melisi¹,

Curcio²,

Luongo³

et al. 2011

CTMC

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“…[15][16] A variety of glycoconjugates with dopamine attached by ester, carbamate, and glycosidic bonds to different O-positions in the glucose were synthesized, and their affinity for the glucose carrier GLUT-1 using human erythrocytes was evaluated. Except for the glucose derivatives substituted at position C6, all other modifications of the sugar gave compounds with low or no binding to the carrier.…”

Section: Introductionmentioning

confidence: 99%

Studies on the Uptake of Glucose Derivatives by Red Blood Cells

2007

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Erythrocytes express the same glucose transporter (GLUT‐1) as is present in the blood‐brain barrier. With the aim of testing the viability of using this transport system to deliver glucosyl drug derivatives to the brain, the uptake of several dopamine–glucose conjugates and a few structurally related analogues by erythrocytes was studied with HPLC and 1H MAS NMR spectroscopy. The results showed that slight structural changes determine the uptake of glycoconjugates by red blood cells. However, experiments in the presence of glucose transport inhibitors showed that none of the conjugates that efficiently crossed the cell membrane were transported by GLUT‐1.

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“…At this point we would require a selective monodeprotection of the primary 6-OH for which there was precedent from Fernández, who showed that 1,2,3,4-tetra- O -trimethylsilylgalactose could be obtained by treating 1,2,3,4,6-penta- O -trimethylsilyl-galactose 13 with acetic acid. (20) We therefore reasoned that alcohol 12 could be accessed from 14 in a similar manner. Glycoside 14 was further disconnected to glycosyl donor 15 and sphingosine acceptor 16 .…”

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confidence: 99%

“…Trimethylsilyl groups were chosen as the protecting groups for the sugar unit owing to (1) their ease of attachment to the galactose starting material, 20,23 (2) the ability to monodeprotect the primary silyl ether selectively,(20) (3) the ease with which the remaining silyl groups can be removed when required, and (4) the “arming” effect that silyl groups impart on the sugar donor in glycosylation reactions. (21) tert -Butyldimethylsilyl (TBDMS) groups were chosen as the protecting groups for the sphingosine acceptor.…”

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confidence: 99%

Synthesis of a Versatile Building Block for the Preparation of 6-N-Derivatized α-Galactosyl Ceramides: Rapid Access to Biologically Active Glycolipids

2010

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A concise route to the 6-azido-6-deoxy-α-galactosyl-phytosphingosine derivative 9 is reported. Orthogonal protection of the two amino groups allows elaboration of 9 into a range of 6-N-derivatized α-galactosyl ceramides by late-stage introduction of the acyl chain of the ceramide and the 6-N-group in the sugar headgroup. Biologically active glycolipids 6 and 8 have been synthesized to illustrate the applicability of the approach.

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Synthesis and biological studies of glycosyl dopamine derivatives as potential antiparkinsonian agents

Cited by 70 publications

References 15 publications

D-Galactose as a Vector for Prodrug Design

D-Galactose as a Vector for Prodrug Design

Studies on the Uptake of Glucose Derivatives by Red Blood Cells

Synthesis of a Versatile Building Block for the Preparation of 6-N-Derivatized α-Galactosyl Ceramides: Rapid Access to Biologically Active Glycolipids

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