Synthesis of glucose-chlorambucil derivatives and their recognition by the human GLUT1 glucose transporter.
A limitation of the use of chemotherapeutic agents against intracerebral tumors lies on their poor uptake into the central nervous system. An approach to enhance brain delivery is to design agents that are transported into the brain by one of the saturable nutrient carriers of the blood-brain barrier, the highly efficient brain and erythrocyte glucose transporter isoform GLUT1. Since the GLUT1 hexose transporter of the blood-brain barrier is also present on erythrocytes, new compounds designed to be transported by the GLUT1 transporter were studied on human erythrocytes, which represent unique, easily accessible human GLUT1 expressing cells. In this paper we describe the synthesis of four glucose-chlorambucil derivatives, namely methyl 6-O-4[bis(2-chloroethyl)amino]benzenebut anoyl-beta-D-glucopyranosi de (3), 6-O-4-[bis(2-chloroethyl)amino]benzenebu tanoyl-D-glucopyranose (6), methyl 6-[4-[bis(2-chloroethyl)amino]benzenebut anoylamido]-6-deoxy-beta-D-glucopyranoside (9) and 6-[4-[bis(2-chloroethyl)amino]benzenebut anoyl amido]-6-deoxy-D-glucopyranose (10), and the study of their interactions with the GLUT1 transporter of the human erythrocytes. All four compounds were able to inhibit [14C]glucose uptake in a concentration-dependent manner. One of them, compound 6, exhibited an approximately 160-fold higher inhibition of [14C]glucose uptake by the GLUT1 transporter than glucose itself. Compound 6 was also able to inhibit [3H]cytochalasin B binding to erythrocytes with approximately 1000-fold higher efficacy than does glucose. The inhibition of glucose uptake was entirely reversible, indicating that it was not due to alkylation of a nucleophilic group of the hexose transporter. The above results suggested specific interactions of compound 6 with the hexose transporter protein. Uptake studies of [14C]compound 6 indicated, in addition, some non-specific interactions with intact and open erythrocyte membranes: only a small amount of the bound [14C]compound 6 can be displaced by cytochalasin B. Collectively, these findings led us to conclude that the interactions of compound 6 with GLUT1 are presumably that of a non-transported inhibitor.
Halmos
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UMR 133 CNRS/RPR, Villejuif, France.
Santarromana
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Antonakis
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Scherman
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D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001812:Blood-Brain Barrier; D002699:Chlorambucil / Q000031:analogs & derivatives* / Q000494:pharmacology; D003571:Cytochalasin B / Q000378:metabolism; D004337:Drug Carriers; D004912:Erythrocytes / Q000378:metabolism; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D051272:Glucose Transporter Type 1; D006801:Humans; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D018906:Antineoplastic Agents, Alkylating; D004337:Drug Carriers; D051272:Glucose Transporter Type 1; D009004:Monosaccharide Transport Proteins; C495677:SLC2A1 protein, human; D002699:Chlorambucil; D003571:Cytochalasin B; D005947:Glucose