Halmos T, Santarromana M, Antonakis K, Scherman D
UMR 133 CNRS/RPR, Villejuif, France.
Eur J Pharmacol. 1996 Dec 30;318(2-3):477-84. doi: 10.1016/s0014-2999(96)00796-0.
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.
使用化疗药物治疗脑内肿瘤存在一定局限性，原因在于这些药物难以进入中枢神经系统。增强脑部给药的一种方法是设计能通过血脑屏障的饱和营养转运体之一（高效的脑和红细胞葡萄糖转运体亚型GLUT1）转运至脑内的药物。由于血脑屏障的GLUT1己糖转运体在红细胞上也有表达，因此针对设计由GLUT1转运体转运的新化合物，在人红细胞上进行了研究，人红细胞是独特的、易于获取的表达人GLUT1的细胞。本文描述了四种葡萄糖 - 苯丁酸氮芥衍生物的合成，即6 - O - 4[双(2 - 氯乙基)氨基]苯丁酰基 - β - D - 吡喃葡萄糖苷甲酯(3)、6 - O - 4 - [双(2 - 氯乙基)氨基]苯丁酰基 - D - 吡喃葡萄糖(6)、6 - [4 - [双(2 - 氯乙基)氨基]苯丁酰胺基] - 6 - 脱氧 - β - D - 吡喃葡萄糖苷甲酯(9)和6 - [4 - [双(2 - 氯乙基)氨基]苯丁酰胺基] - 6 - 脱氧 - D - 吡喃葡萄糖(10)，以及它们与人红细胞GLUT1转运体相互作用的研究。所有四种化合物均能以浓度依赖性方式抑制[¹⁴C]葡萄糖摄取。其中一种化合物6对GLUT1转运体介导的[¹⁴C]葡萄糖摄取的抑制作用比葡萄糖本身高约160倍。化合物6还能抑制[³H]细胞松弛素B与红细胞的结合，其效力比葡萄糖高约1000倍。葡萄糖摄取的抑制作用完全可逆，表明这并非由于己糖转运体亲核基团的烷基化所致。上述结果提示化合物6与己糖转运体蛋白存在特异性相互作用。此外，[¹⁴C]化合物6的摄取研究表明，它与完整和开放的红细胞膜存在一些非特异性相互作用：只有少量结合的[¹⁴C]化合物6能被细胞松弛素B取代。总体而言，这些发现使我们得出结论，化合物6与GLUT1的相互作用可能是一种非转运性抑制剂的相互作用。
