5-Fluorocytosine–Sugar Conjugates for Glucose Transporter-Mediated Tumor Targeting: Synthesis, Cytotoxicity, and Cellular Uptake Mechanism  

作　　者：Yu Wang Xiaofei Cheng Hongxia Zhao Qingzhi Gao 

机构地区：[1]Tianjin Key Laboratory for Modern Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology , Tianjin University

出　　处：《Transactions of Tianjin University》2019年第6期611-617,共7页天津大学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China (No. 21772144 and No. 21801184);Tianjin Municipal Applied Basic and Key Research Scheme, China (No. 18JCQNIC06400)

摘　　要：Two novel sugar-conjugated 5-fluorocytosine(5-FC)antineoplastic compounds were designed and synthesized to improve the selective drug uptake by targeting the tumor-specific glucose transporter(GLUT).The antitumor activity of these compounds was evaluated in four different human cancer cell lines:A549(human lung cancer cell line),HT29(human colorectal cancer cell line),H460(human lung cancer cell line),and PC3(human prostate cancer cell line).The sugar conjugates exhibited cytotoxicity similar to or higher than 5-FC and 1-hexylcarbamoyl-5-FC in A549,HT29,H460,and PC3.Furthermore,GLUT-mediated transport of the glycoconjugate was investigated with GLUT inhibitor-mediated cytotoxicity analysis in a GLUT-overexpressing HT29 cell line.The cell-killing potency of 5-FC glycoconjugate was found to depend significantly on the GLUT inhibitor,and the cellular uptake of molecules was regulated by GLUT-mediated transport.All the results demonstrate the potential advantages of glycoconjugation for Warburg effect-targeted drug design.Two novel sugar-conjugated 5-fluorocytosine(5-FC) antineoplastic compounds were designed and synthesized to improve the selective drug uptake by targeting the tumor-specific glucose transporter(GLUT).The antitumor activity of these compounds was evaluated in four different human cancer cell lines:A549(human lung cancer cell line),HT29(human colorectal cancer cell line),H460(human lung cancer cell line),and PC3(human prostate cancer cell line).The sugar conjugates exhibited cytotoxicity similar to or higher than 5-FC and 1-hexylcarbamoyl-5-FC in A549,HT29,H460,and PC3.Furthermore,GLUT-mediated transport of the glycoconjugate was investigated with GLUT inhibitor-mediated cytotoxicity analysis in a GLUT-overexpressing HT29 cell line.The cell-killing potency of 5-FC glycoconjugate was found to depend significantly on the GLUT inhibitor,and the cellular uptake of molecules was regulated by GLUT-mediated transport.All the results demonstrate the potential advantages of glycoconjugation for Warburg effect-targeted drug design.

关 键 词：WARBURG effect Glucose TRANSPORTER overexpressed 5-FLUOROCYTOSINE GLYCOCONJUGATE Tumor targeting 

分 类 号：R73[医药卫生—肿瘤]