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

Abstract

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.