title: Methyl 6-Amino-6-deoxy-d-pyranoside-Conjugated Platinum(II) Complexes for Glucose Transporter (GLUT)-Mediated Tumor Targeting: Synthesis, Cytotoxicity, and Cellular Uptake Mechanism.
abstract: Methyl 6-aminodeoxy-d-pyranoside-derived platinum(II) glycoconjugates were designed and synthesized based on the clinical drug oxaliplatin for glucose transporter (GLUT)-mediated tumor targeting. In addition to a substantial improvement in water solubility, the conjugates exhibited cytotoxicity similar to or higher than that of oxaliplatin in six different human cancer cell lines. GLUT-mediated transport of the complexes was investigated with a cell-based fluorescence competition assay and GLUT-inhibitor-mediated cytotoxicity analysis in a GLUT-overexpressing human colorectal adenocarcinoma (HT29) cell line. The antitumor effect of the aminodeoxypyranoside-conjugated platinum(II) complexes was found to depend significantly on the GLUT inhibitor, and the cellular uptake of the molecules was regulated by GLUT-mediated transport. The results from this study demonstrate the potential advantages of aminodeoxypyranosides as sugar motifs for glycoconjugation for Warburg-effect-targeted drug design. These fundamental results also support the potential of aminodeoxypyranoside-conjugated platinum(II) complexes as lead compounds for further preclinical evaluation.
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, P.R. China.
authors.forename: Taoli
authors.initials: T
authors.lastname: Li
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, P.R. China.
authors.forename: Xiangqian
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Biochemistry, Gudui BioPharma Technology Inc., 5 Lanyuan Road, Huayuan Industrial Park, Tianjin, 300384, P.R. China.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, P.R. China.
authors.forename: Yunli
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, P.R. China. qingzhi@tju.edu.cn.
authors.forename: Qingzhi
authors.initials: Q
authors.lastname: Gao
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002241:Carbohydrates / Q000737:chemistry*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D051246:Glucose Transport Proteins, Facilitative / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D010984:Platinum / Q000737:chemistry*; D012995:Solubility
chemical_list: D000970:Antineoplastic Agents; D002241:Carbohydrates; D056831:Coordination Complexes; D051246:Glucose Transport Proteins, Facilitative; D010984:Platinum
keywords: Warburg effect; aminodeoxypyranosides; glucose transporter (GLUT); glycoconjugates; platinum(II) complexes