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Methyl 6‐Amino‐6‐deoxy‐ d ‐pyranoside‐Conjugated Platinum(II) Complexes for Glucose Transporter (GLUT)‐Mediated Tumor Targeting: Synthesis, Cytotoxicity, and Cellular Uptake Mechanism
Author(s) -
Li Taoli,
Gao Xiangqian,
Yang Liu,
Shi Yunli,
Gao Qingzhi
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600079
Subject(s) - cytotoxicity , chemistry , glucose transporter , oxaliplatin , biochemistry , glycoconjugate , transporter , cell culture , cancer cell , pharmacology , in vitro , biology , cancer , colorectal cancer , genetics , gene , insulin , endocrinology
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.