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.

Endothelial cell metabolism inhibition: A new approach to the treatment of resistant metastatic colorectal carcinoma

“…Hence, targeting the convergence of angiogenic signals on endothelial metabolism would be an effective alternative to anti-VEGF in metastatic CRC therapy. Drugs targeting the Warburg effect are under pre-clinical and clinical investigations [15][16][17][18][19] . These include GLUT1-targeted therapeutic agents such as small chemical entities, as well as GLUT1-mediated target drug delivery for anticancer agents such as fluorine-substituted platinum(II)-sugar conjugates.…”

GLUT1-mediated selective tumor targeting with fluorine containing platinum(II) glycoconjugates

“…Galactose, mannose as well as glucosamine can also be transported by GLUT1 with distinct efficiencies [23]. Through our previous proof-of-concept studies, we established some useful synthetic and basic biological evaluation methods on different platinum-glycoconjugates including C1-O-glycosides [24], 2-deoxy and 6-deoxy-glycoconjugates [25, 26], as well as developed fluorescent bioprobes as useful tool for cell-based glucose uptake imaging [27]. …”

Enhanced anti-hepatocarcinoma efficacy by GLUT1 targeting and cellular microenvironment-responsive PAMAM–camptothecin conjugate

“…For example, 2-deoxy-2-(18F)-fluoro- d -glucose, as the most convincing example, has been widely adopted for positron emission tomography (PET) imaging for cancer diagnoses (Jadvar, 2016 ). Glufosfamide, a derivative of ifosfamide mustard conjugated to glucose, has shown promise in treating metastatic pancreatic cancer in advanced clinical trials (Lacombe, 2012 ; Li et al., 2016 ). However, highly effective GLUT1-mediated, tumor-targeting nanomedicines have not been widely developed.…”