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. 2016 Feb 12;55(7):2550-4.
doi: 10.1002/anie.201510551. Epub 2016 Jan 8.

A Potent Glucose-Platinum Conjugate Exploits Glucose Transporters and Preferentially Accumulates in Cancer Cells

Malay Patra  1 , Timothy C Johnstone  1 , Kogularamanan Suntharalingam  2 , Stephen J Lippard  3
Affiliations

A Potent Glucose-Platinum Conjugate Exploits Glucose Transporters and Preferentially Accumulates in Cancer Cells

Malay Patra et al. Angew Chem Int Ed Engl. .

Abstract

Three rationally designed glucose-platinum conjugates (Glc-Pts) were synthesized and their biological activities evaluated. The Glc-Pts, 1-3, exhibit high levels of cytotoxicity toward a panel of cancer cells. The subcellular target and cellular uptake mechanism of the Glc-Pts were elucidated. For uptake into cells, Glc-Pt 1 exploits both glucose and organic cation transporters, both widely overexpressed in cancer. Compound 1 preferentially accumulates in and annihilates cancer, compared to normal epithelial, cells in vitro.

Keywords: antitumor agents; glucose transporters; glycoconjugates; medicinal inorganic chemistry; platinum.

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Figures

Figure 1
Figure 1
(a) Structures of Glc-Pts 1-3 and their aglycone 4. (b) The hydrogen-bonding interactions present in the docking model of 1 into XylE (PDB 4GBZ).[9] The protein is shown as grey ribbons with the sidechains of key residues depicted as sticks. Complex 1 is shown as sticks and polar hydrogen atoms are explicitly portrayed. Color code: N blue, O red, H white, C cyan, protein C grey, Pt purple. Hydrogen-bonding interactions are illustrated with dashed yellow lines.
Figure 2
Figure 2
(a) Effect of GLUT1 inhibitor EDG on the cellular uptake of 1–4 and cisplatin (10 μM compounds, 17 h). (b) Effect of externally added D-glucose and L-glucose (10 μM compounds, 17 h). (c) Effect of EDG on the IC50 values (72 h assay). (d) Effect of EDG, Ctd, and their mixture on the cellular up-take of 1, 4 and oxaliplatin (10 μM compounds, 8 h). All experiments were done in A2780 cells and cellular uptake in absence of inhibitor was normalized to 100%. Data represent the mean ± SD of at least three or more replicates. The asterisks denote differences are statistically significant (*p < 0.01, **p < 0.001), ns = not statistically significant.
Figure 3
Figure 3
(a and b) Preferential accumulation of Glc-Pt 1 in prostate and kidney cancer cells as compared to matched normal epithelial cells (20 μM, 8 h). (c and d) Effect of Glc-Pt 1 on the viability of cancer and matched normal cells. The asterisks denote differences that are statistically significant (*p<0.001, **p<0.02, ***p<0.01, ****p<0.002).
Scheme 1
Scheme 1
Synthetic route for glucose-platinum conjugate 1.
See this image and copyright information in PMC

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