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. 2022 Aug 18;13(9):1452-1458.
doi: 10.1021/acsmedchemlett.2c00250. eCollection 2022 Sep 8.

Aroylhydrazone Glycoconjugate Prochelators Exploit Glucose Transporter 1 (GLUT1) to Target Iron in Cancer Cells

Yu-Shien Sung  1 , Baris Kerimoglu  2 , Aikseng Ooi  2 , Elisa Tomat  1
Affiliations

Aroylhydrazone Glycoconjugate Prochelators Exploit Glucose Transporter 1 (GLUT1) to Target Iron in Cancer Cells

Yu-Shien Sung et al. ACS Med Chem Lett. .

Abstract

Glycoconjugation strategies in anticancer drug discovery exploit the high expression of glucose transporters in malignant cells to achieve preferential uptake and hence attractive pharmacological characteristics of increased therapeutic windows and decreased unwanted toxicity. Here we present the design of glycoconjugated prochelators of aroylhydrazone AH1, an antiproliferative scavenger that targets the increased iron demand of rapidly proliferating malignant cells. The constructs feature a monosaccharide (d-glucose, d-glucosamine, or glycolytic inhibitor 2-deoxy-d-glucose) connected at the C2 or C6 position via a short linker, which masks the chelator through a disulfide bond susceptible to intracellular reduction. Cellular assays showed that the glycoconjugates rely on the GLUT1 transporter for uptake, lead to intracellular iron deprivation, and present antiproliferative activity. Ectopic overexpression of GLUT1 in malignant and normal cells increased the uptake and toxicity of the glycoconjugated prochelators, demonstrating that these compounds are well suited for targeting cells overexpressing glucose transporters and therefore for selective iron sequestration in malignant cells.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Chart 1
Chart 1. Structures of 18F-FDG and Examples of Glycoconjugates (top), and Chelators and Disulfide-Masked AH1 Prochelator (bottom)
Chart 2
Chart 2. AH1 Glycoconjugates and Aglycone Control Compound Investigated in This Work
Scheme 1
Scheme 1. Synthesis of Glycoconjugates G6AH1 and GA2AH1
Scheme 2
Scheme 2. Synthesis of 2DG6AH1
Figure 1
Figure 1
Apoptotic cell death in the presence of AH1 glycoconjugates and control compounds in A2780 cells. The compounds (20 μM in all cases) were incubated for 48 h. Following treatment with FITC-AnnV and PI, the cells were analyzed by flow cytometry. Experiments were conducted in triplicate and the values shown are averages ± standard deviation. ** p < 0.01, *** p < 0.001, **** p < 0.0001.
Figure 2
Figure 2
Cellular uptake of fluorescent glucose analog 2-NBDG in the presence of glycoconjugate competitors and aglycone control in A2780 cells. Tested compounds (50 μM) were coincubated with 2-NBDG probe (100 μM) for 20 min. GLUT1 inhibitor phloretin (50 μM) was used as a positive control. Experiments were conducted in triplicate and values shown are averages ± standard deviation. * p < 0.05, ** p < 0.01.
Figure 3
Figure 3
Effects of GLUT1 inhibitor phloretin (12.5 μM) on the IC50 values (72 h, MTT assays) of AH1 glycoconjugates in A2780 cells. Experiments were conducted in triplicate and the values shown are averages ± standard deviation. **** p < 0.0001.
Figure 4
Figure 4
Expression of GLUT1 in different cell lines. (a) Western blot of GLUT1 in MRC-5, A2780, MDA-MB-231 with β-actin as a loading control. (b) GLUT1 expression levels normalized to the control as averages of four replicates ± standard deviation.
Figure 5
Figure 5
Efficiency of GLUT1 overexpression in isogenic MDA-MB-231 and MRC-5 derivative lines. (a) Western blot of GLUT1-transduced vs Turbo-635-transduced control cell lines. β-Actin is used as a loading control. (b) Glucose uptake capacity of the transduced cell lines as indicated by the relative uptake of fluorescent glucose analog 2-NBDG (100 μM, 20 min). Experiments were conducted in triplicate and the values shown are averages ± standard deviation. ** p < 0.01, *** p < 0.001.
Figure 6
Figure 6
Effects of GLUT1 amplification on the antiproliferative activity of AH1 glycoconjugates in transduced (a) MDA-MB-231 and (b) MRC-5 cell lines. IC50 values were obtained from MTT assays (72 h). Experiments were conducted in triplicate and the values shown are averages ± standard deviation. *** p < 0.001, **** p < 0.0001.
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