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Glucose Transport pp 93–108Cite as

Design, Synthesis, and Evaluation of GLUT Inhibitors

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Part of the book series: Methods in Molecular Biology ((MIMB,volume 1713))

Abstract

The Warburg effect describes how most cancer cells exhibit higher-than-normal glucose consumption, not only under hypoxic conditions, but also when normal oxygen levels are present. Although glucose transporter 1 (GLUT1) has been found to play a key role in the cellular uptake of glucose, especially in cancer cells, where it is generally overexpressed, it has not been given consideration as a suitable target for the development of anticancer drugs. In this chapter, an example of molecular design and realization of novel GLUT1 inhibitors, including in silico modeling, chemical synthesis, and biological characterization, is provided. This process started with the identification of a focused series of oxime derivatives, originally designed as estrogen receptor (ER) ligands, which were structurally optimized in order to direct their activity towards GLUT1 and to minimize their binding to the ERs, leading to the production of efficient and selective inhibitors of glucose uptake in cancer cells.

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References

  1. Macheda ML, Rogers S, Best JD (2005) Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol 202(3):654–662. https://doi.org/10.1002/jcp.20166

    Article  CAS  PubMed  Google Scholar 

  2. Warburg O (1956) On the origin of cancer cells. Science 123(3191):309–314

    Article  CAS  PubMed  Google Scholar 

  3. Smith TA (2001) The rate-limiting step for tumor [18F]fluoro-2-deoxy-D-glucose (FDG) incorporation. Nucl Med Biol 28(1):1–4

    Article  CAS  PubMed  Google Scholar 

  4. Denko NC (2008) Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer 8(9):705–713. https://doi.org/10.1038/nrc2468

    Article  CAS  PubMed  Google Scholar 

  5. Granchi C, Fortunato S, Minutolo F (2016) Anticancer agents interacting with membrane glucose transporters. Medchemcomm 7(9):1716–1729. https://doi.org/10.1039/C6MD00287K

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Granchi C, Qian Y, Lee HY, Paterni I, Pasero C, Iegre J, Carlson KE, Tuccinardi T, Chen X, Katzenellenbogen JA, Hergenrother PJ, Minutolo F (2015) Salicylketoximes that target glucose transporter 1 restrict energy supply to lung cancer cells. ChemMedChem 10(11):1892–1900. https://doi.org/10.1002/cmdc.201500320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tuccinardi T, Granchi C, Iegre J, Paterni I, Bertini S, Macchia M, Martinelli A, Qian Y, Chen X, Minutolo F (2013) Oxime-based inhibitors of glucose transporter 1 displaying antiproliferative effects in cancer cells. Bioorg Med Chem Lett 23(24):6923–6927. https://doi.org/10.1016/j.bmcl.2013.09.037

    Article  CAS  PubMed  Google Scholar 

  8. Bertini S, De Cupertinis A, Granchi C, Bargagli B, Tuccinardi T, Martinelli A, Macchia M, Gunther JR, Carlson KE, Katzenellenbogen JA, Minutolo F (2011) Selective and potent agonists for estrogen receptor beta derived from molecular refinements of salicylaldoximes. Eur J Med Chem 46(6):2453–2462. https://doi.org/10.1016/j.ejmech.2011.03.030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Minutolo F, Bellini R, Bertini S, Carboni I, Lapucci A, Pistolesi L, Prota G, Rapposelli S, Solati F, Tuccinardi T, Martinelli A, Stossi F, Carlson KE, Katzenellenbogen BS, Katzenellenbogen JA, Macchia M (2008) Monoaryl-substituted salicylaldoximes as ligands for estrogen receptor beta. J Med Chem 51(5):1344–1351. https://doi.org/10.1021/jm701396g

    Article  CAS  PubMed  Google Scholar 

  10. Minutolo F, Bertini S, Granchi C, Marchitiello T, Prota G, Rapposelli S, Tuccinardi T, Martinelli A, Gunther JR, Carlson KE, Katzenellenbogen JA, Macchia M (2009) Structural evolutions of salicylaldoximes as selective agonists for estrogen receptor beta. J Med Chem 52(3):858–867. https://doi.org/10.1021/jm801458t

    Article  CAS  PubMed  Google Scholar 

  11. Wang D, Chu PC, Yang CN, Yan R, Chuang YC, Kulp SK, Chen CS (2012) Development of a novel class of glucose transporter inhibitors. J Med Chem 55(8):3827–3836. https://doi.org/10.1021/jm300015m

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hillerns PI, Zu Y, Fu YJ, Wink M (2005) Binding of phytoestrogens to rat uterine estrogen receptors and human sex hormone-binding globulins. Z Naturforsch C 60(7–8):649–656

    CAS  PubMed  Google Scholar 

  13. Frolova A, Flessner L, Chi M, Kim ST, Foyouzi-Yousefi N, Moley KH (2009) Facilitative glucose transporter type 1 is differentially regulated by progesterone and estrogen in murine and human endometrial stromal cells. Endocrinology 150(3):1512–1520. https://doi.org/10.1210/en.2008-1081

    Article  CAS  PubMed  Google Scholar 

  14. Takizawa I, Lawrence MG, Balanathan P, Rebello R, Pearson HB, Garg E, Pedersen J, Pouliot N, Nadon R, Watt MJ, Taylor RA, Humbert P, Topisirovic I, Larsson O, Risbridger GP, Furic L (2015) Estrogen receptor alpha drives proliferation in PTEN-deficient prostate carcinoma by stimulating survival signaling, MYC expression and altering glucose sensitivity. Oncotarget 6(2):604–616. https://doi.org/10.18632/oncotarget.2820

  15. Sun L, Zeng X, Yan C, Sun X, Gong X, Rao Y, Yan N (2012) Crystal structure of a bacterial homologue of glucose transporters GLUT1-4. Nature 490(7420):361–366. https://doi.org/10.1038/nature11524

    Article  CAS  PubMed  Google Scholar 

  16. Fiser A, Do RK, Sali A (2000) Modeling of loops in protein structures. Protein Sci 9(9):1753–1773. https://doi.org/10.1110/ps.9.9.1753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cross S, Baroni M, Carosati E, Benedetti P, Clementi S (2010) FLAP: GRID molecular interaction fields in virtual screening. Validation using the DUD data set. J Chem Inf Model 50(8):1442–1450. https://doi.org/10.1021/ci100221g

    Article  CAS  PubMed  Google Scholar 

  18. Liu Y, Zhang W, Cao Y, Liu Y, Bergmeier S, Chen X (2010) Small compound inhibitors of basal glucose transport inhibit cell proliferation and induce apoptosis in cancer cells via glucose-deprivation-like mechanisms. Cancer Lett 298(2):176–185. https://doi.org/10.1016/j.canlet.2010.07.002

    Article  CAS  PubMed  Google Scholar 

  19. Berridge MV, Herst PM, Tan AS (2005) Tetrazolium dyes as tools in cell biology: new insights into their cellular reduction. Biotechnol Annu Rev 11:127–152. https://doi.org/10.1016/S1387-2656(05)11004-7

    Article  CAS  PubMed  Google Scholar 

  20. Paterni I, Bertini S, Granchi C, Tuccinardi T, Macchia M, Martinelli A, Caligiuri I, Toffoli G, Rizzolio F, Carlson KE, Katzenellenbogen BS, Katzenellenbogen JA, Minutolo F (2015) Highly selective salicylketoxime-based estrogen receptor beta agonists display antiproliferative activities in a glioma model. J Med Chem 58(3):1184–1194. https://doi.org/10.1021/jm501829f

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Carlson KE, Choi I, Gee A, Katzenellenbogen BS, Katzenellenbogen JA (1997) Altered ligand binding properties and enhanced stability of a constitutively active estrogen receptor: evidence that an open pocket conformation is required for ligand interaction. Biochemistry 36(48):14897–14905. https://doi.org/10.1021/bi971746l

    Article  CAS  PubMed  Google Scholar 

  22. Katzenellenbogen JA, Johnson HJ Jr, Myers HN (1973) Photoaffinity labels for estrogen binding proteins of rat uterus. Biochemistry 12(21):4085–4092

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacy, University of Pisa, Via Bonanno 33, 56126, Pisa, Italy

    Carlotta Granchi, Tiziano Tuccinardi & Filippo Minutolo

Authors
  1. Carlotta Granchi
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  2. Tiziano Tuccinardi
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  3. Filippo Minutolo
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Corresponding author

Correspondence to Filippo Minutolo .

Editor information

Editors and Affiliations

  1. Department of Experimental Medical Science, Lund University, Lund, Sweden

    Karin Lindkvist-Petersson

  2. Department of Experimental Medical Science, Lund University, Lund, Sweden

    Jesper S Hansen

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Granchi, C., Tuccinardi, T., Minutolo, F. (2018). Design, Synthesis, and Evaluation of GLUT Inhibitors. In: Lindkvist-Petersson, K., Hansen, J. (eds) Glucose Transport. Methods in Molecular Biology, vol 1713. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7507-5_8

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  • DOI: https://doi.org/10.1007/978-1-4939-7507-5_8

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-7506-8

  • Online ISBN: 978-1-4939-7507-5

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