5-Fluorocytosine–Sugar Conjugates for Glucose Transporter-Mediated Tumor Targeting: Synthesis, Cytotoxicity, and Cellular Uptake Mechanism

  • Yu Wang
  • Xiaofei Cheng
  • Hongxia ZhaoEmail author
  • Qingzhi GaoEmail author
Research Article


Two novel sugar-conjugated 5-fluorocytosine (5-FC) antineoplastic compounds were designed and synthesized to improve the selective drug uptake by targeting the tumor-specific glucose transporter (GLUT). The antitumor activity of these compounds was evaluated in four different human cancer cell lines: A549 (human lung cancer cell line), HT29 (human colorectal cancer cell line), H460 (human lung cancer cell line), and PC3 (human prostate cancer cell line). The sugar conjugates exhibited cytotoxicity similar to or higher than 5-FC and 1-hexylcarbamoyl-5-FC in A549, HT29, H460, and PC3. Furthermore, GLUT-mediated transport of the glycoconjugate was investigated with GLUT inhibitor-mediated cytotoxicity analysis in a GLUT-overexpressing HT29 cell line. The cell-killing potency of 5-FC glycoconjugate was found to depend significantly on the GLUT inhibitor, and the cellular uptake of molecules was regulated by GLUT-mediated transport. All the results demonstrate the potential advantages of glycoconjugation for Warburg effect-targeted drug design.


Warburg effect Glucose transporter overexpressed 5-Fluorocytosine glycoconjugate Tumor targeting 



This study was supported by the National Natural Science Foundation of China (No. 21772144 and No. 21801184) and Tianjin Municipal Applied Basic and Key Research Scheme, China (No. 18JCQNIC06400).

Supplementary material

12209_2019_213_MOESM1_ESM.doc (1 mb)
Supplementary material 1 (DOC 1030 kb)


  1. 1.
    Warburg O (1956) On the origin of cancer cells. Science 123(3191):309–314CrossRefGoogle Scholar
  2. 2.
    Warburg O, Wind F, Negelein E (1927) The metabolism of tumors in the body. J Gen Physiol 8(6):519–530CrossRefGoogle Scholar
  3. 3.
    Boado RJ, Black KL, Pardridge WM (1994) Gene expression of GLUT3 and GLUT1 glucose transporters in human brain tumors. Mol Brain Res 27(1):51–57CrossRefGoogle Scholar
  4. 4.
    Godoy A, Ulloa V, Rodrıguez F et al (2006) Differential subcellular distribution of glucose transporters GLUT1-6 and GLUT9 in human cancer: ultrastructural localization of GLUT1 and GLUT5 in breast tumor tissues. J Cell Physiol 207(3):614–627CrossRefGoogle Scholar
  5. 5.
    Kurata T, Oguri T, Isobe T et al (1999) Differential expression of facilitative glucose transporter (GLUT) genes in primary lung cancers and their liver metastases. Jpn J Cancer Res 90(11):1238–1243CrossRefGoogle Scholar
  6. 6.
    Younes M, Brown RW, Stephenson M et al (1997) Overexpression of Glut1 and Glut3 in stage I nonsmall cell lung carcinoma is associated with poor survival. Cancer 80(6):1046–1051CrossRefGoogle Scholar
  7. 7.
    Plathow C, Weber WA (2008) Tumor cell metabolism imaging. J Nucl Med 49(Suppl 2):43S–63SCrossRefGoogle Scholar
  8. 8.
    Pohl J, Bertram B, Hilgard P et al (1995) D-19575: a sugar-linked isophosphoramide mustard derivative exploiting transmembrane glucose transport. Cancer Chemother Pharmacol 35(5):364–370CrossRefGoogle Scholar
  9. 9.
    Schechter NR, Erwin WD, Yang DJ et al (2009) Radiation dosimetry and biodistribution of 99mTc-ethylene dicysteine-deoxyglucose in patients with non-small-cell lung cancer. Eur J Nucl Med Mol Imaging 36(10):1583–1591CrossRefGoogle Scholar
  10. 10.
    Zhang M, Zhang Z, Blessington D et al (2003) Pyropheophorbide 2-deoxyglucosamide: a new photosensitizer targeting glucose transporters. Bioconjug Chem 14(4):709–714CrossRefGoogle Scholar
  11. 11.
    Bronstein Y, Tummala S, Rohren E et al (2011) F-18 FDG PET/CT for detection of malignant involvement of peripheral nerves. Clin Nucl Med 36(2):96–100CrossRefGoogle Scholar
  12. 12.
    Ben-Haim S, Ell P (2009) 18F-FDG PET and PET/CT in the evaluation of cancer treatment response. J Nucl Med 50(1):88–99CrossRefGoogle Scholar
  13. 13.
    Malet-Martino M, Jolimaitre P, Martino R (2002) The prodrugs of 5-fluorouracil. Curr Med Chem Anti-Cancer Agents 2(2):267–310CrossRefGoogle Scholar
  14. 14.
    Longley DB, Harkin DP, Johnston PG (2003) 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3(5):330–338CrossRefGoogle Scholar
  15. 15.
    Martino-Echarri E, Henderson BR, Brocardo MG (2014) Targeting the DNA replication checkpoint by pharmacologic inhibition of Chk1 kinase: a strategy to sensitize APC mutant colon cancer cells to 5-fluorouracil chemotherapy. Oncotarget 5(20):9889–9900CrossRefGoogle Scholar
  16. 16.
    Cassidy J, Saltz L, Twelves C et al (2011) Efficacy of capecitabine versus 5-fluorouracil in colorectal and gastric cancers: a meta-analysis of individual data from 6171 patients. Ann Oncol 22(12):2604–2609CrossRefGoogle Scholar
  17. 17.
    Kodama Y, Fumoto S, Nishi J et al (2008) Absorption and distribution characteristics of 5-fluorouracil (5-FU) after an application to the liver surface in rats in order to reduce systemic side effects. Biol Pharm Bull 31(5):1049–1052CrossRefGoogle Scholar
  18. 18.
    Suzuki K, Oda H, Sugawara Y et al (2013) Oxaliplatin-induced acute thrombocytopenia: a case report and review of the literature. Intern Med 52(5):611–615CrossRefGoogle Scholar
  19. 19.
    Bautista MA, Stevens WT, Chen CS et al (2010) Hypersensitivity reaction and acute immune-mediated thrombocytopenia from oxaliplatin: two case reports and a review of the literature. J Hematol Oncol 3(1):12–19CrossRefGoogle Scholar
  20. 20.
    Gao Y, Xiao X, Zhang C et al (2016) Melatonin synergizes the chemotherapeutic effect of 5-fluorouracil in colon cancer by suppressing PI3 K/AKT and NF-κB/iNOS signaling pathways. J Pineal Res 62(2):e12380CrossRefGoogle Scholar
  21. 21.
    Yata VK, Gopinath P, Ghosh SS (2012) Emerging implications of nonmammalian cytosine deaminases on cancer therapeutics. Appl Biochem Biotechnol 167(7):2103–2116CrossRefGoogle Scholar
  22. 22.
    Liu M, Zhang T, Li D et al (1993) A first step in the development of gene therapy for colorectal carcinoma: cloning, sequencing, and expression of Escherichia coli cytosine deaminase. Mol Pharmacol 43(3):380–387Google Scholar
  23. 23.
    Huber BE, Austin EA, Good S et al (1993) In vivo antitumor activity of 5-fluorocytosine on human colorectal carcinoma cells genetically modified to express cytosine deaminase. Can Res 53(19):4619–4626Google Scholar
  24. 24.
    Corban-Wilhelm H, Ehemann V, Becker G et al (2004) Comparison of different methods to assess the cytotoxic effects of cytosine deaminase and thymidine kinase gene therapy. Cancer Gene Ther 11(3):208–214CrossRefGoogle Scholar
  25. 25.
    Gopinath P, Ghosh SS (2009) Understanding apoptotic signaling pathways in cytosine deaminase-uracil phosphoribosyl transferase-mediated suicide gene therapy in vitro. Mol Cell Biochem 324(1–2):21–29CrossRefGoogle Scholar
  26. 26.
    Lv Z, Zhang TY, Yin JC et al (2013) Enhancement of anti-tumor activity of newcastle disease virus by the synergistic effect of cytosine deaminase. Asian Pac J Cancer Prev 14(12):7489–7496CrossRefGoogle Scholar
  27. 27.
    Wang W, Zhang N, Zhao T et al (2015) Inhibition of tumor growth by polyarginine-fused mutant cytosine deaminase. Appl Biochem Biotechnol 175(3):1633–1643CrossRefGoogle Scholar
  28. 28.
    Mitchell LA, Espinoza FL, Mendoza D et al (2017) Toca 511 gene transfer and treatment with the prodrug, 5-fluorocytosine, promotes durable antitumor immunity in a mouse glioma model. Neuro Oncology 19(7):930–939CrossRefGoogle Scholar
  29. 29.
    Liu PX, Lu YH, Gao XQ et al (2013) Highly water-soluble platinum(II) complexes as GLUT substrates for targeted therapy: improved anticancer efficacy and transporter-mediated cytotoxic properties. Chem Commun 49(24):2421–2423CrossRefGoogle Scholar
  30. 30.
    Li H, Gao XQ, Liu R et al (2015) Glucose conjugated platinum(II) complex: Antitumor superiority to oxaliplatin, combination effect and mechanism of action. Eur J Med Chem 101:400–408CrossRefGoogle Scholar
  31. 31.
    Wu M, Li H, Liu R et al (2016) Galactose conjugated platinum(II) complex targeting the Warburg effect for treatment of non-small cell lung cancer and colon cancer. Eur J Med Chem 110:32–42CrossRefGoogle Scholar
  32. 32.
    Mi Q, Ma Y, Gao X et al (2016) 2-Deoxyglucose conjugated platinum(II) complexes for targeted therapy: design, synthesis, and antitumor activity. J Biomol Struct Dyn 34(11):2339–2350CrossRefGoogle Scholar
  33. 33.
    Gao X, Liu S, Shi Y et al (2017) Mechanistic and biological characteristics of different sugar conjugated 2-methyl malonatoplatinum(II) complexes as new tumor targeting agents. Eur J Med Chem 125:372–384CrossRefGoogle Scholar
  34. 34.
    Liu R, Li H, Gao X et al (2017) Mannose-conjugated platinum complexes reveals effective tumor targeting mediated by glucose transporter 1. Biochem Biophy Res Commun 487(1):34–40CrossRefGoogle Scholar
  35. 35.
    Han J, Gao X, Liu R et al (2016) Design, synthesis of novel platinum(II) glycoconjugates, and evaluation of their antitumor effects. Chem Biol Drug Des 87(6):867–877CrossRefGoogle Scholar
  36. 36.
    Ozaki S, Watanabe Y, Nagase T et al (1986) 5-Fluorouracil derivatives. XI. Synthesis of 1-hexylcarbamoyl-5-fluorouracil metabolites. Chem Pharm Bull 34(2):893–896CrossRefGoogle Scholar
  37. 37.
    Pizzirani D, Pagliuca C, Realini N et al (2013) discovery of a new class of highly potent inhibitors of acid ceramidase: synthesis and structure–activity relationship (SAR). J Med Chem 56(9):3518–3530CrossRefGoogle Scholar
  38. 38.
    Li T, Gao X, Yang L et al (2016) Methyl 6-amino-6-deoxy-d-pyranoside-conjugated platinum(II) complexes for glucose transporter (GLUT)-mediated tumor targeting: synthesis, cytotoxicity, and cellular uptake mechanism. ChemMedChem 11(10):1069–1077CrossRefGoogle Scholar

Copyright information

© Tianjin University and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Tianjin Key Laboratory for Modern Drug Delivery and High-Efficiency, School of Pharmaceutical Science and TechnologyTianjin UniversityTianjinChina

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