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RESEARCH ARTICLE
Contents Vol 74(11)

Sialyltransferase Inhibitors as Potential Anti-Cancer Agents*

Danielle Skropeta https://orcid.org/0000-0002-2293-7916 A B C , Christopher Dobie https://orcid.org/0000-0003-2918-8302 A , Andrew P. Montgomery A , Harrison Steele A , Rémi Szabo A and Haibo Yu https://orcid.org/0000-0002-1099-2803 A B
+ Author Affiliations
- Author Affiliations

A Molecular Horizons and School of Chemistry and Molecular Bioscience, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia.

B Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia.

C Corresponding author. Email: skropeta@uow.edu.au

Australian Journal of Chemistry 74(11) 758-766 https://doi.org/10.1071/CH21195
Submitted: 12 August 2021  Accepted: 8 October 2021   Published: 22 November 2021

Abstract

Sialic acid occupies a privileged position at the terminus of the glycan chain of many cell-surface glycoconjugates. Owing to both their structure and location, charged sialic acid residues mediate numerous critical interactions in cell–cell communication including cell recognition, invasion, migration, receptor binding, and immunological responses. Sialyltransferases (STs) are the enzymes involved in the biosynthesis of sialylated glycans and are highly upregulated, up to 40–60 %, in a range of cancers, with tumour hypersialylation strongly correlated with both tumour progression and treatment resistance. Accordingly, inhibiting sialylation is currently being explored by several research groups worldwide as a potential new cancer treatment strategy. However, to progress small molecule ST inhibitors into the clinic, issues around selectivity, synthetic accessibility, and cell permeability need to be addressed. Using computationally guided design principles, we produced a leading series of ST inhibitors by replacing the cytidine nucleoside with uridine and substituting the charged phosphodiester linker with a carbamate or triazole moiety. Biological evaluation of the newly developed inhibitors was performed using commercially available human ST enzymes, with the Ki inhibition values of the lead compounds ranging from 1 to 20 µM. Compared with earlier generations of sialylation inhibitors, our inhibitors are non-toxic in a range of cell studies, with improved synthetic accessibility.

Keywords: organic synthesis, medicinal chemistry, molecular docking, enzyme inhibitors, sialyltransferase, sialic acid, cancer, metastasis.


References

[1]  J. Munkley, D. J. Elliott, Oncotarget 2016, 7, 35478.
         | Crossref | GoogleScholarGoogle Scholar | 27007155PubMed |

[2]  H. Läubli, L. Borsig, Front. Immunol. 2019, 10, 2120.
         | Crossref | GoogleScholarGoogle Scholar | 31552050PubMed |

[3]  K. F. Boligan, C. Mesa, L. E. Fernandez, S. von Gunten, Cell. Mol. Life Sci. 2015, 72, 1231.
         | Crossref | GoogleScholarGoogle Scholar | 25487607PubMed |

[4]  H. Steele, A. J. Tague, D. Skropeta, Curr. Med. Chem. 2021, 28, 5251.
         | 33593248PubMed |

[5]  M. Cohen, A. Varki, OMICS 2010, 14, 455.
         | Crossref | GoogleScholarGoogle Scholar | 20726801PubMed |

[6]  A. Varki, Trends Mol. Med. 2008, 14, 351.
         | Crossref | GoogleScholarGoogle Scholar | 18606570PubMed |

[7]  D. Skropeta, Bioorg. Med. Chem. 2009, 17, 2645.
         | Crossref | GoogleScholarGoogle Scholar | 19285412PubMed |

[8]  O. M. Pearce, H. Läubli, Glycobiology 2016, 26, 111.
         | Crossref | GoogleScholarGoogle Scholar | 26518624PubMed |

[9]  A. Harduin-Lepers, V. Vallejo-Ruiz, M. A. Krzewinski-Recchi, B. Samyn-Petit, S. Julien, P. Delannoy, Biochimie 2001, 83, 727.
         | Crossref | GoogleScholarGoogle Scholar | 11530204PubMed |

[10]  R. Szabo, D. Skropeta, Med. Res. Rev. 2017, 37, 219.
         | Crossref | GoogleScholarGoogle Scholar | 27678392PubMed |

[11]  T. Miyagi, K. Takahashi, K. Hata, K. Shiozaki, K. Yamaguchi, Glycoconj. J. 2012, 29, 567.
         | Crossref | GoogleScholarGoogle Scholar | 22644327PubMed |

[12]  E. Rodrigues, M. S. Macauley, Cancers 2018, 10, 207.
         | Crossref | GoogleScholarGoogle Scholar |

[13]  C. Büll, M. A. Stoel, M. H. den Brok, G. J. Adema, Cancer Res. 2014, 74, 3199.
         | Crossref | GoogleScholarGoogle Scholar | 24830719PubMed |

[14]  A. Peixoto, M. Relvas-Santos, R. Azevedo, L. L. Santos, J. A. Ferreira, Front. Oncol. 2019, 9, 380.
         | Crossref | GoogleScholarGoogle Scholar | 31157165PubMed |

[15]  C. Dobie, D. Skropeta, Br. J. Cancer 2021, 124, 76.
         | Crossref | GoogleScholarGoogle Scholar | 33144696PubMed |

[16]  W. H. D. Bowles, T. M. Gloster, Front. Mol. Biosci. 2021, 8, 705133.
         | Crossref | GoogleScholarGoogle Scholar |

[17]  A. F. Swindall, S. L. Bellis, J. Biol. Chem. 2011, 286, 22982.
         | Crossref | GoogleScholarGoogle Scholar | 21550977PubMed |

[18]  A. T. Holdbrooks, C. M. Britain, S. L. Bellis, J. Biol. Chem. 2018, 293, 1610.
         | Crossref | GoogleScholarGoogle Scholar | 29233887PubMed |

[19]  Y. Liu, D. Pan, S. L. Bellis, Y. Song, Proteins 2008, 73, 989.
         | Crossref | GoogleScholarGoogle Scholar | 18536010PubMed |

[20]  R. T. Almaraz, Y. Tian, R. Bhattarcharya, E. Tan, S.-H. Chen, M. R. Dallas, et al. Mol. Cell. Proteomics 2012, 11, M112.017558-1.
         | Crossref | GoogleScholarGoogle Scholar |

[21]  E. C. Seales, G. A. Jurado, B. A. Brunson, J. K. Wakefield, A. R. Frost, S. L. Bellis, Cancer Res. 2005, 65, 4645.
         | Crossref | GoogleScholarGoogle Scholar | 15930282PubMed |

[22]  J. G. Rodrigues, M. Balmaña, J. A. Macedo, J. Poças, Â. Fernandes, J. C. M. de-Freitas-Junior, et al. Cell. Immunol. 2018, 333, 46.
         | Crossref | GoogleScholarGoogle Scholar | 29576316PubMed |

[23]  P. M. Drake, W. Cho, B. Li, A. Prakobphol, E. Johansen, N. L. Anderson, et al. Clin. Chem. 2010, 56, 223.
         | Crossref | GoogleScholarGoogle Scholar | 19959616PubMed |

[24]  W. Huang, L. Sun, B. Wang, Y. Ma, D. Yao, W. Han, et al. Z. Natforsch. C: J. Biosci. 2020, 75, 41.
         | Crossref | GoogleScholarGoogle Scholar |

[25]  K.-H. Chang, L. Lee, J. Chen, W.-S. Li, Chem. Commun. 2006, 629.

[26]  C.-H. Chiang, C.-H. Wang, H.-C. Chang, S. V. More, W.-S. Li, W.-C. Hung, J. Cell. Physiol. 2010, 223, 492.
         | 20112294PubMed |

[27]  C. Büll, T. J. Boltje, M. Wassink, A. M. A. de Graaf, F. L. van Delft, M. H. den Brok, et al. Mol. Cancer Ther. 2013, 12, 1935.
         | Crossref | GoogleScholarGoogle Scholar | 23974695PubMed |

[28]  C. D. Rillahan, A. Antonopoulos, C. T. Lefort, R. Sonon, P. Azadi, K. Ley, et al. Nat. Chem. Biol. 2012, 8, 661.
         | Crossref | GoogleScholarGoogle Scholar | 22683610PubMed |

[29]  M. S. Macauley, B. M. Arlian, C. D. Rillahan, P.-C. Pang, N. Bortell, M. C. G. Marcondes, et al. J. Biol. Chem. 2014, 289, 35149.
         | Crossref | GoogleScholarGoogle Scholar | 25368325PubMed |

[30]  F. Amann, C. Schaub, B. Müller, R. R. Schmidt, Chem. – Eur. J. 1998, 4, 1106.
         | Crossref | GoogleScholarGoogle Scholar |

[31]  B. Muller, C. Schaub, R. R. Schmidt, Angew. Chem. Int. Ed. 1998, 37, 2893.
         | Crossref | GoogleScholarGoogle Scholar |

[32]  G. Dufner, R. Schworer, B. Muller, R. R. Schmidt, Eur. J. Org. Chem. 2000, 1467.
         | Crossref | GoogleScholarGoogle Scholar |

[33]  D. Skropeta, R. Schworer, T. Haag, R. R. Schmidt, Glycoconj. J. 2004, 21, 205.
         | Crossref | GoogleScholarGoogle Scholar | 15486453PubMed |

[34]  W. Li, Y. Niu, D.-C. Xiong, X. Cao, X.-S. Ye, J. Med. Chem. 2015, 58, 7972.
         | Crossref | GoogleScholarGoogle Scholar | 26406919PubMed |

[35]  D. Skropeta, R. Schworer, R. R. Schmidt, Bioorg. Med. Chem. Lett. 2003, 13, 3351.
         | Crossref | GoogleScholarGoogle Scholar | 12951124PubMed |

[36]  J. Guo, W. Li, W. Xue, X.-S. Ye, J. Med. Chem. 2017, 60, 2135.
         | Crossref | GoogleScholarGoogle Scholar | 28165727PubMed |

[37]  R. Kumar, R. Nasi, M. Bhasin, N. Huan Khieu, M. Hsieh, M. Gilbert, et al. Carbohydr. Res. 2013, 378, 45.
         | Crossref | GoogleScholarGoogle Scholar | 23374752PubMed |

[38]  C. Dobie, A. P. Montgomery, R. Szabo, D. Skropeta, H. Yu, J. Mol. Recognit. 2018, 31, e2684.
         | Crossref | GoogleScholarGoogle Scholar |

[39]  A. Montgomery, R. Szabo, D. Skropeta, H. Yu, J. Mol. Recognit. 2016, 29, 210.
         | Crossref | GoogleScholarGoogle Scholar | 26669681PubMed |

[40]  A. P. Montgomery, D. Skropeta, H. Yu, Sci. Rep. 2017, 7, 14428.
         | Crossref | GoogleScholarGoogle Scholar | 29089525PubMed |

[41]  A. P. Montgomery, K. Xiao, X. Wang, D. Skropeta, H. Yu, Adv. Protein Chem. Struct. Biol. 2017, 109, 25.
         | Crossref | GoogleScholarGoogle Scholar | 28683920PubMed |

[42]  A. K. Ghosh, M. Brindisi, J. Med. Chem. 2015, 58, 2895.
         | Crossref | GoogleScholarGoogle Scholar | 25565044PubMed |

[43]  B. Kuhn, J. Benz, M. Greif, A. M. Engel, H. Sobek, M. G. Rudolph, Acta Crystallogr. D Biol. Crystallogr. 2013, 69, 1826.
         | Crossref | GoogleScholarGoogle Scholar | 23999306PubMed |

[44]  A. P. Montgomery, C. Dobie, R. Szabo, L. Hallam, M. Ranson, H. Yu, et al. Bioorg. Med. Chem. 2020, 28, 115561.
         | Crossref | GoogleScholarGoogle Scholar | 32616185PubMed |

[45]  C. Dobie, A. P. Montgomery, R. Szabo, H. Yu, D. Skropeta, RSC Med. Chem. Advance article 2021,

[46]  M. Noel, P. A. Gilormini, V. Cogez, C. Lion, C. Biot, A. Harduin-Lepers, et al. Bioconjug. Chem. 2018, 29, 3377.
         | Crossref | GoogleScholarGoogle Scholar | 30192128PubMed |

[47]  D. Das, M. T. C. Walvoort, V. Lukose, B. Imperiali, Sci. Rep. 2016, 6, 33412.
         | Crossref | GoogleScholarGoogle Scholar | 27624811PubMed |

[48]  S. G. Smith, J. M. Goodman, J. Am. Chem. Soc. 2010, 132, 12946.
         | Crossref | GoogleScholarGoogle Scholar | 20795713PubMed |

[49]  L. Grauso, R. Teta, G. Esposito, M. Menna, A. Mangoni, Nat. Prod. Rep. 2019, 36, 1005.
         | Crossref | GoogleScholarGoogle Scholar | 31166350PubMed |

[50]  E. P. Gillis, K. J. Eastman, M. D. Hill, D. J. Donnelly, N. A. Meanwell, J. Med. Chem. 2015, 58, 8315.
         | Crossref | GoogleScholarGoogle Scholar | 26200936PubMed |

[51]  C.-W. Fu, H.-E. Tsai, W.-S. Chen, T.-T. Chang, C.-L. Chen, P.-W. Hsiao, et al. J. Med. Chem. 2021, 64, 527.
         | Crossref | GoogleScholarGoogle Scholar | 33371679PubMed |

[52]  H. Xiao, E. C. Woods, P. Vukojicic, C. R. Bertozzi, Proc. Natl. Acad. Sci. USA 2016, 113, 10304.
         | Crossref | GoogleScholarGoogle Scholar | 27551071PubMed |

[53]  C. T. Manhardt, P. R. Punch, C. W. L. Dougher, J. T. Y. Lau, J. Biol. Chem. 2017, 292, 13514.
         | Crossref | GoogleScholarGoogle Scholar | 28717006PubMed |

[54]  Q. Z. Lin, R. X. Yin, T. Guo, J. Wu, J. Q. Sun, S. W. Shen, et al. Lipids Health Dis. 2014, 13, 123.
         | Crossref | GoogleScholarGoogle Scholar | 25086711PubMed |

[55]  J. Song, C. Xue, J. S. Preisser, D. W. Cramer, K. L. Houck, G. Liu, et al. PLoS One 2016, 11, e0160757.
         | Crossref | GoogleScholarGoogle Scholar | 27584569PubMed |

[56]  K. K. Leung, G. M. Wilson, L. L. Kirkemo, N. M. Riley, J. J. Coon, J. A. Wells, Proc. Natl. Acad. Sci. USA 2020, 117, 7764.
         | Crossref | GoogleScholarGoogle Scholar | 32205440PubMed |

[57]  K. W. Moremen, M. Tiemeyer, A. V. Nairn, Nat. Rev. Mol. Cell Biol. 2012, 13, 448.
         | Crossref | GoogleScholarGoogle Scholar | 22722607PubMed |

[58]  B. Kuhn, J. Benz, M. Greif, A. M. Engel, H. Sobek, M. G. Rudolph, Acta Crystallogr. D Biol. Crystallogr. 2013, 69, 1826.
         | Crossref | GoogleScholarGoogle Scholar | 23999306PubMed |

[59]  G. Volkers, L. J. Worrall, D. H. Kwan, C. C. Yu, L. Baumann, E. Lameignere, et al. Nat. Struct. Mol. Biol. 2015, 22, 627.
         | Crossref | GoogleScholarGoogle Scholar | 26192331PubMed |

[60]  K. W. Moremen, A. Ramiah, M. Stuart, J. Steel, L. Meng, F. Forouhar, et al. Nat. Chem. Biol. 2018, 14, 156.
         | Crossref | GoogleScholarGoogle Scholar | 29251719PubMed |

[61]  F. V. Rao, J. R. Rich, B. Rakic, S. Buddai, M. F. Schwartz, K. Johnson, et al. Nat. Struct. Mol. Biol. 2009, 16, 1186.
         | Crossref | GoogleScholarGoogle Scholar | 19820709PubMed |

[62]  J. Jumper, R. Evans, A. Pritzel, T. Green, M. Figurnov, O. Ronneberger, et al. Nature 2021, 596, 583.
         | Crossref | GoogleScholarGoogle Scholar | 34265844PubMed |

[63]  C. Bull, T. J. Boltje, E. A. W. van Dinther, T. Peters, A. M. A. de Graaf, J. H. W. Leusen, et al. ACS Nano 2015, 9, 733.
         | Crossref | GoogleScholarGoogle Scholar | 25575241PubMed |