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  3. Biological evaluation of sulfonate and sulfate analogues of lithocholic acid: A bioisosterism-guided approach towards the discovery of potential sialyltransferase inhibitors for antimetastatic study

Biological evaluation of sulfonate and sulfate analogues of lithocholic acid: A bioisosterism-guided approach towards the discovery of potential sialyltransferase inhibitors for antimetastatic study

  • Bioorg Med Chem Lett. 2024 Jun 1:105:129760. doi: 10.1016/j.bmcl.2024.129760.
Ser John Lynon P Perez 1,  Chia-Ling Chen 2,  Tzu-Ting Chang 3,  Wen-Shan Li 4
Affiliations

Affiliations

  • 1 Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan; Department of Applied Chemistry, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan; Sustainable Chemical Science and Technology, Taiwan International Graduate Program, Academia Sinica, Taipei 115, Taiwan; Biomedical Translation Research Center, Academia Sinica, Taipei 115, Taiwan.
  • 2 Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan.
  • 3 Biomedical Translation Research Center, Academia Sinica, Taipei 115, Taiwan.
  • 4 Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan; Sustainable Chemical Science and Technology, Taiwan International Graduate Program, Academia Sinica, Taipei 115, Taiwan; Biomedical Translation Research Center, Academia Sinica, Taipei 115, Taiwan; Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University; Doctoral Degree Program in Marine Biotechnology, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Chemistry, College of Science, Tamkang University, New Taipei City 251, Taiwan. Electronic address: wenshan@gate.sinica.edu.tw.
PMID: 38641151 DOI: 10.1016/j.bmcl.2024.129760
Abstract

The naturally occurring bile acid lithocholic acid (LCA) has been a crucial core structure for many non-sugar-containing sialyltranferase (ST) inhibitors documented in literature. With the aim of elucidating the impact of the terminal carboxyl acid substituent of LCA on its ST inhibition, in this present study, we report the (bio)isosteric replacement-based design and synthesis of sulfonate and sulfate analogues of LCA. Among these compounds, the sulfate analogue SPP-002 was found to selectively inhibit N-glycan sialylation by at least an order of magnitude, indicating a substantial improvement in both potency and selectivity when compared to the unmodified parent bile acid. Molecular docking analysis supported the stronger binding of the synthetic analogue in the Enzyme active site. Treatment with SPP-002 also hampered the migration, adhesion, and invasion of MDA-MB-231 cells in vitro by suppressing the expression of signaling proteins involved in the Cancer metastasis-associated Integrin/FAK/paxillin pathway. In totality, these findings offer not only a novel structural scaffold but also valuable insights for the future development of more potent and selective ST inhibitors with potential therapeutic effects against tumor Cancer metastasis.

Keywords

Cancer metastasis; Integrin-FAK-paxillin signaling pathway; Lithocholic acid; Sialyltransferase inhibitor.

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