1. Biological evaluation of sulfonate and sulfate analogues of lithocholic acid: A bioisosterism-guided approach towards the discovery of potential sialyltransferase inhibitors for antimetastatic study.
- Author
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Perez SJLP, Chen CL, Chang TT, and Li WS
- Subjects
- Humans, Cell Line, Tumor, Cell Movement drug effects, Enzyme Inhibitors pharmacology, Enzyme Inhibitors chemistry, Enzyme Inhibitors chemical synthesis, Structure-Activity Relationship, Sulfates chemistry, Sulfates pharmacology, Sulfates chemical synthesis, Neoplasm Metastasis, Sulfonic Acids pharmacology, Sulfonic Acids chemistry, Sulfonic Acids chemical synthesis, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Molecular Structure, Cell Adhesion drug effects, Dose-Response Relationship, Drug, Paxillin metabolism, Paxillin antagonists & inhibitors, Focal Adhesion Kinase 1 antagonists & inhibitors, Focal Adhesion Kinase 1 metabolism, Drug Discovery, Lithocholic Acid pharmacology, Lithocholic Acid chemistry, Lithocholic Acid chemical synthesis, Lithocholic Acid analogs & derivatives, Sialyltransferases antagonists & inhibitors, Sialyltransferases metabolism, Molecular Docking Simulation
- 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
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