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Biological evaluation of sulfonate and sulfate analogues of lithocholic acid: A bioisosterism-guided approach towards the discovery of potential sialyltransferase inhibitors for antimetastatic study.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2024 Jun 01; Vol. 105, pp. 129760. Date of Electronic Publication: 2024 Apr 17. - Publication Year :
- 2024
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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.<br />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.<br /> (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 105
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 38641151
- Full Text :
- https://doi.org/10.1016/j.bmcl.2024.129760