Xanthenylacetic Acid Derivatives Effectively Target Lysophosphatidic Acid Receptor 6 to Inhibit Hepatocellular Carcinoma Cell Growth.
Acetic Acid
/ chemical synthesis
Antineoplastic Agents
/ chemical synthesis
Carcinoma, Hepatocellular
/ drug therapy
Cell Cycle
/ drug effects
Cell Proliferation
/ drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Liver Neoplasms
/ drug therapy
Molecular Structure
Receptors, Lysophosphatidic Acid
/ antagonists & inhibitors
Structure-Activity Relationship
Tumor Cells, Cultured
Xanthenes
/ chemical synthesis
drug design
enantioselectivity
hepatocellular carcinoma
lysophosphatidic acid receptor 6 antagonists
therapeutic tools
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
06 07 2021
06 07 2021
Historique:
revised:
02
04
2021
received:
14
01
2021
pubmed:
9
4
2021
medline:
17
2
2022
entrez:
8
4
2021
Statut:
ppublish
Résumé
Despite the increasing incidence of hepatocellular carcinoma (HCC) worldwide, current pharmacological treatments are still unsatisfactory. We have previously shown that lysophosphatidic acid receptor 6 (LPAR6) supports HCC growth and that 9-xanthenylacetic acid (XAA) acts as an LPAR6 antagonist inhibiting HCC growth without toxicity. Here, we synthesized four novel XAA derivatives, (±)-2-(9H-xanthen-9-yl)propanoic acid (compound 4 - MC9), (±)-2-(9H-xanthen-9-yl)butanoic acid (compound 5 - MC6), (±)-2-(9H-xanthen-9-yl)hexanoic acid (compound 7 - MC11), and (±)-2-(9H-xanthen-9-yl)octanoic acid (compound 8 - MC12, sodium salt) by introducing alkyl groups of increasing length at the acetic α-carbon atom. Two of these compounds were characterized by X-ray powder diffraction and quantum mechanical calculations, while molecular docking simulations suggested their enantioselectivity for LPAR6. Biological data showed anti-HCC activity for all XAA derivatives, with the maximum effect observed for MC11. Our findings support the view that increasing the length of the alkyl group improves the inhibitory action of XAA and that enantioselectivity can be exploited for designing novel and more effective XAA-based LPAR6 antagonists.
Identifiants
pubmed: 33831272
doi: 10.1002/cmdc.202100032
doi:
Substances chimiques
Antineoplastic Agents
0
LPAR6 protein, human
0
Receptors, Lysophosphatidic Acid
0
Xanthenes
0
Acetic Acid
Q40Q9N063P
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2121-2129Informations de copyright
© 2021 Wiley-VCH GmbH.
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