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Article: Discovery of dearomatized isoprenylated acylphloroglucinols with colon tumor suppressive activities in mice via inhibiting NFκB-FAT1-PDCD4 signaling activation

TitleDiscovery of dearomatized isoprenylated acylphloroglucinols with colon tumor suppressive activities in mice via inhibiting NFκB-FAT1-PDCD4 signaling activation
Authors
KeywordsColon cancer
Dearomatized isoprenylated acylphloroglucinols
FAT1
HCT116
Hypericum
Issue Date2022
Citation
European Journal of Medicinal Chemistry, 2022, v. 239, article no. 114532 How to Cite?
AbstractDearomatized isoprenylated acylphloroglucinols (DIAPs) are specific natural products mainly distributed in the plants of genus Hypericum. In this study, guided by HPLC-UV screening, 46 DIAPs (approximately 70% of all DIAPs) including 20 new ones and an unprecedented architecture, were discovered from the roots of Hypericum henryi, which were elucidated by comprehensive spectroscopic, X-ray crystallography, and ECD methods. Compounds 1–7, 39, and 41–42 exhibited remarkable cytotoxicities (IC50 = 0.84–5.63 μM) in human colon cancer HCT116 cells, in which 2 and 6 possessed selective cytotoxicities towards colon cancer cells. The preliminary structure-activity relationships of these tested compounds were discussed. In addition, mechanistic investigations demonstrated that 2 and 6 could significantly suppress the expressions of NFκB, FAT1, and promoted novel tumor suppressor gene PDCD4 in HCT116 cells. Furthermore, in HCT116 colon xenograft-bearing mouse model, treatments with 2 and 6 reduced the growth of xenograft tumors in dose-dependent manner. Expressions of FAT1 in tumors were also decreased in mice treated with 2 and 6, suggesting their anti-tumor effects were via FAT1 signaling pathway. In conclusion, this is the first report on the mechanistic and in vivo studies of DIAP, indicating that these metabolites can be considered as a new type of anti-colon cancer lead agents for further drug development.
Persistent Identifierhttp://hdl.handle.net/10722/343380
ISSN
2023 Impact Factor: 6.0
2023 SCImago Journal Rankings: 1.151

 

DC FieldValueLanguage
dc.contributor.authorJiang, Na Na-
dc.contributor.authorGar-Lee Yue, Grace-
dc.contributor.authorLi, Peng-
dc.contributor.authorYe, Yan Song-
dc.contributor.authorGomes, Adele Joyce-
dc.contributor.authorHin-Fai Kwok, Frankie-
dc.contributor.authorKin-Ming Lee, Julia-
dc.contributor.authorGao, Si-
dc.contributor.authorLau, Clara Bik San-
dc.contributor.authorXu, Gang-
dc.date.accessioned2024-05-10T09:07:38Z-
dc.date.available2024-05-10T09:07:38Z-
dc.date.issued2022-
dc.identifier.citationEuropean Journal of Medicinal Chemistry, 2022, v. 239, article no. 114532-
dc.identifier.issn0223-5234-
dc.identifier.urihttp://hdl.handle.net/10722/343380-
dc.description.abstractDearomatized isoprenylated acylphloroglucinols (DIAPs) are specific natural products mainly distributed in the plants of genus Hypericum. In this study, guided by HPLC-UV screening, 46 DIAPs (approximately 70% of all DIAPs) including 20 new ones and an unprecedented architecture, were discovered from the roots of Hypericum henryi, which were elucidated by comprehensive spectroscopic, X-ray crystallography, and ECD methods. Compounds 1–7, 39, and 41–42 exhibited remarkable cytotoxicities (IC50 = 0.84–5.63 μM) in human colon cancer HCT116 cells, in which 2 and 6 possessed selective cytotoxicities towards colon cancer cells. The preliminary structure-activity relationships of these tested compounds were discussed. In addition, mechanistic investigations demonstrated that 2 and 6 could significantly suppress the expressions of NFκB, FAT1, and promoted novel tumor suppressor gene PDCD4 in HCT116 cells. Furthermore, in HCT116 colon xenograft-bearing mouse model, treatments with 2 and 6 reduced the growth of xenograft tumors in dose-dependent manner. Expressions of FAT1 in tumors were also decreased in mice treated with 2 and 6, suggesting their anti-tumor effects were via FAT1 signaling pathway. In conclusion, this is the first report on the mechanistic and in vivo studies of DIAP, indicating that these metabolites can be considered as a new type of anti-colon cancer lead agents for further drug development.-
dc.languageeng-
dc.relation.ispartofEuropean Journal of Medicinal Chemistry-
dc.subjectColon cancer-
dc.subjectDearomatized isoprenylated acylphloroglucinols-
dc.subjectFAT1-
dc.subjectHCT116-
dc.subjectHypericum-
dc.titleDiscovery of dearomatized isoprenylated acylphloroglucinols with colon tumor suppressive activities in mice via inhibiting NFκB-FAT1-PDCD4 signaling activation-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.ejmech.2022.114532-
dc.identifier.pmid35749988-
dc.identifier.scopuseid_2-s2.0-85132524003-
dc.identifier.volume239-
dc.identifier.spagearticle no. 114532-
dc.identifier.epagearticle no. 114532-
dc.identifier.eissn1768-3254-

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