PMID- 35749988 OWN - NLM STAT- MEDLINE DCOM- 20220712 LR - 20220712 IS - 1768-3254 (Electronic) IS - 0223-5234 (Linking) VI - 239 DP - 2022 Sep 5 TI - Discovery of dearomatized isoprenylated acylphloroglucinols with colon tumor suppressive activities in mice via inhibiting NFkappaB-FAT1-PDCD4 signaling activation. PG - 114532 LID - S0223-5234(22)00434-2 [pii] LID - 10.1016/j.ejmech.2022.114532 [doi] AB - Dearomatized 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 (IC(50) = 0.84-5.63 muM) 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 NFkappaB, 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. CI - Copyright (c) 2022 Elsevier Masson SAS. All rights reserved. FAU - Jiang, Na-Na AU - Jiang NN AD - State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, and Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming, 650201, China; University of Chinese Academy of Sciences, Beijing, 100049, China. FAU - Gar-Lee Yue, Grace AU - Gar-Lee Yue G AD - Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China. FAU - Li, Peng AU - Li P AD - Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China. FAU - Ye, Yan-Song AU - Ye YS AD - State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, and Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming, 650201, China. FAU - Gomes, Adele Joyce AU - Gomes AJ AD - Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China. FAU - Hin-Fai Kwok, Frankie AU - Hin-Fai Kwok F AD - Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China. FAU - Kin-Ming Lee, Julia AU - Kin-Ming Lee J AD - Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China. FAU - Gao, Si AU - Gao S AD - Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China. FAU - Lau, Clara Bik-San AU - Lau CB AD - Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China. Electronic address: claralau@cuhk.edu.hk. FAU - Xu, Gang AU - Xu G AD - State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, and Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming, 650201, China. Electronic address: xugang008@mail.kib.ac.cn. LA - eng PT - Journal Article DEP - 20220614 PL - France TA - Eur J Med Chem JT - European journal of medicinal chemistry JID - 0420510 RN - 0 (Antineoplastic Agents) RN - 0 (Apoptosis Regulatory Proteins) RN - 0 (Cadherins) RN - 0 (FAT1 protein, human) RN - 0 (PDCD4 protein, human) RN - 0 (RNA-Binding Proteins) RN - DHD7FFG6YS (Phloroglucinol) SB - IM MH - Animals MH - *Antineoplastic Agents/pharmacology MH - Apoptosis Regulatory Proteins/metabolism MH - Cadherins/metabolism MH - Cell Line, Tumor MH - *Colonic Neoplasms/drug therapy MH - Humans MH - *Hypericum/chemistry/metabolism MH - Mice MH - Phloroglucinol/chemistry/pharmacology MH - RNA-Binding Proteins/metabolism MH - Signal Transduction OTO - NOTNLM OT - Colon cancer OT - Dearomatized isoprenylated acylphloroglucinols OT - FAT1 OT - HCT116 OT - Hypericum EDAT- 2022/06/25 06:00 MHDA- 2022/07/14 06:00 CRDT- 2022/06/24 18:24 PHST- 2022/04/18 00:00 [received] PHST- 2022/06/09 00:00 [revised] PHST- 2022/06/10 00:00 [accepted] PHST- 2022/06/25 06:00 [pubmed] PHST- 2022/07/14 06:00 [medline] PHST- 2022/06/24 18:24 [entrez] AID - S0223-5234(22)00434-2 [pii] AID - 10.1016/j.ejmech.2022.114532 [doi] PST - ppublish SO - Eur J Med Chem. 2022 Sep 5;239:114532. doi: 10.1016/j.ejmech.2022.114532. Epub 2022 Jun 14.