Limonoids with Wnt signal inhibitory activity isolated from the fruits of Azadirachta excelsa |
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| Institution: | 1. Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan;2. Pharmacy Discipline, Life Science School, Khulna University, Khulna 9208, Bangladesh;3. Department of Pharmaceutical Chemistry, University of Dhaka, Dhaka 1000, Bangladesh;4. University of the Philippines Visayas Tacloban College, Tacloban City 6500, Philippines;1. School of Pharmacy, Shihezi University, Shihezi 832002, China;2. Xinjiang Academy of Forestry, Urumqi 830000, China;3. School of Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China;1. College of Resource and Environment, Yuxi Normal University, Yuxi 653100, PR China;2. Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Yunnan University of Nationalities, Kunming 650031, PR China;3. College of Resources and Environment, Southwest University, Chongqing 400716, PR China;1. Department of Pharmacognosy, Faculty of Pharmacy, Atatürk University, 25240 Erzurum, Turkey;2. Department of Pharmacognosy, Faculty of Pharmacy, Hacettepe University, 06100 Ankara, Turkey;3. Department of Chemistry, Faculty of Science, Atatürk University, 25240 Erzurum, Turkey |
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| Abstract: | The Wnt signal regulates various biological processes, and its aberrant activation is associated with the development of diseases. Thus, inhibiting the Wnt signal provides a promising strategy to treat these diseases. Our cell-based luciferase assay system, which targets the Wnt signal (TOP assay), revealed that Azadirachta excelsa inhibited the Wnt signal. The activity-guided isolation of the MeOH fruit extract of A. excelsa provided one new (1) and seven known (2–8) limonoids. Their structures were elucidated based on their spectroscopic data, and their NMR data were compared with those in the literature. Compounds 3–6 potently inhibited the Wnt signal with IC50 values of 127 nM, 300 nM, 252 nM, and 121 nM, respectively. Compound 4 exhibited selective cytotoxicity against AGS and HCT116. Western blot analysis showed that 4 did not affect the level or localization of β-catenin, but downregulated the level of c-myc. Our results suggested that 4 may have inhibited the Wnt signal by affecting the components downstream of β-catenin. |
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| Keywords: | β-Catenin Limonoids Adenomatous polyposis coli Colorectal cancer |
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