TY - JOUR
T1 - Exploration and biological evaluation of 7-methoxy-3-methyl-1H-chromeno[4,3-c]pyrazol-4-one as an activating transcription factor 3 inducer for managing metabolic syndrome
AU - Chang, Yi Han
AU - Lin, Heng
AU - Li, Hsiao Fen
AU - Chen, Hsi Hsien
AU - Hung, Hsin Yi
N1 - Funding Information:
The authors gratefully acknowledge the assistance of Mr. Tsung-Lun Kan ( the Core Facility Center, National Cheng Kung University, Tainan, Taiwan ) for the operation of NMR005700 ( AVIII HD 700NMR ) and NMR 005000 ( AVNEO 500NMR ), as well as Ms. Hsiao-Ching Yu (the High Valued Instrument Center, National Sun Yat-sen University, Kaohsiung, Taiwan ) for the HRMS spectra ( MS000600 ). This work was supported by the Ministry of Science and Technology ( MOST 111-2314-B-038 -114 -MY3 to H.L.).
Funding Information:
Granted that stimulation of ATF3 is supposed to confer a benefit for those suffering from MetS, few compounds have been identified as an ATF3 inducer to alleviate MetS, not to mention the paucity of structure-activity relationship (SAR) studies. A few cases in point are sulfuretin (1a) [23] and a naphthopyrone derivative (1b) [24] (Fig. 1); the latter ameliorated weight gain coupled with improving the serum glucose profile in mice on an HFD without affecting food intake. A gene expression analysis of adipose tissues revealed that 1b not only repressed adipogenesis and lipogenesis, but also facilitated lipolysis, browning, and fatty acid oxidation in an ATF3-dependent manner. Additionally, in vitro pharmacological elucidation suggested that suppression of both C/EBPα expression and the C/EBP homologous protein (CHOP) pathway were involved in lipid-lowering mechanisms [24].The authors gratefully acknowledge the assistance of Mr. Tsung-Lun Kan (the Core Facility Center, National Cheng Kung University, Tainan, Taiwan) for the operation of NMR005700 (AVIII HD 700NMR) and NMR 005000 (AVNEO 500NMR), as well as Ms. Hsiao-Ching Yu (the High Valued Instrument Center, National Sun Yat-sen University, Kaohsiung, Taiwan) for the HRMS spectra (MS000600). This work was supported by the Ministry of Science and Technology (MOST 111-2314-B-038 -114 -MY3 to H.L.).
Publisher Copyright:
© 2022 Elsevier Masson SAS
PY - 2023/1/15
Y1 - 2023/1/15
N2 - The induction of activating transcription factor 3 (ATF3) was identified as a promising therapeutic mechanism to overcome metabolic syndrome. Hence, a structure-activity relationship campaign on the chiral lead (1b) was conducted with a scaffold-hopping approach, whereby achiral 7-methoxy-3-methyl-1H-chromeno[4,3-c]pyrazol-4-one (16c) was recognized as a potential ATF3 inducer with a lipid-lowering feature in a pre-differentiated 3T3-L1 cell model. Also, in a high-fat diet scenario, mice subjected to 16c demonstrated robust weight loss with shrinkage of the white adipose mass and fewer hypertrophic adipocytes, accompanied by a preferable glycemic profile compared to 1b. Additionally, the biochemical analysis revealed that 16c further ameliorated the liver function and improved the plasma triglyceride profile that were absent from mice treated with 1b. Taken together, 16c shows promise as an ATF3 stimulant for further development to alleviate metabolic syndrome.
AB - The induction of activating transcription factor 3 (ATF3) was identified as a promising therapeutic mechanism to overcome metabolic syndrome. Hence, a structure-activity relationship campaign on the chiral lead (1b) was conducted with a scaffold-hopping approach, whereby achiral 7-methoxy-3-methyl-1H-chromeno[4,3-c]pyrazol-4-one (16c) was recognized as a potential ATF3 inducer with a lipid-lowering feature in a pre-differentiated 3T3-L1 cell model. Also, in a high-fat diet scenario, mice subjected to 16c demonstrated robust weight loss with shrinkage of the white adipose mass and fewer hypertrophic adipocytes, accompanied by a preferable glycemic profile compared to 1b. Additionally, the biochemical analysis revealed that 16c further ameliorated the liver function and improved the plasma triglyceride profile that were absent from mice treated with 1b. Taken together, 16c shows promise as an ATF3 stimulant for further development to alleviate metabolic syndrome.
KW - Activating transcription factor 3
KW - Metabolic syndrome
KW - Scaffold-hopping
KW - Structure-activity relationship
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U2 - 10.1016/j.ejmech.2022.114951
DO - 10.1016/j.ejmech.2022.114951
M3 - Article
C2 - 36455354
AN - SCOPUS:85142750221
SN - 0223-5234
VL - 246
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 114951
ER -