Synthesis and antidiabetic activity evaluation of benzopyrimidine derivatives

XU Yuantao; WANG Jundong; GUAN Li; ZHAO Ning; LI Weize

doi:10.11665/j.issn.1000-5048.2023041701

Journal of China Pharmaceutical University > 2023 > 54(5): 569-576. > DOI: 10.11665/j.issn.1000-5048.2023041701

XU Yuantao, WANG Jundong, GUAN Li, ZHAO Ning, LI Weize. Synthesis and antidiabetic activity evaluation of benzopyrimidine derivatives[J]. Journal of China Pharmaceutical University, 2023, 54(5): 569-576. DOI: 10.11665/j.issn.1000-5048.2023041701

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Synthesis and antidiabetic activity evaluation of benzopyrimidine derivatives

1.
Shaanxi Panlong Pharmaceutical Group Co., Ltd., Zhashui 714000
2.
Shandong Yantai Food and Drug Inspection and Testing Center, Yantai 264000
3.
College of Pharmacy, Xi'an Medical University, Xi'an 710021, China

Funds: This study was supported by the National Natural Science Foundation of China (No.82004075); the Project of Shaanxi Provincial Department of Science and Technology (No.2023-JC-QN-0827); the Youth Innovation Team Construction Project for Universities in Shaanxi Province (Shaanxi Education [2019] No.90); and the Science and Technology Innovation Team Project of Xi’an Medical University (No.2021TDPT04)

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Received Date: April 16, 2023
Revised Date: October 17, 2023

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Abstract

Thioredoxin-interacting protein (TXNIP), which mainly regulates glucose homeostasis in pancreatic β cells, is a novel target in the treatment of diabetes.In this study, 4-hydroxybenzopyrimidine was used as the raw material, four nitrogen-containing rings (imidazole, methylpiperazine, pyrazole, morpholine) were introduced, benzopyrimidine skeleton with nitrogen-containing rings derivatives targeting TXNIP was designed and synthesized, and the protective effect of compounds on palmitic acid-stimulated islet β cells was investigated.A total of 20 benzopyrimidine derivatives were designed and synthesized, and the structures were confirmed by ¹H NMR and ESI-MS.Pharmacological studies showed that most of the compounds exhibited protective effects on islet β cells, with better axtivity for compounds C-1, C-2, C-4 and D-2 (cell survival rate > 70%) compared with PA model group (38.3%), Among the four compounds, D-2 had the highest activity of 87.2%, so it could become a potential new anti-diabetic chemical entity.
- diabetes,
- thioredoxin interaction protein inhibitor,
- benzopyrimidine derivative,
- cell protection

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[1]	Guthrie RA, Guthrie DW. Pathophysiology of diabetes mellitus[J]. Crit Care Nurs Q, 2004, 27(2): 113-125.
[2]	Lenzen S, Drinkgern J, Tiedge M. Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues[J]. Free Radic Biol Med, 1996, 20(3): 463-466.
[3]	Kehm R, J?hnert M, Deubel S, et al. Redox homeostasis and cell cycle activation mediate beta-cell mass expansion in aged, diabetes-prone mice under metabolic stress conditions: role of thioredoxin-interacting protein (TXNIP)[J]. Redox Biol, 2020, 37: 101748.
[4]	Chen JQ, Couto FM, Minn AH, et al. Exenatide inhibits beta-cell apoptosis by decreasing thioredoxin-interacting protein[J]. Biochem Biophys Res Commun, 2006, 346(3): 1067-1074.
[5]	Nishiyama A, Matsui M, Iwata S, et al. Identification of thioredoxin-binding protein-2/vitamin D(3) up-regulated protein 1 as a negative regulator of thioredoxin function and expression[J]. J Biol Chem, 1999, 274(31): 21645-21650.
[6]	Junn E, Han SH, Im JY, et al. Vitamin D3 up-regulated protein 1 mediates oxidative stress via suppressing the thioredoxin function[J]. J Immunol, 2000, 164(12): 6287-6295.
[7]	Schulze PC, Yoshioka J, Takahashi T, et al. Hyperglycemia promotes oxidative stress through inhibition of thioredoxin function by thioredoxin-interacting protein[J]. J Biol Chem, 2004, 279(29): 30369-30374.
[8]	Shalev A, Pise-Masison CA, Radonovich M, et al. Oligonucleotide microarray analysis of intact human pancreatic islets: identification of glucose-responsive genes and a highly regulated TGFbeta signaling pathway[J]. Endocrinology, 2002, 143(9): 3695-3698.
[9]	Shalev A. Lack of TXNIP protects beta-cells against glucotoxicity[J]. Biochem Soc Trans, 2008, 36(Pt 5): 963-965.
[10]	Thielen LA, Chen JQ, Jing G, et al. Identification of an anti-diabetic, orally available small molecule that regulates TXNIP expression and glucagon action[J]. Cell Metab, 2020, 32(3): 353-365.
[11]	Zheng S, Chen NX, Kang XJ, et al. Irisin alleviates FFA induced β-cell insulin resistance and inflammatory response through activating PI3K/AKT/FOXO1 signaling pathway[J]. Endocrine, 2022, 75(3):740-751.

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