Journal
BIOORGANIC CHEMISTRY
Volume 115, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2021.105172
Keywords
Tetrahydrocarbazole; Hypoglycemic activity; Metabolic stability; Synthesis; Adenosine 5'-monophosphate-activated protein kinase
Funding
- National Natural Science Foundation of China [82060625, 82060632]
- Guizhou Provincial Natural Science Foundation [[2020]1Z073]
- National Science Fundation of Health and Family planning Commission of Guizhou Province [gzwjkj2019-1-179]
- Young crop project of Guizhou Medical University [19NSP073]
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Two series of tetrahydrocarbazole derivatives based on a promising candidate ZG02 were designed and synthesized, and compound 12b showed potent hypoglycemic activity by potentially activating the AMPK pathway. Metabolic stability assays and OGTT results confirmed 12b as an effective hypoglycemic agent.
Two series of tetrahydrocarbazole derivatives have been designed and synthesized based on ZG02, a promising candidate developed in our previous studies. The newly prepared compounds were screened for glucose consumption activity in HepG2 cell lines. Aza-tetrahydrocarbazole compound 12b showed the most potent hypoglycemic activity with a 45% increase in glucose consumption when compared to the solvent control, which had approximately 1.2-fold higher activity than the positive control compounds (metformin and ZG02). An investigation of the potential mechanism indicated that 12b may exhibit hypoglycemic activity via activation of the AMPK pathway. Metabolic stability assays revealed that 12b showed good stability profiles in both artificial gastrointestinal fluids and blood plasma from SD rats. An oral glucose tolerance test (OGTT) was performed and the results further confirmed that 12b was a potent hypoglycemic agent.
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