Abstract
Glycogen synthase kinase 3β (GSK-3β) is a widely investigated molecular target for numerous diseases, and inhibition of GSK-3β activity has become an attractive approach for the treatment of diabetes. Meridianin C, an indole-based natural product isolated from marine Aplidium meridianum, has been reported as a potent GSK-3β inhibitor. In the present study, applying the structural-based optimization strategy, the pyrimidine group of meridianin C was modified by introducing different substituents based on the 2-aminopyrimidines-substituted pyrazolo pyridazine scaffold. Among them, compounds B29 and B30 showed a much higher glucose uptake than meridianin C (<5%) and the positive compound 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8, 16%), with no significant toxicity against HepG2 cells at the same time. Furthermore, they displayed good GSK-3β inhibitory activities (IC50 = 5.85; 24.4 μM). These results suggest that these meridianin C analogues represent novel lead compounds with therapeutic potential for diabetes.
Highlights
There is still an urgent need for new and better antihyperglycemic agents or therapeutics to reduce both the morbidity and mortality caused by diabetes mellitus
Of Glycogen synthase kinase 3β (GSK-3β) can inhibit the activation of GCS effectively, and pharmacological inhibitors of GSK-3β can inhibit the activation of GCS effectively, and pharmacological inhibitors of of GSK-3β have been demonstrated to activate glycogen synthase and improve glycogen
Considering that there are still several key upstream signaling proteins that would influence glucose uptake in the body, such as glucose transporters (GLUT), glycogen synthase (GCS), and glycogen phosphorylase (GP) (Figure 3), in this study, we set up a cell model of glucose uptake in human hepatocellular carcinoma (HepG2) cells, instead of a GSK-3β assay, to screen active5 comof 24 pounds and investigate the structure–activity relationship in order to evaluate the glucose uptake improving activity more accurately
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The major contemporary conventional oral antihyperglycemic agents include biguanides (metformin), second- and third-generation sulfonylureas, α-glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists [3]. The inhibition of GSK-3β might provide an important and alternative therapeutic strategy for the treatment of diabetes. Inhibition of GSK-3β might provide an important and alternative therapeutic strategy for we onofstructural thefocused treatment diabetes. It has been reported that the 2-aminopyrimidine-substituted pyrazolo[1,5-b] pyridazine compound (Figure 2), developed by Tavares’s group, possesses excellent inhibitory activity against GSK-3β [11]. Based on the chemical structure of meridianin C and the predicted binding mode with GSK-3β, modifications (highlighted arrows in red) at the amino group (20 -position and 50 -position) are proposed according to important substitutions of the pyrazolo[1,5-b]. The hydrogen drogen bonds are by shown by the dashed yellow dashed bonds are shown the yellow lines. lines
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
