Structural-Based Optimizations of the Marine-Originated Meridianin C as Glucose Uptake Agents by Inhibiting GSK-3β

Glycogen synthase kinase 3 beta (GSK-3 beta) is a widely investigated molecular target for numerous diseases, and inhibition of GSK-3 beta 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-3 beta 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-3 beta inhibitory activities (IC50 = 5.85; 24.4 mu M). These results suggest that these meridianin C analogues represent novel lead compounds with therapeutic potential for diabetes.

Automated summary

Meridianin C, a natural product derived from marine organisms, and its analogues B29 and B30 showed enhanced glucose uptake and GSK-3 beta inhibitory activities, indicating therapeutic potential for diabetes.