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

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

  • Mar Drugs. 2021 Mar 12;19(3):149. doi: 10.3390/md19030149.
Shuwen Han 1 2,  Chunlin Zhuang 2 3,  Wei Zhou 4,  Fener Chen 1 2 3
Affiliations

Affiliations

  • 1 Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, China.
  • 2 Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China.
  • 3 Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China.
  • 4 Department of Chemistry, Fudan University, Shanghai 200438, China.
PMID: 33809065 DOI: 10.3390/md19030149
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.

Keywords

diabetes; glucose uptake; glycogen synthase kinase 3β; inhibitor; structural-based optimization.

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