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. 2023 Jul 17;28(14):5468.
doi: 10.3390/molecules28145468.

Design and Synthesis of AMPK Activators and GDF15 Inducers

Meijian Zhang  1   2   3 , Andrea Bagán  4 , Donna Martínez  4 , Emma Barroso  1   2   3 , Xavier Palomer  1   2   3 , Santiago Vázquez  4 , Carmen Escolano  4 , Manuel Vázquez-Carrera  1   2   3
Affiliations

Design and Synthesis of AMPK Activators and GDF15 Inducers

Meijian Zhang et al. Molecules. .

Abstract

Targeting growth differentiation factor 15 (GDF15) is a recent strategy for the treatment of obesity and type 2 diabetes mellitus (T2DM). Here, we designed, synthesized, and pharmacologically evaluated in vitro a novel series of AMPK activators to upregulate GDF15 levels. These compounds were structurally based on the (1-dibenzylamino-3-phenoxy)propan-2-ol structure of the orphan ubiquitin E3 ligase subunit protein Fbxo48 inhibitor, BC1618. This molecule showed a better potency than metformin, increasing GDF15 mRNA levels in human Huh-7 hepatic cells. Based on BC1618, structural modifications have been performed to create a collection of diversely substituted new molecules. Of the thirty-five new compounds evaluated, compound 21 showed a higher increase in GDF15 mRNA levels compared with BC1618. Metformin, BC1618, and compound 21 increased phosphorylated AMPK, but only 21 increased GDF15 protein levels. Overall, these findings indicate that 21 has a unique capacity to increase GDF15 protein levels in human hepatic cells compared with metformin and BC1618.

Keywords: (1-dibenzylamino-3-phenoxy)propan-2-ol; AMPK; BC1618; GDF15.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Scheme 1
Scheme 1
General procedure for the synthesis of compounds (1–35) with modifications in the amino substituents (in blue) and in the substituents of the phenoxy group (in red). General structures, (A) variations in the substituents in the amino group of the p-trichlorophenyl general structure, (B) variations in the substituents in the phenoxy group, and (C) variations in the substituents in the amino group of the p-chlorophenyl general structure.
Figure 1
Figure 1
Compound 21 increases GDF15 protein abundance. GDF15 and phosphorylated AMPK protein levels in Huh-7 human hepatic cells exposed to metformin (MET) (5 mM), BC1618 (10 µM), or 21 (10 µM) for 72 h. Data are presented as the mean ± SEM (n = 3). * p < 0.05, and *** p < 0.001 vs. control. # p < 0.05 vs. metformin-treated cells. & p < 0.05 vs. BC1618-treated cells. p-values determined by one-way ANOVA with Tukey’s post hoc test.
See this image and copyright information in PMC

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