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Functional Group-Dependent Induction of Astrocytogenesis and Neurogenesis by Flavone Derivatives

1
College of Pharmacy, Chung-Ang University, Seoul 06974, Korea
2
College of Pharmacy, Seoul National University, Seoul 08826, Korea
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this paper.
Biomolecules 2019, 9(12), 812; https://doi.org/10.3390/biom9120812
Received: 5 November 2019 / Revised: 26 November 2019 / Accepted: 29 November 2019 / Published: 2 December 2019
(This article belongs to the Section Chemical Biology)
Neural stem cells (NSCs) differentiate into multiple cell types, including neurons, astrocytes, and oligodendrocytes, and provide an excellent platform to screen drugs against neurodegenerative diseases. Flavonoids exert a wide range of biological functions on several cell types and affect the fate of NSCs. In the present study, we investigated whether the structure-activity relationships of flavone derivatives influence NSC differentiation. As previously reported, we observed that PD98059 (2′-amino-3′-methoxy-flavone), compound 2 (3′-methoxy-flavone) induced astrocytogenesis. In the present study, we showed that compound 3 (2′-hydroxy-3′-methoxy-flavone), containing a 3′-methoxy group, and a non-bulky group at C2′ and C4′, induced astrocytogenesis through JAK-STAT3 signaling pathway. However, compound 1 and 712 without the methoxy group did not show such effects. Interestingly, the compounds 4 (2′,3′-dimethoxyflavone), 5 (2′-N-phenylacetamido-3′-methoxy-flavone), and 6 (3′,4′-dimethoxyflavone) containing only 3′-methoxy could not promote astrocytic differentiation, suggesting that both the methoxy groups at C3′ and non-bulky group at C2′ and C4′ are required for the induction of astrocytogenesis. Notably, compound 6 promoted neuronal differentiation, whereas its 4′-demethoxylated analog, compound 2, repressed neurogenesis, suggesting an essential role of the methoxy group at C4′ in neurogenesis. These findings revealed that subtle structural changes of flavone derivatives have pronounced effects on NSC differentiation and can guide to design and develop novel flavone chemicals targeting NSCs fate regulation.
Keywords: astrocytogenesis; neurogenesis; neural stem cells; differentiation; flavone; structure-activity relationships astrocytogenesis; neurogenesis; neural stem cells; differentiation; flavone; structure-activity relationships
MDPI and ACS Style

Lee, H.-R.; Kang, J.M.; Kim, Y.M.; Kim, S.; Ann, J.; Lee, J.; Kim, H.-J. Functional Group-Dependent Induction of Astrocytogenesis and Neurogenesis by Flavone Derivatives. Biomolecules 2019, 9, 812.

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