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Identification of small molecules that direct neural stem cells (NSCs) into specific cell types would be helpful to understand the molecular mechanisms involved in regulation of NSC fate, and facilitate the development of therapeutic applications. In the current study, we developed and screened small molecules that can modulate the fate of NSCs that are derived from rat fetal cortex. Among these compounds, compounds 5 and 6 successfully differentiated NSCs into astrocytes and neurons, respectively. Compound 5 induced astrocytogenesis by increasing expression of interleukin-6, bone morphogenetic protein 2 and leukemia inhibitory factor and through consequent phosphorylation of signal transducer and activator of transcription 3 and Sma- and Mad-related protein 1/5/8 in NSCs. In addition, compound 5 increased the expression of fibroblast growth factor (FGF) 2 and FGF8 which may regulate the branching and morphology of astrocytes. Taken together, our results suggest that these small molecules can serve as a useful tool to study cell fate determination in NSCs and be used as an inexpensive alternative to cytokines to study mechanisms of astrocytogenesis.

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An efficient and convenient synthesis of 2-amino-6-aryl-4-methylsulfanylnicotinonitriles (2), 2-amino-6-aryl-4-substituted-aminonicotinonitriles (4), and 2-amino-6-aryl-4-substituted-aminopyridines (6) has been delineated and illustrated through base-catalyzed ring transformation of 6-aryl-3-cyano-4-methylsulfanyl/substituted-amino-2H-pyran-2-ones (1, 3, and 5) with cyanamide and ammonium carbonate separately.

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