Synthesis of a FTO inhibitor with anticonvulsant activity.

Abstract

We describe the rationale for and the synthesis of a new class of compounds utilizing a modular approach that are designed to mimic ascorbic acid and to inhibit 2-oxoglutarate-dependent hydroxylases. Preliminary characterization of one of these compounds indicates in vivo anticonvulsant activity (6 Hz mouse model) at nontoxic doses, inhibition of the 2-oxoglutarate-dependent hydroxylase FTO, and expected increase in cellular N(6)-methyladenosine. This compound is also able to modulate various microRNA, an interesting result in light of the recent view that modulation of microRNAs may be useful for the treatment of CNS disease.

• Authors: Guanqun Zheng, Thomas Cox, Leah Tribbey, Gloria Z Wang, Paulina Iacoban, Matthew E Booher, Gregory J Gabriel, Lu Zhou, Nancy Bae, Joie Rowles, Chuan He, Mark J Olsen
• Journal: ACS chemical neuroscience (ACS Chem Neurosci) Vol. 5 Issue 8 Pg. 658-65 (Aug 20 2014) ISSN: 1948-7193 [Electronic] United States
• PMID: 24834807 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anticonvulsants
• MicroRNAs
• Proteins
• N-methyladenosine
• Mixed Function Oxygenases
• FTO protein, mouse
• Alpha-Ketoglutarate-Dependent Dioxygenase FTO
• FTO protein, human
• Oxo-Acid-Lyases
• Adenosine

Topics

• Adenosine (analogs & derivatives, metabolism)
• Alpha-Ketoglutarate-Dependent Dioxygenase FTO
• Animals
• Anticonvulsants (chemical synthesis, chemistry, pharmacology)
• Blotting, Western
• Catalytic Domain
• Disease Models, Animal
• Epilepsy (drug therapy)
• HeLa Cells
• Humans
• Mice
• MicroRNAs (metabolism)
• Mixed Function Oxygenases (antagonists & inhibitors, chemistry)
• Models, Chemical
• Molecular Structure
• Oxo-Acid-Lyases (antagonists & inhibitors, chemistry)
• Proteins (antagonists & inhibitors, chemistry)