Synthesis of a FTO inhibitor with anticonvulsant activity.
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.
Department of Chemistry, University of Chicago , 929 E. 57th St., Chicago, Illinois 60637, United States.
Guanqun
G
Zheng
Thomas
T
Cox
Leah
L
Tribbey
Gloria Z
GZ
Wang
Paulina
P
Iacoban
Matthew E
ME
Booher
Gregory J
GJ
Gabriel
Lu
L
Zhou
Nancy
N
Bae
Joie
J
Rowles
Chuan
C
He
Mark J
MJ
Olsen
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015153:Blotting, Western; D020134:Catalytic Domain; D004195:Disease Models, Animal; D004827:Epilepsy / Q000188:drug therapy; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008956:Models, Chemical; D015394:Molecular Structure; D007652:Oxo-Acid-Lyases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
D000927:Anticonvulsants; D035683:MicroRNAs; D011506:Proteins; C010223:N-methyladenosine; D006899:Mixed Function Oxygenases; C524916:FTO protein, mouse; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human; D007652:Oxo-Acid-Lyases; D000241:Adenosine