Adenosine kinase (AdK) inhibitors raise endogenous adenosine levels, particularly in disease states, and have potential for treatment of seizures, neurodegeneration, and inflammation. On the basis of the South (S) ribose conformation and molecular dynamics (MD) analysis of nucleoside inhibitors bound in AdK X-ray crystallographic structures, (S)- and North (N)-methanocarba (bicyclo[3. 1.0]hexane) derivatives of known inhibitors were prepared and compared as human (h) AdK inhibitors. 5'-Hydroxy (34, MRS4202 (S); 55, MRS4380 (N)) and 5'-deoxy 38a (MRS4203 (S)) analogues, containing 7- and N(6)-NH phenyl groups in 7-deazaadenine, robustly inhibited AdK activity (IC50 ∼ 100 nM), while the 5'-hydroxy derivative 30 lacking the phenyl substituents was weak. Docking in the hAdK X-ray structure and MD simulation suggested a mode of binding similar to 5'-deoxy-5-iodotubercidin and other known inhibitors. Thus, a structure-based design approach for further potency enhancement is possible. The potent AdK inhibitors in this study are ready to be further tested in animal models of epilepsy.
Journal of medicinal chemistry. 2016 Jul 13 [Epub ahead of print]
Kiran S Toti, Danielle Osborne, Antonella Ciancetta, Detlev Boison, Kenneth A Jacobson
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bldg. 8A, Rm. B1A-19, Bethesda, Maryland 20892-0810, United States., Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute , 1225 NE Second Avenue, Portland, Oregon 97232, United States., Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bldg. 8A, Rm. B1A-19, Bethesda, Maryland 20892-0810, United States., Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute , 1225 NE Second Avenue, Portland, Oregon 97232, United States., Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bldg. 8A, Rm. B1A-19, Bethesda, Maryland 20892-0810, United States.