1069040-48-7Relevant articles and documents
South (S)- and north (N)-methanocarba-7-deazaadenosine analogues as inhibitors of human adenosine kinase
Toti, Kiran S.,Osborne, Danielle,Ciancetta, Antonella,Boison, Detlev,Jacobson, Kenneth A.
, p. 6860 - 6877 (2016/08/05)
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 N6-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.
Synthesis of enantiomerically pure (S)-methanocarbaribo uracil nucleoside derivatives for use as antiviral agents and P2Y receptor ligands
Melman, Artem,Zhong, Minghong,Marquez, Victor E.,Jacobson, Kenneth A.
, p. 8085 - 8088 (2008/12/22)
(Chemical Equation Presented) We have developed an approach toward enantiomerically pure (S)-methanocarba ribonucleosides based on several functional group transformations on a sensitive bicyclo[3.1.0]-hexane system. D-Ribose was transformed into methanocarba alcohol 3 followed by conversion of the OH group to a nitrile with inversion of configuration at C4. The nitrile group was subsequently reduced in two stages to the 5′-hydroxymethyl group. An ester group appended to a tertiary carbon (Cl) was transformed to an amino group as a nucleobase precursor.
