5'-substituted adenosynes, preparation thereof and use as...

Details 5'-substituted adenosynes, preparation thereof and use as... 5'-substituted adenosynes, preparation thereof and use as...

C - Chemistry, Metallurgy

07

H

C07H 19/167 (2006.01) A61K 31/7076 (2006.01) A61P 33/06 (2006.01) A61P 33/08 (2006.01) C07H 19/16 (2006.01)

Patent

CA 2696005

The crystal structure of the complex of S-adenosylmethionine methyl ester with h?doMetDC F223A, a mutant where the stacking of the aromatic rings of F7, adenine and F223 would be eliminated. The structure of this mutant with the ester shows that the ligand still maintains a syn conformation aided by pi-pi interactions to F7, hydrogen bonds to the backbone of Glu67, and electrostatic interactions. Several series of AdoMet substrate analogues with a variety of substituents at the 8 position of adenine were synthesized and analyzed for their ability to inhibit hAdoMetDC. To understand these results, virtual modeling of the enzyme inhibitor complexes and the crystal structures of human AdoMetDC with 5'-deoxy-5'-[N-methyl-N-[2- (aminooxy)ethyl]amino-8-rnethyl]adenosine (MAOEMA) and 5'-deoxy-5'-[N-methyl-N-[4- (aminooxy)butyl]amino-8-ethyl]adenosine (MAOBEA) at the active site have been determined experimentally.

L'invention concerne la structure cristalline du complexe de l'ester de méthyle de S-adénosylméthionine avec h?doMetDC F223A, un mutant où l'empilage des cycles aromatiques de F7, d'adénine et de F223 serait éliminé. La structure de ce mutant avec l'ester montre que le ligand maintient toujours une conformation syn facilitée par les interactions pi-pi avec F7, les liaisons hydrogène avec le squelette de Glu67, et les interactions électrostatiques. Plusieurs séries d'analogues de substrat AdoMet avec une variété de substituants en position 8 d'adénine ont été synthétisés et analysés concernant leur capacité à inhiber hAdoMetDC. Pour comprendre ces résultats, une modélisation virtuelle des complexes inhibiteurs d'enzyme et des structures cristallines de l'AdoMetDC humain avec la 5'-désoxy-5'-[N-méthyl-N-[2- (aminooxy)éthyl]amino-8-méthyl]adénosine (MAOEMA) et la 5'-désoxy-5'-[N-méthyl-N-[4- (aminooxy)butyl]amino-8-éthyl]adénosine (MAOBEA) au niveau du site actif a été déterminée de manière empirique.

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