5'-SUBSTITUTED ADENOSINES, PREPARATION THEREOF AND USE AS INHIBITORS OF S-ADENOSYLMETHIONINE DECARBOXYLASE

• Main Authors: PEGG ANTHONY E, GUIDA WAYNE C, BALE SHRIDHAR, EALICK STEVE, MCCLOSKEY DIANE E, SECRIST JOHN A. III
• Format: Patent
• Language: English; Korean
• Published: 20.05.2010
• Subjects: CHEMISTRY; HETEROCYCLIC COMPOUNDS; HUMAN NECESSITIES; HYGIENE; MEDICAL OR VETERINARY SCIENCE; METALLURGY; ORGANIC CHEMISTRY; PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES; SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS

The crystal structure of the complex of S-adenosylmethionine methyl ester with hλdoMetDC 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 aconformation 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.