5′,-substituted adenosynes preparation thereof and use as inhibitors of S-adenosylmethionine decarboxylase

US8637485B2 · kind B2 · utility

Assignees

• Southern Research Institute · US
• Cornell University · IT
• H. Lee Moffitt Cancer and Research Institute, Inc. · US
• The Penn State Research Foundation · US

Inventors

• John A. Secrist, III · Birmingham, US
• Steven Ealick · Ithaca, US
• Shridhar Bale · Ithaca, US
• Anthony E. Pegg · Hershey, US
• Diane E. McCloskey · Hershey, US
• Wayne Charles Guida · Fanwood, US

Key dates

• Filing date: Aug 1, 2008
• Grant date: Jan 28, 2014
• Expiry date: Sep 13, 2029

Classification

• Technology area (CPC Y): Emerging Cross-Sectional Technologies
• CPC primary: Y02A50/30
• WIPO field: Pharmaceuticals
• WIPO sector: Chemistry

Abstract

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 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-methyl]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.