Diversity-oriented synthesis of a cytisine-inspired pyridone library leading to the discovery of novel inhibitors of Bcl-2

Lisa A Marcaurelle; Charles Johannes; Daniel Yohannes; Bonnie P Tillotson; David Mann

doi:10.1016/j.bmcl.2009.03.037

Diversity-oriented synthesis of a cytisine-inspired pyridone library leading to the discovery of novel inhibitors of Bcl-2

Bioorg Med Chem Lett. 2009 May 1;19(9):2500-3. doi: 10.1016/j.bmcl.2009.03.037. Epub 2009 Mar 17.

Authors

Lisa A Marcaurelle¹, Charles Johannes, Daniel Yohannes, Bonnie P Tillotson, David Mann

Affiliation

¹ Infinity Pharmaceuticals, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA.

PMID: 19329314
DOI: 10.1016/j.bmcl.2009.03.037

Abstract

Four enantiopure cytisine-inspired scaffolds can be accessed via a versatile pyrrolidine template derived from a stereocontrolled [3+2] azomethine ylide-alkene cycloaddition. Differential ester protection allows for the selective formation of either a bridged bicyclic or tricyclic scaffold via pyridone cyclization. Solid-phase diversification of the pyridone scaffolds yielded a diverse library of 15,000 compounds enabling the discovery of a novel class of Bcl-2 inhibitors.

MeSH terms

Alkaloids / pharmacology*
Apoptosis
Azocines / pharmacology
Chemistry, Pharmaceutical / methods*
Drug Design
Humans
Kinetics
Models, Chemical
Molecular Structure
Protein Interaction Mapping
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
Pyridones / chemical synthesis*
Pyridones / chemistry
Pyrrolidines / chemistry
Quinolizines / pharmacology
Stereoisomerism
bcl-X Protein / antagonists & inhibitors
bcl-X Protein / chemistry

Substances

Alkaloids
Azocines
Proto-Oncogene Proteins c-bcl-2
Pyridones
Pyrrolidines
Quinolizines
bcl-X Protein
cytisine