Accessing unexplored chemical space with organometallic compounds: Synthesis of highly potent protein kinase inhibitors

ORGN 438

Howard Bregman, and Eric Meggers, Department of Chemistry, University of Pennsylvania, 231 S. 34th Street, Philadelphia, PA 19104
The development of a bidentate ligand which can interact with the ATP binding pocket of ATP was inspired by the potent but nonspecific kinase inhibitor staurosporine. This ligand can coordinate strongly to ruthenium and has led to the discovery of potent organometallic inhibitors. By taking advantage of the chemistry of ruthenium, a diverse array of three dimensional structures can be rapidly assembled. Many complexes can be easily prepared through the action of a common precursor complex. This precursor bears the aforementioned pyridocarbazole chelate in addition to three acetonitrile and one chloride ligand, which can act as leaving groups in ligand substitution reactions. Although quite kinetically inert, at elevated temperatures this ‘precursor complex' undergoes facile ligand substitution reactions with a diverse array of functional groups allowing for the convergent assembly of complex three dimensional shapes. This unique approach has led to the identification of highly potent protein kinase inhibitors.


Bioorganic, Metal-Mediated Reactions, and Molecular Recognition
8:00 PM-10:00 PM, Tuesday, 30 August 2005 Washington DC Convention Center -- Hall A, Poster

8:00 PM-10:00 PM, Monday, 29 August 2005 Washington DC Convention Center -- Hall A, Sci-Mix

Division of Organic Chemistry

The 230th ACS National Meeting, in Washington, DC, Aug 28-Sept 1, 2005