Substituted alpha-Hydroxy Acids and Their Thioesters as Pharmacophores: Development of New Peptide Derived Caspase Inhibitors

• Applicant: Dr. Rolf Roers
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2000 to 2002
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5295082

Caspases regulate cellular processes of fundamental importance to higher organisms, e.g. the promotion of inflammation of the mediation of apoptosis. While serving important homeostatic functions under normal conditions, the deregulation of inflammation and apoptosis can lead to fatal consequences. Therefore, pharmacological regulation or disruption of caspase mediated signalling pathways represents a promising therapeutic target which, in principle, can be achieved by using small molecule inhibitors. Peptidylic inhibitors of caspases have two components: the relevant pharmacophore moiety responsible for the inhibition of the enzyme, and a peptide element required for additional interactions near the active site.We reasoned that a combination of effective pharmacophore moieties with "morphed" peptide segments may be the key to synthesis of bioavailable strong inhibitors. We chose highly substituted a-hydroxy-ß-amino acids and their thioesters as general pharmacophoric moities and hydroxyethylene units as the "morphed" peptide segments. Semirational, combinatorial approach leading to the potential inhibitors should be possible by recent developments in asymmetric aldol reactions.

• DFG Programme: Emmy Noether International Fellowships