Chemistry of Bifunctional Photoprobes

The synthesis and biological activity of functionalized lisinopril, a potent angiotensin converting enzyme (ACE) inhibitor is described. Selective functionalization of lisinopril is achieved at the secondary amino position by a photochemical method, whereas esterfication of the carboxylic groups and modification at the primary amino group is achieved by chemical methods. Autoradiographic investigations using competitive125I radioactive binding assays with the modified lisinopril reveal that the terminal amino group modification enhanced the binding to ACE, whereas the secondary amino group functionalization did not differ significantly from the binding properties of native lisinopril. However, esterification of the carboxyl groups reduced the inhibitory potentency from nMto μM. These results suggest that lisinopril can be derivatized with preservation of inhibition potency toward ACE. These modifications may find utility in the development of photoaffinity labeling agents for ACE or to incorporate bifunctional chelating agents carrying diagnostic radiometals for the development of cardiac imaging agents.