Targeting the polyamine transport system with benzazepine- and azepine-polyamine conjugates

Abstract

The polyamine transport system (PTS) whose activity is up-regulated in cancer cells is an attractive target for drug design. Two heterocyclic (azepine and benzazepine) systems were conjugated to various polyamine moieties through an amidine bound to afford 18 compounds which were evaluated for their affinity for the PTS and their ability to use the PTS for cell delivery. Structure-activity relationship studies and lead optimization afforded two attractive PTS targeting compounds. The azepine-spermidine conjugate 14 is a very selective substrate of the PTS that may serve as a vector for radioelements used for diagnoses or therapeutics in nuclear medicine. The nitrobenzazepine-spermine conjugate 28 is a very powerful PTS inhibitor with very low intrinsic cytotoxicity, able to prevent the growth of polyamine depleted cells in presence of exogenous polyamines.