Targeting the Polyamine Transport System with Benzazepine- and Azepine-Polyamine Conjugates

详细信息    查看全文

• 作者：Sophie Tomasi ; Jacques Renault ; Bndicte Martin ; Stephane Duhieu ; Virginie Cerec ; Myriam Le Roch ; Philippe Uriac ; Jean-Guy Delcros
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：November 11, 2010
• 年：2010
• 卷：53
• 期：21
• 页码：7647-7663
• 全文大小：1256K
• 年卷期：v.53,no.21(November 11, 2010)
• ISSN：1520-4804

文摘

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.