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.

Spermidine-mediated poly(lactic-<em>co</em>-glycolic acid)&nbsp;nanoparticles containing fluorofenidone for the treatment of idiopathic pulmonary fibrosis

“…78 In the lung, the accumulation of natural PAs in the epithelium has been studied in various mammalian species, including rat, rabbit, hamster, and human. [79][80][81][82] This suggests that Spd or PA conjugates might be substrates for the PTS, although further research is required.…”

Quilamine HQ1-44, an iron chelator vectorized toward tumor cells by the polyamine transport system, inhibits HCT116 tumor growth without adverse effect

“…The efficiency of the polyamine transport system (PTS) is also greatly increased in tumoral cells. This property is of potential interest for targeting antitumor agents [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. Based on these observations, we have developed a new generation of iron chelators, the Quilamines, in which an 8-hydroxyquinoline chelating subunit is grafted onto polyamine vectors, in order to vectorize the iron chelator inside the cancerous cell with an overactive PTS [29].…”

Bulk gold catalyzed oxidation reactions of amines and isocyanides and iron porphyrin catalyzed N-H and O-H bond insertion/cyclization reactions of diamines and aminoalcohols

“…13 Caprolactim methyl ether was prepared according to a published procedure. 28 Reaction products were identified by comparison of their mass spectra and GC retention times with those of authentic samples. Yields were determined by GC integrations using authentic samples of the products for response factors.…”