Polyaminoquinoline Iron Chelators for Vectorization of Antiproliferative Agents: Design, Synthesis, and Validation

Abstract

Iron chelation in tumoral cells has been reported as potentially useful during antitumoral treatment. Our aim was to develop new polyaminoquinoline iron chelators targeting tumoral cells. For this purpose, we designed, synthesized, and evaluated the biological activity of a new generation of iron chelators, which we named Quilamines, based on an 8-hydroxyquinoline (8-HQ) scaffold linked to linear polyamine vectors. These were designed to target tumor cells expressing an overactive polyamine transport system (PTS). A set of Quilamines bearing variable polyamine chains was designed and assessed for their ability to interact with iron. Quilamines were also screened for their cytostatic/cytotoxic effects and their selective uptake by the PTS in the CHO cell line. Our results show that both the 8-HQ moiety and the polyamine part participate in the iron coordination. HQ1-44, the most promising Quilamine identified, presents a homospermidine moiety and was shown to be highly taken up by the PTS and to display an efficient antiproliferative activity that occurred in the micromolar range. In addition, cytotoxicity was only observed at concentrations higher than 100 μM. We also demonstrated the high complexation capacity of HQ1-44 with iron while much weaker complexes were formed with other cations, indicative of a high selectivity. We applied the density functional theory to study the binding energy and the electronic structure of prototypical iron(III)-Quilamine complexes. On the basis of these calculations, Quilamine HQ1-44 is a strong tridentate ligand for iron(III) especially in the form of a 1:2 complex.

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

“…As reported above, such a concept has been proposed to target other molecules. Our in vivo data, with a low level of side effects, reinforce those obtained in vitro showing the higher sensitivity of proliferating HCT116 cells compared to confluent cells, as well as those previously reported, showing that cells not expressing the PTS are less sensitive to HQ1-44 [29]. In addition, the HQ1-44 targeting can be reinforced through polyamine metabolism manipulation using polyamine depletion tools by providing animals with a polyamine-deficient diet and DFMO, an inhibitor of polyamine biosynthesis, in their drinking water.…”

“…We previously reported that the Quilamine HQ1-44 was highly taken up by the PTS and displayed an efficient antiproliferative activity [29]. As expected during the design of Quilamines, the polyamine chain, involved in the metal coordination, reinforced the affinity for iron (III) and the ferric complex was shown to adopt preferentially a 1:2 [Fe/HQ1-44] stoichiometry at pH = 7.4.…”

“…These data are in accordance with those we previously reported, demonstrating the iron-chelating activity of Quilamines, including HQ1-44. In HQ1-44, the iron-chelating activity of the chelating motif is reinforced by the polyamine backbone, with both the 8-HQ moiety and the polyamine part participating in the iron coordination [29]. In addition, a role of the amino groups of polyamines in the chelation of metallic cations and in the stability of iron chelates has previously been reported [39,40].…”

“…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]. The difference in PTS activation between healthy and tumor cells enables tumor cells to be targeted whereas the stronger dependence of these latter cells on iron ensures a secondary targeting.…”

The Total Synthesis of Spermine Alkaloid Kukoamine Bimesylate

“…Then the diamine was treated with t-butyloxy carbonyl ((Boc) 2 O) to give the monoprotected amine 13 in 71% yield. Exposure of compound 13 to vinyl nitrile 5 resulted in an aza-Michael addition reaction to afford amine 14 in 98% yield, 14 and then the remained amino group of 14 was subjected to benzyl chloroformate to furnish compound 15 in 90% yield, which underwent hydro- Letter Syn lett genation in the presence of Raney Ni and hydrogen (3 MPa) to deliver the corresponding amine 6 in 88% yield. 15 Treatment of compound 6 with freshly prepared acyl chloride 3 followed by deprotection of the Boc group gave amine 16 in 84% yield for two steps.…”