Design, Synthesis, and Testing of Polyamine Vectored Iron Chelators

Bergeron, Raymond J.; Singh, Shailendra P.; Bharti, Neelam; Jiang, Yi

doi:10.1055/s-0030-1258245

Cited by 6 publications

(2 citation statements)

References 12 publications

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“…Such a concept has been reported in previous studies on the synthesis and the biological properties of a chelating Deferiprone-type moiety linked to spermine. 41 In addition, other studies revealed that homospermidine−anthracene conjugates were more selectively recognized by the PTS than spermine derivatives. 38 Instead, we chose the hydroxyquinoline moiety, found in the iron chelator O-Trensox, which has a higher affinity for iron than Deferiprone.…”

Section: ■ Introductionmentioning

confidence: 99%

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

et al. 2012

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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.

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Section: ■ Introductionmentioning

confidence: 99%

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

et al. 2012

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“…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].…”

Section: Polyamine a Vector For Anticancer Agentsmentioning

confidence: 99%

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

Renaud

Cannie

Ropert

et al. 2015

Biochemical Pharmacology

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Tumor cell growth requires large iron quantities and the deprivation of this metal induced by synthetic metal chelators is therefore an attractive method for limiting the cancer cell proliferation. The antiproliferative effect of the Quilamine HQ1-44, a new iron chelator vectorized toward tumor cells by a polyamine chain, is related to its high selectivity for the Polyamine Transport System (PTS), allowing its preferential uptake by tumoral cells. The difference in PTS activation between healthy cells and tumor cells enables tumor cells to be targeted, whereas the strong dependence of these cells on iron ensures a secondary targeting. Here, we demonstrated in vitro that HQ1-44 inhibits DNA synthesis and cell proliferation of HCT116 cells by modulating the intracellular metabolism of both iron and polyamines. Moreover, in vivo, in xenografted athymic nude mice, we found that HQ1-44 was as effective as cis-platin in reducing HCT116 tumor growth, without its side effects. Furthermore, as suggested by in vitro data, the depletion in exogenous or endogenous polyamines, known to activate the PTS, dramatically enhanced the antitumor efficiency of HQ1-44. These data support the need for further studies to assess the value of HQ1-44 as an adjuvant treatment in cancer.

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Structure–activity relationship of polyamine conjugates for uptake via polyamine transport system

et al. 2018

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Design, Synthesis, and Testing of Polyamine Vectored Iron Chelators

Cited by 6 publications

References 12 publications

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

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

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

Structure–activity relationship of polyamine conjugates for uptake via polyamine transport system

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