Synthesis and Biological Properties of Quilamines II, New Iron Chelators with Antiproliferative Activities

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• 作者：Vincent Corcé ; Stéphanie Renaud ; Isabelle Cannie ; Karine Julienne ; Sébastien G. Gouin ; Olivier Loréal ; Fran?ois Gaboriau ; David Deniaud
• 刊名：Bioconjugate Chemistry
• 出版年：2014
• 出版时间：February 19, 2014
• 年：2014
• 卷：25
• 期：2
• 页码：320-334
• 全文大小：569K
• ISSN：1520-4812

文摘

To selectively target tumor cells expressing an overactive Polyamine Transport System (PTS), we designed, synthesized, and evaluated the biological activity of a new generation of iron chelators, derived from the lead compound HQ1鈥?4, which we named Quilamines II. The structures of four new antiproliferative agents were developed. They differ in the size of the linker (HQ0鈥?4 and HQ2鈥?4) or in the nature of the linker (HQCO-44 and HQCS-44) between a hydroxyquinoline moiety (HQ) and a homospermidine (44) chain, the best polyamine vector. The Quilamines II were obtained after 6 to 9 steps by Michael addition, peptide linkage, and reductive amination or by using the Willgerodt-Kindler reaction. The biological evaluation of these second-generation Quilamines showed that modifying the size of the linker increased the selectivity of these compounds for the PTS. In addition, measurement of the toxicity of Quilamines HQ0鈥?4 and HQ2鈥?4 highlighted their marked antiproliferative nature on several cancerous cell lines as well as a differential activity on nontransformed cells (fibroblasts). In contrast, Quilamines HQCO-44 and HQCS-44 presented low selectivity for the PTS, probably due to a loss of electrostatic interaction. We also demonstrated that the HCT116 cell line, originating from a human colon adenocarcinoma, was the most responsive to the various Quilamines. As deduced from the calcein and HVA assays, the higher iron chelating capacity of HQ1鈥?4 could explain its higher antiproliferative efficiency.