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Evaluation of a novel oral iron chelator 1-(N-acetyl-6-aminohexyl)-3-hydroxypyridin-4-one (CM1) for treatment of iron overload in mice

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Advances in Bioscience and Biotechnology 2013年第2期4卷 153-163页

作者： Somdet Srichairatanakool Kanjana Pangjit Chada Phisalaphong Suthat Fucharoen Department of Biochemistry Faculty of Medicine Chiang Mai University Chiang Mai Thailand Institute of Research and Development Government Pharmaceutical Organization Ministry of Public Health Bangkok Thailand Thalassemia Research Center Institute of Molecular Bioscience Mahidol University Salaya Campus Nakornpathom Thailand

Desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX) are promising effective iron chelators for the treatment of iron overload in b-thalassemia patients;nonetheless, their side effects have also been reported. 3-hydroxypyridinone derivatives are being developed as a safer new chelator and in combined chelation therapy. We evaluated the iron-chelating activity of 1-(N-acetyl-6-aminohexyl)-3-hydroxypyridin-4-one (CM1) in iron-loaded C57BL6 mice. The feeding of a ferrocene-supplemented diet (Fe diet) to mice resulted in iron overload, detectable plasma nontransferrin-bound iron (NTBI) and labile plasma iron (LPI), and increases of red cell membrane iron, plasma malondialdehyde (MDA) and excessive tissue iron deposits. Like DFP, the CM1 lowered the levels of the membrane non-heme iron, the NTBI and LPI (p < 0.05) and the MDA after 3 months of treatment. Administration of the Fe diet and the Fe diet along with the chelators did not change the morphology of the liver and heart. Numerous iron accumulations were observed in the liver and spleen tissues of the Fe dietfed mice, whereas the CM1 reduced such iron deposition. Thus, 1-(N-acetyl-6-aminohexyl)-3-hydro- xypyridin-4-one (CM1) can be considered a candidate bidentate oral iron chelator and is effective in the removal of toxic irons in blood compartment and tissues. The effectiveness and toxicity of the CM1 need to be investigated extensively in thalassemia mice and patients with iron overload.

关键词： Thalassemia Iron Overload Iron Chelator hydroxypyridinone Lipid Peroxidation Malondialdehyde

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Study of the decorporation efficacy and toxicity of tetradentate 3-hydroxy- 2-pyridinone ligands at the cellular level

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Radiation Medicine and Protection 2020年第4期1卷 159-165页

作者： Xiaomei Wang Cen Shi Manni Gao Ying Xu Yang Jiao Jianmei Wan Jianping Cao Zhifang Chai Juan Diwu State Key Laboratory of Radiation Medicine and Protection School for Radiological and Interdisciplinary Sciences(RAD-X)Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education InstitutionsSoochow UniversitySuzhou215123China Beijing Nuclear Industry Hospital-Fangshan Campus Beijing102413China

Objective:A series of experiments were carried out to study the comparative decorporation efficacy and toxicity of three tetradentate hydroxypyridinone ligands(3LI-1-Cm-3,2-HOPO,5LIO-1-Cm-3,2-HOPO,and 7LIO-1-Cm-3,2-HOPO)with the variation of the linker length and the ***:Three ligands were obtained from a 4-step synthesis via the amidation of HOPO unit and different *** titrations were carried out to evaluate the formation constants of their corresponding uranyl ***-8 and colony formation assays were used to compare the cytotoxicity of the three ligands and uranyl using renal proximal tubular epithelial(NRK-52E)*** vitro uranium removal assays were performed to assess decorporation efficiencies of those ligands by co-incubating uranium and chelators with NRK-52E cells for 48 ***:Among the three ligands,5LIO-1-Cm-3,2-HOPO exhibits the highest uranyl affinity(logβ110?18.6(7))in comparison to the other two ligands(logβ110?14.9(2)for 3LI-1-Cm-3,2-HOPO and logβ110?16.7(1)for 7LIO-1-Cm-3,2-HOPO).The results of CCK-8 tests and colony formation assays further elucidate that 5LIO-1-Cm-3,2-HOPO and 7LIO-1-Cm-3,2-HOPO both show a similar level of cytotoxicity compared with ZnNa3-DTPA at relatively low ligand *** contrast,in the 3LI-1-Cm-3,2-HOPO treated group,the cell viability decreased markedly with the increase of the ligand concentrations,and the colony formation capability of NRK-52E cells was ***,the comparative decorporation efficacy of the three ligands was obtained from in vitro uranium removal assays,suggesting that these ligands could significantly inhibit the cellular uptake and prompt the cellular release of uranium from NRK-52E cells by the level of 81.9%,91.8%,and 87.1%,***:Our current results demonstrate that the linker/backbone species would significantly affect the decorporation efficacy and toxicity of the tetradentate 3-hydroxy-2-pyridinone ligands

关键词： Uranium hydroxypyridinone Decorporation efficacy Cytotoxicity Metal complexation

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