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

Srichairatanakool, Somdet; Pangjit, Kanjana; Phisalaphong, Chada; Fucharoen, Suthat

doi:10.4236/abb.2013.42023

Cited by 8 publications

(6 citation statements)

References 67 publications

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“…Instead, the greatest emphases have been placed on generating novel bi and tridentate chelators or modifying the properties of existing ligands. Over the years, several promising agents which vary in denticity, metal selectivity for Fe(III), toxicity, stability of the Fe-chelator complex and lipophilicity have been proposed and tested in several in vivo models including rodents, marmosets, dogs, and primates, with promising agents progressing to clinical trials [ 40 - 43 ]. Figure 5 shows the structures of a few previously reported iron chelators with potential clinical utility.…”

Section: Reviewmentioning

confidence: 99%

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Polymeric nanocarriers for the treatment of systemic iron overload

Hamilton

Kizhakkedathu

2015

Mol and Cell Ther

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Desferrioxamine (DFO), deferiprone (L1) and desferasirox (ICL-670) are clinically approved iron chelators used to treat secondary iron overload. Although iron chelators have been utilized since the 1960s and there has been much improvement in available therapy, there is still the need for new drug candidates due to limited long-term efficacy and drug toxicity. Moreover, all currently approved iron chelators are of low molecular weight (MW) (<600 Da) and the objectives reported for the “ideal” chelator of low MW, including possessing the ability to promote iron excretion without causing toxic side effects, has proven difficult to realize in practice. With prolonged iron chelator use, patients may develop toxicities or become insensitive. In contrast, the limited research that has been geared towards developing higher MW, polymeric, long circulating iron chelators has shown promise. The inherent potential of polymeric iron chelators toward longer plasma half-lives and reduction in toxicity provides optimism and may be a significant addition to the currently available low MW iron chelators. This article reviews knowledge pertaining to this theme, highlights some unique advantages that these nanomedicines have in treating systemic iron overload as well as their potential utility in the treatment of other disease states.

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Section: Reviewmentioning

confidence: 99%

“…Importantly, CM1 showed efficacy in preventing lipid peroxidation, the underlying cause of cellular damage. Future studies are needed to determine clinical utility of this agent [ 43 ].…”

Section: Reviewmentioning

confidence: 99%

Polymeric nanocarriers for the treatment of systemic iron overload

Hamilton

Kizhakkedathu

2015

Mol and Cell Ther

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“…It is DFP analogue and is more lipophilic than DFP. In a previous study, we found that CM1 was able to bind both ferric and ferrous ions, and was also able to chelate plasma non-transferrin bound iron (NTBI), efficiently [8]. Moreover, we found that the CM1 was not toxic to peripheral blood mononuclear cells and liver cells in an in vitro study [9].…”

Section: Introductionmentioning

confidence: 91%

Toxicity Study of a Novel Oral Iron Chelator: 1-(N-Acetyl-6-Aminohexyl)-3 Hydroxy-2-Methylpyridin-4-One (CM1) in Transgenic b-Thalassemia Mice

Chansiw¹,

Pangjit²,

Phisalaphong³

et al. 2013

Vitam Miner

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Deferiprone (DFP) (MW=139 Da, Kpart=0.11) is an effective iron chelator used for the treatment of iron overload in thalassemia patients, but the drug is not free from side effects. We have synthesized a novel oral bidentate iron chelator, 1-(N-acetyl-6-aminohexyl)-3-hydroxypyridin-4-one (CM1) (MW=256 Da, Kpart=0.53), which is an analogue of DFP. This compound is more lipophilic than DFP and can bind iron efficiently. Our current results have demonstrated that CM1 reduced iron-induced redox damage and decreased levels of the intracellular iron pool (LIP) in cultured hepatocytes, effectively. However, the toxicity of CM1 remains largely unknown. The aim of this study was to therefore examine the toxicity of CM1 treatment in an animal model under normal and iron overload conditions. To induce iron overload, transgenic ß-thalassemia (BKO) mice were fed with a 0.2% (w/w) ferrocene-supplemented diet (Fe diet) for 240 days. The mice received three doses of CM1 orally (50,100 and 200 mg/kg), every day for 180 days. Blood was collected from the tail vein every 45 days during treatment for the measurement of hemoglobin (Hb) levels, white blood cells (WBC) and platelet numbers. We also determined the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP), which are markers of liver damage. Treatment with CM1 at the assigned doses did not markedly alter the numbers of WBC and the platelets, and the Hb level in BKO mice fed with either N diet or Fe diet. Importantly, all the treatments slightly increased the activities of plasma AST, ALT and ALP in BKO mice after 150 days. Nonetheless, hematoxylin and eosin staining results did not show abnormal morphological changes of the spleen, liver and heart tissues. The results imply that CM1 may not be toxic to bone marrow cells and liver cell function in BKO mice under normal and iron overload conditions.

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“…71 A closely related pyridinone has been developed by the Chiang Mai group (Thailand), namely CM1 ( Figure 1I). 72 The chelator is orally active in the rat and relatively nontoxic. CM1 is currently being subjected to systematic toxicity studies.…”

Section: Dialkylhydroxypyridinonesmentioning

confidence: 99%

Recent Developments Centered on Orally Active Iron Chelators

Hider¹

2014

Thalassemia Reports

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Over the past twenty years there has been a growing interest in the orally active iron chelators, deferiprone and deferasirox, both have been extensively studied. The ability of these compounds to mobilize iron from the heart and endocrine tissue has presented the clinician with some advantages over desferrioxamine, the first therapeutic iron chelator. Other orally active iron chelators are currently under development. The critical features necessary for the design of therapeutically useful orally active iron chelators are presented in this review, together with recent studies devoted to the design of such chelators. This newly emerging range of iron chelators will enable clinicians to apply iron chelation methodology to other disease states and to begin to design personalized chelation regimes.

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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

Cited by 8 publications

References 67 publications

Polymeric nanocarriers for the treatment of systemic iron overload

Polymeric nanocarriers for the treatment of systemic iron overload

Toxicity Study of a Novel Oral Iron Chelator: 1-(N-Acetyl-6-Aminohexyl)-3 Hydroxy-2-Methylpyridin-4-One (CM1) in Transgenic b-Thalassemia Mice

Recent Developments Centered on Orally Active Iron Chelators

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