Iron chelator

In MEF cells, deferoxamine mesylate (1 mM; 16 hours or 4 weeks) lowers ROS and enhances HIF-1α function in hypoxic and hypertensive environments [1]. Deferoxamine mesylate (5, 10, 25, 50, 100 μM; 7 or 9 days) suppresses the expression of tumor-associated MSCs and bone marrow MSCs proliferate and produce an increase in p-Akt/total Akt/PKB levels. Deferoxamine mesylate (100 μM; 24 hours) enhances InsR expression and activity. In depleted stem cells, deferoxamine mesylate (5, 10, 25, 50, 100 μM; 7 days) causes inflammation [3]. Cell Expression of Damage Proteins in Mesenchymal Stem Cells[3] Deferoxamine mesylate (10 μM; 3 days) influences deferoxamine mesylate (100 μM; 24 h) in SH-SY5Y cells, producing autophagy changes mediated by HIF-1α levels.

In elderly or diabetic people, deferoxamine mesylate (6.57 μg/mouse; intravenous drip; once daily for 21 days) accelerates wound healing and increases new blood vessels [1]. Deferoxamine mesylate (200 mg/kg; intraperitoneal; once day for two weeks) elevates trophic, glucose InsR expression, and in vivo signaling prevalence in addition to stabilizing HIF-1α [2].

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In vivo, both dimethyloxalylglycine and deferoxamine enhance wound healing and vascularity in aged mice, but only deferoxamine universally augmented wound healing and neovascularization in the setting of both advanced age and diabetes. Conclusion: This first direct comparison of deferoxamine and dimethyloxalylglycine in the treatment of impaired wound healing suggests significant therapeutic potential for topical deferoxamine treatment in ischemic and diabetic disease. [1]

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Deferoxamine, but not DMOG, enhances wound healing in diabetic mice [1]
Given our in vitro observations on the efficacy of DMOG and Deferoxamine/DFO at attenuating the diabetes-induced impairments in HIF-1α activity, we explored the therapeutic potential of these molecules in diabetic wound healing. Splinted excisional wounds were created on the dorsum of type 2 diabetic mice (db/db) as previously described, and mice received daily treatment with either 10 ul of 1mM DMOG solution, 10 ul of 1mM DFO solution, or saline. Wounds were monitored and photographed every other day until closure (Figure 2A). DFO-treated wounds displayed significantly accelerated healing from day 7 onward and healed significantly faster than control-treated wounds (15 days vs 20 days, p < 0.05), whereas DMOG-treated wounds exhibited no improvement over control (18.7 days vs 20 days, p = 0.39) (Figure 2B–C). These results are consistent with our in vitro findings on the differential efficacy of DFO over DMOG in reversing the effects of chronic hyperglycemia and could be further confirmed on a histological level with an increase of neovascularization exclusive to the DFO treatment group (Figure 2D).

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Iron Depletion by Deferoxamine/Dfo Results in HIF-1α Stabilization and Increased Glucose Uptake, Hepatic InsR Expression, and Signaling in an in Vivo Model [2]
At the end of Deferoxamine/Dfo or control treatment, nonfasting glucose levels (198 ± 29 mg/dl versus 185 ± 25 mg/dl) and body weight (260 ± 14 g versus 243 ± 13 g) were not significantly different between control (n = 5) and Deferoxamine-treated rats (n = 4). Dfo induced a significant decrease in serum iron (38 ± 13 μg/dl versus 83 ± 37 μg/dl, P = 0.03) and blood hematocrit (43 ± 8% versus 53 ± 2%, P = 0.03). It also reduced liver iron concentration (42 ± 25 versus 106 ± 88 μg/100 mg dry tissue; P = 0.1). Two hours after intraperitoneal GTT Dfo-treated rats had a lower increase in glucose values compared to baseline levels versus control rats (P = 0.007, Figure 9A), in the presence of lower serum insulin levels (1 ± 0.3 ng/ml versus 1.7 ± 1.3 ng/ml; P = ns). Gene expression analysis in liver samples showed up-regulation of Glut1 mRNA levels (up to 10-fold, P < 0.005; Figure 9B) in Dfo-treated rats, whereas levels of glycolytic genes, and of the rate limiting genes of gluconeogenesis glucose-6-phosphatase (G6pc) and phosphoenolpyruvate-carboxy-kinase (Pck1) were not significantly different between the two groups (Figure 9B). We did not observe significant differences in Glut1 mRNA levels in the muscle and adipose tissue between Dfo-treated and control rats (not shown).

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Deferoxamine/Dfo treatment significantly increased hepatic HIF-1α protein levels (P < 0.005; Figure 9, C and D). InsR protein levels, as well as Akt/PKB and activated Akt/PKB, were significantly higher in the liver of Dfo-treated rats (Figure 9, C and D). These data indicate that iron depletion by Dfo was associated with increased glucose clearance, characterized by up-regulated InsR expression, insulin signaling, and glucose uptake by the liver.

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Effect of Iron Status in a Rat Model of Fatty Liver [2]
At the end of treatment HFD fed rats had significantly higher basal glucose levels compared to littermates (105 ± 18 versus 73.8 ± 38, P < 0.05). Basal glucose levels were not significantly different among controls, iron-depleted, and iron-supplemented rats. After intraperitoneal GTT, after 2 hours Deferoxamine/Dfo-treated rats had a lower increase, whereas iron supplemented rats had a higher increase, in glucose values compared to baseline levels versus controls

Western Blot Analysis[1]
Cell Types: MEFs Cell
Tested Concentrations: 1 mM
Incubation Duration: 16 hrs (hours) (hypoxic conditions); 4 weeks (hyperglycemic conditions)
Experimental Results: Under hypoxic and high glucose conditions, the increase in ROS levels associated with hyperglycemia was Dramatically attenuated. Normoxia HIF transactivation is Dramatically increased in MEFs under both high- and normoglycemic conditions.

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Western Blot Analysis[2]
Cell Types: HepG2 Cell
Tested Concentrations: 100 µM
Incubation Duration: 24 hrs (hours)
Experimental Results: Twofold increase in InsR mRNA levels in cells. At the half-maximal concentration of 1.1 nM, InsR binding activity increased twofold.

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Cell proliferation assay[3]
Cell Types: TAMSC and BMMSC (all isolated from male C57BL/6J mice (8 weeks old; EG-7 induced tumor model))
Tested Concentrations: 5, 10, 25, 50, 100 µM
Incubation Duration: Day 7 (TAMSC); Day 9 (BMMSCs)
Experimental Results: When exposed to 50 and 100 μM doses, the growth of TAMSCs and BMMSCs wa

Animal/Disease Models: Aged (21 months old) and diabetic (12 weeks old) C57BL/6J mice (excision wound model) [1].
Doses: 6.57 µg/each (10 uL, 1 mM)
Route of Administration: Infusion; one time/day for 21 days.
Experimental Results: Demonstrated Dramatically accelerated healing and increased neovascularization in aged and diabetic mouse models.

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Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rat (180-200 g) [2].
Doses: 200 mg/kg
Route of Administration: intraperitoneal (ip) injection; one time/day for 2 weeks.
Experimental Results: The liver HIF-1α protein level was Dramatically increased, and the InsR protein level, Akt/PKB and activated Akt/PKB in the liver were Dramatically increased.

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In vivo Excisional Wound Model To evaluate the effect of DFO and DMOG on murine wound healing, paired 6-mm full-thickness cutaneous wounds were created on the dorsa of mice as previously described (22). Each wound was held open by donut shaped silicone rings fastened with 6-0 nylon sutures to prevent wound contraction. Aged and diabetic mice respectively were randomized into three treatment groups: daily application of 10 ul of DFO or DMOG drip-on (1 mM solutions) and PBS vehicle control (n=4 per group).

Absorption, Distribution and Excretion
Deferoxamine is rapidly absorbed after intramuscular or subcutaneous injection, but its absorption rate is low when the gastrointestinal mucosa is intact.
Deferoxamine mesylate is primarily metabolized by plasma enzymes, but the metabolic pathway is not fully understood. Part of the drug is also excreted in feces via bile.
This drug…is readily excreted in urine.
Metabolism/Metabolites
Deferoxamine is primarily metabolized in plasma, with minimal hepatic metabolism. Several metabolites have been isolated but not yet identified. Some metabolites of deferoxamine, particularly oxidative deamination products, can also chelate iron; therefore, the detoxification effect of this drug appears to be unaffected by hepatic metabolism.
Deferoxamine is primarily metabolized by plasma enzymes, but the metabolic pathway is not fully understood.
Biological Half-Life
In healthy volunteers, deferoxamine exhibits a biphasic elimination pattern, with a rapid first-phase half-life of 1 hour and a slow second-phase half-life of 6 hours.

Hepatotoxicity
In large clinical trials, elevated serum transaminase levels were rare in patients receiving deferoxamine, and no cases of acute, clinically significant liver injury were reported. Patients with transfusion-related iron overload often have chronic hepatitis B or C, and elevated serum transaminase levels during chelation therapy are likely due to natural fluctuations in the activity of underlying chronic liver disease. Nevertheless, elevated serum transaminase levels and "liver dysfunction" are listed as potential adverse events in the deferoxamine product information. An earlier report described a patient undergoing hemodialysis and taking deferoxamine to lower aluminum levels who developed hepatitis, but no other published cases of clinically significant liver injury deferencing deferoxamine treatment have been reported since. Probability Score: E (Unlikely to be the cause of clinically significant liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation Deferoxamine is poorly absorbed orally and is therefore unlikely to enter the infant's bloodstream or cause any adverse effects on breastfed infants. Limited information suggests that daily administration of up to 2 grams of deferoxamine by the mother does not affect the iron content in breast milk and had no adverse effects on the two breastfed infants. Some experts recommend that women taking deferoxamine for iron overload due to β-thalassemia should breastfeed. However, due to the limited publicly available information on deferoxamine use during lactation, monitoring of the infant's serum iron levels is recommended.
◉ Effects on Breastfed Infants
A woman with β-thalassemia restarted subcutaneous deferoxamine at 2 grams per dose, 5 days a week, 3 days after delivery. She breastfed one of the twins from birth (feeding extent not specified). After 17 days of breastfeeding, the infant's serum iron levels were as follows: iron 17.4 μmol/L, ferritin 200 μg/L, transferrin 16.8 μmol/L, all within the normal range. Serum urea, calcium, and magnesium levels were also normal. The other twin had a longer hospital stay, and breastfeeding during hospitalization was not reported. Both infants were breastfed for 4 months postpartum (feeding extent not specified). At 4 months of age, both infants had normal neurological and motor development, and laboratory results were consistent with a diagnosis of heterozygous β-thalassemia: fetal hemoglobin 11.1% and 8.4%, hemoglobin 10.5 g/L and 10.5 g/L, reticulocyte percentage 3.3% and 2.6%, and median erythrocyte volume 60 fL and 58 fL, respectively. Their serum iron, ferritin, transferrin, liver enzymes, plasma urea, and bilirubin levels were normal. One woman with β-thalassemia delivered by cesarean section and breastfed her infant from birth (feeding extent not specified) while taking deferoxamine (dosage not specified). No adverse reactions were reported in her infant. ◉ Effects on lactation and breast milk: As of the revision date, no relevant published information was found. Protein binding: In vitro serum protein binding was less than 10%.

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Interaction
Concurrent oral administration of ascorbic acid (0.5 to 1 gram, twice daily) appears to improve the chelating effect of deferoxamine in hemochromatosis, especially in the presence of vitamin C deficiency.

[1]. Comparison of the Hydroxylase Inhibitor Dimethyloxalylglycine and the Iron Chelator Deferoxamine in Diabetic and Aged Wound Healing. Plast Reconstr Surg. 2017 Mar;139(3):695e-706e.

[2]. Iron depletion by deferoxamine up-regulates glucose uptake and insulin signaling in hepatoma cells and in rat liver. Am J Pathol. 2008 Mar;172(3):738-47.

[3]. In vitro assessment of deferoxamine on mesenchymal stromal cells from tumor and bone marrow. Environ Toxicol Pharmacol. 2017 Jan;49:58-64.

[4]. Neuroprotection of deferoxamine on rotenone-induced injury via accumulation of HIF-1 alpha and induction of autophagy in SH-SY5Y cells. Neurochem Int. 2010 Oct;57(3):198-205.

[5]. Deferoxamine B: A Natural, Excellent and Versatile Metal Chelator. Molecules. 2021 May 28;26(11):3255.

Deferroamine mesylate is a methanesulfonate salt of an iron chelating agent that forms a stable complex with free iron, preventing it from participating in chemical reactions. Deferroamine chelates ferritin and ferroamine (a water-soluble complex excreted by the kidneys and bile) in lysosomes. This drug does not readily chelate iron bound to transferrin, hemoglobin, myoglobin, or cytochrome. It is a natural product isolated from Streptomyces pilosus. It forms iron complexes and is used as a chelating agent, especially in its methanesulfonate form. Deferroamine B is an acyclic deferroamine belonging to the succinic acid family, in which one carboxyl group undergoes a condensation reaction with the primary amino group of N-(5-aminopentyl)-N-hydroxyacetamide, and the other carboxyl group undergoes a condensation reaction with the hydroxyamino group of N(1)-(5-aminopentyl)-N(1)-hydroxy-N(4)-[5-(hydroxyamino)pentyl]succinic acid. It is a natural siderophore from Streptomyces pilosus, biosynthesized by the DesABCD enzyme cluster, and is a high-affinity Fe(III) chelator. It functions as an iron chelator, siderophore, ferroptosis inhibitor, and bacterial metabolite. It is the conjugate base of deferoxamine B(1+). It is the conjugate acid of deferoxamine B(3-). It is a natural product isolated from Streptomyces pilosus. It can form iron complexes and is used as a chelating agent, especially in its methanesulfonate form. Deferoxamine is an iron chelator. The mechanism of action of deferoxamine is iron chelation. Deferoxamine is a parenteral iron chelator used to treat transfusion-related chronic iron overload. Deferoxamine rarely causes elevations in serum transaminases during treatment, and there is no conclusive evidence that it is associated with clinically significant cases of liver injury.
It has been reported that deferoxamine is present in Streptomyces malaysiense, Streptomyces argillaceus, and several other microorganisms with relevant data.
Deferoxamine is an iron chelating agent that binds to free iron to form stable complexes, thereby preventing its participation in chemical reactions. Deferoxamine chelates iron in lysosome ferritin and ferritin to form the water-soluble chelate ferroamine, which is excreted via the kidneys and bile. This drug does not readily bind to iron in transferrin, hemoglobin, myoglobin, or cytochromes. (NCI04)
A natural product isolated from Streptomyces pilosus. It forms iron complexes and is used as a chelating agent, especially in its mesylate form.
Indications

For the treatment of acute iron or aluminum poisoning (excessive aluminum in the body) in certain patients. Also used for certain anemic patients requiring multiple blood transfusions.

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Mechanism of Action
Deferoxamine treats iron poisoning by binding to ferric iron (Fe3+), forming a stable ferroamine complex. The ferroamine complex is excreted by the kidneys. 100 mg of deferoxamine can bind approximately 8.5 mg of ferric iron (ferric ions). Deferoxamine also treats aluminum poisoning by binding to tissue-bound aluminum, forming a stable water-soluble complex—aluminoxamine. The formation of aluminoxamine increases the concentration of aluminum in the blood, leading to a greater concentration gradient between the blood and dialysate, thus promoting aluminum removal during dialysis. 100 mg of deferoxamine can bind approximately 4.1 mg of aluminum.
Deferoxamine has an extremely high affinity for ferric iron…it competes with ferritin and hemosiderin for iron binding, but removes only a small amount of iron from transferrin. After oral administration, deferoxamine binds to iron in the intestinal lumen, preventing iron absorption.
It readily complexes with ferric ions to form a colored, stable, water-soluble chelate—ferroamine; its affinity for ferrous ions is limited. /Mesylate/

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Therapeutic Uses
Antidote; Chelating Agent
/Deferroamine is/a chelating agent with specific iron affinity. It is used to treat severe iron poisoning, hemolysis (caused by drugs, thalassemia, sickle cell anemia, frequent transfusions, etc.) or iron overload caused by iron storage disorders. Although its binding affinity for ferrous iron is not strong, it remains effective in treating ferrous and iron salt poisoning…
Although its efficacy in primary hemochromatosis and secondary hemosiderosis due to cirrhosis is disappointing, some patients with transfusion-induced hemosiderosis respond well to deferroamine treatment.
…Clinically, it has been used for systemic and local treatment of ocular hemosiderosis and intraocular iron foreign bodies.
For complete data on more therapeutic uses of deferroamine (14 in total), please visit the HSDB record. Page number.

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Drug Warning
Although deferoxamine is effective as an iron chelator, other measures, such as inducing vomiting, maintaining an open airway, gastric lavage with sodium phosphate or sodium bicarbonate to form non-absorbable iron salts, and controlling metabolic acidosis and shock, are equally important.
Deferoxamine should not be used to treat mild iron poisoning due to its side effects.
/Mesylates/
There are no absolute contraindications to the use of deferoxamine in the treatment of acute iron poisoning or hemochromatosis. Because the drug and the deferoxamine complex are primarily excreted by the kidneys, deferoxamine is contraindicated in patients with severe kidney disease or anuria.
Although chronic kidney infection may be exacerbated in some patients, no otherwise normal individuals have been found to have kidney damage, even after 2 years of deferoxamine treatment.Pharmacodynamics
Deferoxamine, also known as deferoxamine or deferoxaldehyde, is a chelator used to remove excess iron or aluminum from the body.
Its mechanism of action is to bind with free iron or aluminum in the blood and promote their excretion in urine. By removing excess iron or aluminum, the drug can reduce damage to various organs and tissues, such as the liver.

C26H52N6O11S

656.79

752.329

C, 47.55; H, 7.98; N, 12.80; O, 26.80; S, 4.88

138-14-7

Deferoxamine;70-51-9; 1950-39-6 (HCl); 138-14-7 (mesylate); 25442-95-9 (hydrate)

62881

White to off-white solid powder

966.9ºC at 760 mmHg

148-149°

538.5ºC

0mmHg at 25°C

2.989

7

12

23

44

832

0

IDDIJAWJANBQLJ-UHFFFAOYSA-N

InChI=1S/C25H48N6O8.CH4O3S/c1-21(32)29(37)18-9-3-6-16-27-22(33)12-14-25(36)31(39)20-10-4-7-17-28-23(34)11-13-24(35)30(38)19-8-2-5-15-261-5(2,3)4/h37-39H,2-20,26H2,1H3,(H,27,33)(H,28,34)1H3,(H,2,3,4)

N4-[5-[[4-[[5-(acetylhydroxyamino)pentyl]amino]-1,4-dioxobutyl]hydroxyamino]pentyl]-N1-(5-aminopentyl)-N1-hydroxy-butanediamide, monomethanesulfonate

Deferoxaminum; Deferoxamin; Desferin; Deferoxamine mesylate; 138-14-7; Desferal; Desferrioxamine B mesylate; Deferoxamine mesilate; Desferrioxamine mesylate; Deferoxamine methanesulfonate; Deferoxamine B mesylate; Deferrioxamine B; DFOA; Desferal; Ba 33112; DFOM; DFX; NSC 644468

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~250 mg/mL (~380.64 mM)
DMSO : ~100 mg/mL (~152.26 mM)

Solubility in Formulation 1: 5.56 mg/mL (8.47 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)