Iron chelator

In MEF cells, deferoxamine (1 mM; 16 hours or 4 weeks) lowers ROS and enhances HIF-1α function in hypoxic and hyperglycemic environments [1]. Deferoxamine (100 µM; 24 hours) raises the levels of p-Akt/total Akt/PKB and enhances the expression and activity of InsR [2]. Both bone marrow MSCs and tumor-associated MSCs are inhibited in their ability to proliferate by defremoxiamine (5, 10, 25, 50, 100 µM; 7 or 9 days). MSC apoptosis is induced by defremoxamine (5, 10, 25, 50, and 100 µM; 7 days) [3]. On MSCs, deferoxamine (10 µM; 3 days) had an impact on adhesion protein expression [3]. In SH-SY5Y cells, deferoxamine (100 µM; 24 hours) promotes autophagy mediated by HIF-1α levels [4].

In aged or diabetic mice, deferoxamine (560.68 mg/tube; infusion; once daily for 21 days) improves wound healing and increases neovascularization [1]. In vivo, deferoxamine (200 mg/kg; i.p.; once daily for two weeks) boosts glucose uptake, hepatic InsR expression, and signaling while 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, Dramatically attenuated hyperglycemia-related The ROS levels increase. 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: 7 days (TAMSC); 9 days (BMMSC).
Experimental Results: At doses of 50 and 100 μM, the growth of TAMSC and BMMSC was inhibited, and most cells died on day 7 or 9.

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Apoptosis analysis [3]
Cell Types: TAMSCs,

Animal/Disease Models: Aged (21 months old) and diabetic (12 weeks old) C57BL/6J mice (excision wound model) [1].
Doses: 560.68 mg/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 administration, but only poorly absorbed from the gastrointestinal tract in the presence of intact mucosa.
Deferoxamine mesylate is metabolized principally by plasma enzymes, but the pathways have not yet been defined. Some is also excreted in the feces via the bile.
THE DRUG IS...READILY EXCRETED IN URINE.

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Metabolism / Metabolites
Deferoxamine is mainly metabolised in the plasma and hepatic metabolism is minimal. A number of metabolites have been isolated but not characterised. Some metabolites of deferoxamine, most notably the product of oxidative deamination, also chelate iron, and thus the antidotal effect of the drug appears unaffected by hepatic metabolism.
DEFEROXAMINE IS METABOLIZED PRINCIPALLY BY PLASMA ENZYMES, ALTHOUGH THE PATHWAYS HAVE NOT YET BEEN DEFINED.

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Biological Half-Life
Biphasic elimination pattern in healthy volunteers with a first rapid phase half life of 1 hour and a second slow phase half-life of 6 hours.

Hepatotoxicity
In large clinical trials, elevations in serum aminotransferase levels were rare in patients receiving deferoxamine and instances of acute, clinically apparent liver injury were not reported. Patients with transfusion related iron overload often have concurrent chronic hepatitis B or C, and elevations of serum aminotransferase levels during chelation therapy may be due to natural fluctuations in the underlying chronic liver disease activity. Nevertheless, elevations in serum aminotransferase levels and “hepatic dysfunction” are listed as potential adverse events in product labels for deferoxamine. After an early report of hepatitis occurring in patient on hemodialysis receiving deferoxamine to reduce aluminum levels, there have been no further published instances of clinically apparent liver injury that have been convincingly linked to deferoxamine therapy.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Deferoxamine is poorly absorbed orally, so it is not likely to reach the bloodstream of the infant or cause any adverse effects in breastfed infants. Limited information indicates that maternal doses of deferoxamine up to 2 grams daily do not affect iron levels in breastmilk and did not cause any adverse effects in two breastfed infants. Some experts advocate breastfeeding in women receiving deferoxamine for iron overload caused by beta-thalassemia. However, since little published information is available on the use of deferoxamine during breastfeeding, monitoring of the infant's serum iron is recommended.
◉ Effects in Breastfed Infants
A woman with beta-thalassemia restarted deferoxamine 2 grams subcutaneously 5 days per week 3 days after delivery. She breastfed (extent not stated) one of her twins from birth. After 17 days of breastfeeding, the infant's serum levels were as follows: iron 17.4 micromoles/L, ferritin 200 mcg/L, and transferrin16.8 micromoles/L, all in the normal range. Serum urea, calcium and magnesium were also normal. The second twin was hospitalized for longer and breastfeeding status in the hospital was not reported. Both infants were breastfed (extent not stated) for 4 months postpartum. Both had normal neurologic and motor development at 4 months and laboratory values consistent with their heterozygous beta-thalassemia: hemoglobin F 11.1% and 8.4%, hemoglobin 10.5 g/L and 10.5 g/L, reticulocytes 3.3% and 2.6%, and median erythrocyte volume 60 fL and 58 fL. Their serum levels of iron, ferritin, transferrin, liver enzymes, plasma urea and bilirubin were all normal.
A woman with beta-thalassemia gave birth to an infant by cesarean section and breastfed her infant (extent not stated) from birth while receiving deferoxamine (dosage not stated). No adverse effects were reported in her infant.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Less than 10% bound to serum proteins in vitro.

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Interactions
THE CONCOMITANT ORAL ADMINISTRATION OF ASCORBIC ACID (0.5 TO 1 G TWICE DAILY) SEEMS TO IMPROVE THE CHELATING ACTION OF DEFEROXAMINE IN HEMOCHROMATOSIS, PARTICULARLY IF THERE IS A 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.

Desferrioxamine B is an acyclic desferrioxamine that is butanedioic acid in which one of the carboxy groups undergoes formal condensation with the primary amino group of N-(5-aminopentyl)-N-hydroxyacetamide and the second carboxy group undergoes formal condensation with the hydroxyamino group of N(1)-(5-aminopentyl)-N(1)-hydroxy-N(4)-[5-(hydroxyamino)pentyl]butanediamide. It is a siderophore native to Streptomyces pilosus biosynthesised by the DesABCD enzyme cluster as a high affinity Fe(III) chelator. It has a role as an iron chelator, a siderophore, a ferroptosis inhibitor and a bacterial metabolite. It is a conjugate base of a desferrioxamine B(1+). It is a conjugate acid of a desferrioxamine B(3-).
Natural product isolated from Streptomyces pilosus. It forms iron complexes and is used as a chelating agent, particularly in the mesylate form.
Deferoxamine is an Iron Chelator. The mechanism of action of deferoxamine is as an Iron Chelating Activity.
Deferoxamine is a parenterally administered iron chelating agent used to treat transfusion related chronic iron overload. Deferoxamine rarely causes serum aminotransferase elevations during therapy and has not been convincingly linked to instances of clinically apparent liver injury.
Deferoxamine has been reported in Streptomyces malaysiense, Streptomyces argillaceus, and other organisms with data available.
Deferoxamine is an iron-chelating agent that binds free iron in a stable complex, preventing it from engaging in chemical reactions. Deferoxamine chelates iron from intra-lysosomal ferritin and siderin forming ferrioxamine, a water-soluble chelate excreted by the kidneys and in the feces via the bile. This agent does not readily bind iron from transferrin, hemoglobin, myoglobin or cytochrome. (NCI04)
Natural product isolated from Streptomyces pilosus. It forms iron complexes and is used as a chelating agent, particularly in the mesylate form.

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Drug Indication
Used to treat acute iron or aluminum toxicity (an excess of aluminum in the body) in certain patients. Also used in certain patients with anemia who must receive many blood transfusions.

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Mechanism of Action
Deferoxamine works in treating iron toxicity by binding trivalent (ferric) iron (for which it has a strong affinity), forming ferrioxamine, a stable complex which is eliminated via the kidneys. 100 mg of deferoxamine is capable of binding approximately 8.5 mg of trivalent (ferric) iron. Deferoxamine works in treating aluminum toxicity by binding to tissue-bound aluminum to form aluminoxamine, a stable, water-soluble complex. The formation of aluminoxamine increases blood concentrations of aluminum, resulting in an increased concentration gradient between the blood and dialysate, boosting the removal of aluminum during dialysis. 100 mg of deferoxamine is capable of binding approximately 4.1 mg of aluminum.
DEFEROXAMINE HAS...REMARKABLY HIGH AFFINITY FOR FERRIC IRON... IT...COMPETES FOR IRON OF FERRITIN & HEMOSIDERIN, BUT IT REMOVES ONLY SMALL AMOUNT OF IRON OF TRANSFERRIN. ... GIVEN ORALLY, DEFEROXAMINE BINDS IRON IN LUMEN OF BOWEL & RENDERS THE METAL NONABSORBABLE.
IT READILY COMPLEXES WITH FERRIC ION TO FORM FERRIOXAMINE, COLORED, STABLE, WATER-SOL CHELATE; IT ALSO HAS LIMITED AFFINITY FOR FERROUS ION. /MESYLATE/

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Therapeutic Uses
Antidotes; Chelating Agents
/DEFEROXAMINE IS/ A CHELATING AGENT THAT IS SPECIFIC FOR IRON. IT IS USED FOR THE TREATMENT OF SEVERE IRON INTOXICATION, IRON OVERLOAD RESULTING FROM HEMOLYSIS (FROM DRUGS, THALASSEMIA, SICKLE-CELL ANEMIA, FREQUENT BLOOD TRANSFUSIONS, ETC) OR IRON STORAGE DISEASE. ... ALTHOUGH IT DOES NOT APPRECIABLY BIND FERROUS IRON, IT HAS NEVERTHELESS PROVEN USEFUL IN THE TREATMENT OF INTOXICATION BY FERROUS AS WELL AS BY FERRIC SALTS...
ALTHOUGH RESULTS...IN PRIMARY HEMOCHROMATOSIS & HEMOSIDEROSIS SECONDARY TO HEPATIC CIRRHOSIS ARE DISAPPOINTING, SOME PATIENTS WITH TRANSFUSION SIDEROSIS RESPOND WELL TO DEFEROXAMINE THERAPY.
...HAS BEEN USED CLINICALLY BOTH SYSTEMICALLY & LOCALLY IN EYE FOR OCULAR SIDEROSIS & FOR IRON FOREIGN BODIES IN EYE.
For more Therapeutic Uses (Complete) data for DESFERRIOXAMINE (14 total), please visit the HSDB record page.

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Drug Warnings
/DESPITE EFFECTIVENESS OF DEFEROXAMINE AS IRON CHELATING AGENT/...OTHER MEASURES SUCH AS INDUCED VOMITING, AIRWAY MAINTENANCE, GASTRIC LAVAGE WITH SODIUM PHOSPHATE OR SODIUM BICARBONATE TO FORM NONABSORBABLE IRON SALTS, AND CONTROL OF METABOLIC ACIDOSIS AND SHOCK, ARE ALSO IMPORTANT.
BECAUSE OF SIDE EFFECTS, DEFEROXAMINE SHOULD NOT BE USED TO TREAT MILD IRON INTOXICATION. /MESYLATE/
THERE ARE NO ABSOLUTE CONTRAINDICATIONS TO THE USE OF DEFEROXAMINE WHEN TREATING ACUTE IRON INTOXICATION OR HEMOCHROMATOSIS. SINCE THE DRUG AND THE FERRIOXAMINE COMPLEX ARE EXCRETED PRIMARILY BY THE KIDNEYS, DEFEROXAMINE IS CONTRAINDICATED IN PATIENTS WITH SEVERE RENAL DISEASE OR ANURIA.
ALTHOUGH CHRONIC RENAL INFECTION MAY BE EXACERBATED IN SOME PATIENTS, RENAL DAMAGE IN OTHERWISE-NORMAL INDIVIDUALS HAS NOT BEEN DEMONSTRATED EVEN AFTER 2 YR OF DEFEROXAMINE THERAPY.

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Pharmacodynamics
Deferoxamine, otherwise known as desferrioxamine or desferal, is a chelating agent used to remove excess iron or aluminum from the body. It acts by binding free iron or aluminum in the bloodstream and enhancing its elimination in the urine. By removing excess iron or aluminum, the agent reduces the damage done to various organs and tissues, such as the liver.

C25H48N6O8

560.68402

560.353

C, 53.55; H, 8.63; N, 14.99; O, 22.83

70-51-9

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

2973

White to off-white solid powder

1.212g/cm3

627.9°C (rough estimate)

139°C

1.537

2.404

6

9

23

39

739

0

O=C(CCC(NCCCCCN(C(C)=O)O)=O)N(O)CCCCCNC(CCC(N(O)CCCCCN)=O)=O

UBQYURCVBFRUQT-UHFFFAOYSA-N

InChI=1S/C25H48N6O8/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)19-8-2-5-15-26/h37-39H,2-20,26H2,1H3,(H,27,33)(H,28,34)

N-[5-[[4-[5-[acetyl(hydroxy)amino]pentylamino]-4-oxobutanoyl]-hydroxyamino]pentyl]-N'-(5-aminopentyl)-N'-hydroxybutanediamide

deferoxamine; 70-51-9; Desferrioxamine B; DESFERRIOXAMINE; Deferoxamin; Deferrioxamine; Deferoxamine B; Deferrioxamine B;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO : ~12.5 mg/mL (~22.29 mM)

Solubility in Formulation 1: ≥ 1.25 mg/mL (2.23 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 1.25 mg/mL (2.23 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 1.25 mg/mL (2.23 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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