Free iron chelating agent
Intracellular iron chelator. Targets iron-containing enzymes, specifically mitochondrial aconitase (m-Acon), leading to its inhibition. [1]

Deferiprone (66-660 μM, 48-96 h) significantly inhibits the growth of 22rv1, Myc-CaP, and TRAMP-C2 cells[1].
Deferiprone (100 μM, for a maximum of 192 hours) prevents TRAMP-C2, Myc-CaP, and 22rv1 cells from migrating[1].
Deferiprone (100 μM, 24 h) decreases m-Acon expression and activity in Myc-CaP, 22rv1, and TRAMP-C2 cells[1].
Deferiprone lowers the free iron in thalassemic red blood cells by up to 1μM over 0.5–24 hours[2].
Deferiprone (10 min) has IC50 values of 0.24, 0.25, 3.36, and 3.73 mM, respectively, and inhibits human platelet aggregation stimulated by AA, ADP, epinephrine, and collagen[3].
With an IC50 value of 0.33 μM, deferiprone (0.1-3.2 μM, 5 mins) inhibits COX-1 activity[3].
The production of cAMP induced by ADP is inhibited by deferiprone (4 mM, 5 min)[3].
In aged fibroblasts, deferiprone (156.25 μg/mL, 24 h) improves survival rate, lowers LDH levels, and exhibits normal cell morphology[4].
Conventional antibiotics' antibacterial activity against S. epidermidis is amplified by deferiprone (25μM, 6 h)[5].

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Deferiprone inhibited proliferation of three prostate cancer cell lines (murine metastatic TRAMP-C2, murine non-metastatic Myc-CaP, and human non-metastatic 22rv1) after 48h incubation. The IC50 values ranged from 51 to 67 µM, and IC90 values ranged from 81 to 186 µM. [1]
Deferiprone (100 µM) inhibited cell migration in a scratch assay, with significant effects observed at different time points depending on the cell line's doubling time (12h for TRAMP-C2, 30h for Myc-CaP, 48h for 22rv1). [1]
In TRAMP-C2 cells, Deferiprone (100 µM) exposure for 24h significantly decreased mitochondrial aconitase (m-Acon) protein expression (by up to 55% in Myc-CaP) and enzymatic activity (reduced by 2-fold in Myc-CaP and 22rv1, and by 79% in TRAMP-C2). [1]
Extracellular flux analysis showed that Deferiprone (100 µM, 24h) significantly reduced oxygen consumption rate (OCR) parameters (basal respiration, maximal respiration, ATP production, spare respiratory capacity, proton leak) in all three cell lines. [1]
MR perfusion studies on TRAMP-C2 cells exposed to 100 µM Deferiprone showed early metabolic changes: a 6-fold decrease in 1-13C-glucose uptake after 5h, blockade of glutamate synthesis via the TCA cycle after 7h, and increased glycerophosphocholine-to-phosphocholine ratio after 23h. [1]

In the tauopathy model of rTg(tauP301L)4510 mice, deferiprone (100 mg/kg/daily for e.g., 4 weeks) has a neuroprotective effect[6].

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In six thalassemic patients, a 2-week course of Deferiprone at 25 mg/kg/day reduced RBC membrane free iron by 50% ± 29%.[2]
Increasing the dose to 50 mg/kg/day (n=5) and 75 mg/kg/day (n=4) resulted in removal of 67% ± 14% and 79% ± 11% of RBC membrane free iron, respectively.[2]
In thalassemic patients treated with 25 mg/kg/day for an average of 5 weeks, H2O2-induced lipid peroxidation in RBC membranes decreased by 32% ± 16%.[2]
Over a 3-month study period, the heme content of RBC membranes from five thalassemic patients decreased by 28% ± 10% (from 7.1 ± 2.4 to 5.5 ± 2.1 nmol/mg).[2]

Cancer growth and proliferation rely on intracellular iron availability. We studied the effects of Deferiprone (DFP), a chelator of intracellular iron, on three prostate cancer cell lines: murine, metastatic TRAMP-C2; murine, non-metastatic Myc-CaP; and human, non-metastatic 22rv1. The effects of DFP were evaluated at different cellular levels: cell culture proliferation and migration; metabolism of live cells (time-course multi-nuclear magnetic resonance spectroscopy cell perfusion studies, with 1-13 C-glucose, and extracellular flux analysis); and expression (Western blot) and activity of mitochondrial aconitase, an iron-dependent enzyme. The 50% and 90% inhibitory concentrations (IC50 and IC90 , respectively) of DFP for the three cell lines after 48 h of incubation were within the ranges 51-67 μM and 81-186 μM, respectively. Exposure to 100 μM DFP led to: (i) significant inhibition of cell migration after different exposure times, ranging from 12 h (TRAMP-C2) to 48 h (22rv1), in agreement with the respective cell doubling times; (ii) significantly decreased glucose consumption and glucose-driven tricarboxylic acid cycle activity in metastatic TRAMP-C2 cells, during the first 10 h of exposure, and impaired cellular bioenergetics and membrane phospholipid turnover after 23 h of exposure, consistent with a cytostatic effect of DFP. At this time point, all cell lines studied showed: (iii) significant decreases in mitochondrial functional parameters associated with the oxygen consumption rate, and (iv) significantly lower mitochondrial aconitase expression and activity. Our results indicate the potential of DFP to inhibit prostate cancer proliferation at clinically relevant doses and plasma concentrations.[1]

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Mitochondrial aconitase (m-Acon) activity was measured using a specific enzyme activity microplate assay kit. The protocol involved isolating mitochondria from fresh cell lysates and measuring m-Acon activity as an increase in absorbance at 240 nm associated with the formation of cis-aconitate. Activity was determined from the slope between measurements at 10 and 30 minutes of incubation and normalized to total cellular protein content. [1]

Cell Line: TRAMP-C2, Myc-CaP, and 22rv1 cells
Concentration: 0, 16, 30, 66, 100, 160, 300, 660 μM
Incubation Time: 48 h, 72 h
Result: exhibited cytostatic activity in three cell lines, with IC50 and IC90 values of roughly 50 and 100 μM, in relation to each other.

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Cell proliferation was assessed by seeding cells in 12-well plates and incubating with various concentrations of Deferiprone (0, 16, 30, 66, 100, 120, 300, 660 µM) for 48h or 96h. Viable cells were counted using the Trypan Blue exclusion assay with an automated cell counter. Doubling times, IC50, and IC90 values were calculated. [1]
Cell migration was measured using a scratch (wound healing) assay. Confluent cell monolayers were scratched with a pipette tip, washed, and migration (wound closure) was monitored over time using microscopy. The percentage of cell-free area was quantified using image analysis software. [1]
For extracellular flux analysis (Seahorse), cells were seeded in 96-well plates, allowed to attach, and then incubated with or without 100 µM Deferiprone for 24h. After changing to unbuffered assay medium, basal extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were measured in response to sequential injections of oligomycin, FCCP, and antimycin A plus rotenone. OCR data were normalized to total protein content. [1]
Western Blot for m-Acon expression: Cells were seeded in flasks, incubated with or without 100 µM Deferiprone for 24h, lysed, and proteins were separated by electrophoresis, transferred to a membrane, and probed with anti-m-Acon and anti-β-Actin antibodies. Bands were quantified using image analysis software. [1]
MR-compatible cell perfusion studies: TRAMP-C2 cells were grown on microcarrier beads, loaded into a perfusion system, and continuously perfused with medium containing 1-13C-glucose with or without 100 µM Deferiprone for 32h. 31P and 13C MR spectra were acquired repeatedly to monitor changes in metabolites like phosphates, NTP, NAD(P), choline metabolites, and 13C-labeled glucose metabolites. Metabolite peak areas were normalized to the initial β-NTP level. [1]

Animal Model: The rTg(tauP301L)4510 mouse model of tauopathy[6].
Dosage: 100 mg/kg/daily, 4 weeks
Administration: Intragastric administration (i.g.)
Result: enhanced performance on the Y-maze and open field, as well as a 28% reduction in brain iron levels and a decrease in AT8-labeled p-tau in the hippocampus of transgenic tau mice.

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Deferiprone was dissolved in a standard suspension vehicle containing 0.9% NaCl, 0.05% carboxy methyl cellulose, 0.05% benzyl alcohol, and 0.04% Tween 80 by probe sonication at room temperature.
The drug was administered daily via oral gavage at a dose of 100 mg/kg for 4 weeks to 12-month-old rTg4510 transgenic mice and wild-type controls.
Behavioral tests (open field, rotarod, Y-maze, Morris water maze) were conducted during the treatment period, and tissues were collected for biochemical and histological analysis. [6]

Absorption, Distribution and Excretion
Deferiprox is absorbed through the upper gastrointestinal tract. Absorption is rapid, with peak plasma concentrations reaching 1 hour after fasting and 2 hours after a meal. Over 90% of deferiprox is cleared from plasma within 5–6 hours after administration. 75% to 90% of deferiprox is excreted in the urine as metabolites. The volume of distribution (VOD) of deferiprox is 1 L/kg in healthy subjects and 1.6 L/kg in patients with thalassemia. In healthy subjects, the mean maximum concentration (Cmax) of deferiprox in serum after oral administration of 1500 mg Ferriprox tablets on an empty stomach was 20 μg/mL, and the mean area under the concentration-time curve (AUC) was 53 μg/h/mL. Dose-proportioning relationships within the recommended dose range (25 to 33 mg/kg three times daily, i.e., 75 to 99 mg/kg daily) have not been investigated. The elimination half-life of Deferiprone is 1.9 hours. Accumulation of Deferiprone and its glucuronide metabolites at the highest approved dose (33 mg/kg three times daily) has not been investigated. The volume of distribution of Deferiprone is 1.6 L/kg in patients with thalassemia and approximately 1 L/kg in healthy subjects. Defereriphenone has less than 10% plasma protein binding in humans. Defereriphenone is rapidly absorbed from the upper gastrointestinal tract, entering the bloodstream within 5 to 10 minutes after oral administration. Peak serum concentrations are reached approximately 1 hour after a single dose in fasting healthy subjects and patients, compared to up to 2 hours after a meal. Co-administration with food reduces the Cmax of Deferiprone by 38% and the AUC by 10%. While the effect of food cannot be ruled out, the variation in exposure is not significant enough to warrant dose adjustment. Over 90% of Deferiprone is cleared from plasma within 5 to 6 hours after ingestion. Following oral administration, 75% to 90% of the drug is excreted in the urine within 24 hours, primarily as metabolites.
/Breast Milk/ It is unclear whether deferoxone is secreted into human breast milk.
For more complete data on the absorption, distribution, and excretion of deferoxone (a total of 8 types), please visit the HSDB record page.

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Metabolism/Metabolites
Deferoxone is primarily metabolized via UGT1A6 to a 3-O-glucuronide metabolite. This metabolite does not chelate iron.
In humans, most deferoxone is primarily metabolized via UGT1A6. The contribution of extrahepatic (e.g., renal) UGT1A6 is unclear. The major metabolite of deferoxone is 3-O-glucuronide, which is not iron-binding. Peak serum glucuronide concentrations in fasting subjects occur between 2 and 4 hours after administration of deferoxone.

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Biological Half-Life
The half-life is 1.9 hours. The pharmacokinetics of deferiprone were evaluated in seven children aged 11 to 18 years (mean age 15 ± 2.7 years; median age 16 years) with thalassemia and iron overload. These patients had been on long-term deferiprone treatment and were therefore considered to have reached steady state. Serum concentrations of deferiprone peaked approximately 2 hours after administration and decreased over a half-life of 1.8 hours; deferiprone glucuronide concentrations peaked approximately 3 hours after administration and decreased over a half-life of 2.0 hours. In healthy subjects, the elimination half-life after oral administration of 1500 mg Ferriprox tablets on an empty stomach was 1.9 hours. The study noted that plasma deferiprone concentrations peaked within 0.5 to 1 hour after administration, ranging from 0.1 to 0.45 mmol/L, and gradually decreased over the next 4 to 6 hours. Concentrations used in in vitro experiments (0.125 to 0.5 mmol/L) encompass these clinical plasma concentration ranges. [2]

Hepatotoxicity
In large clinical trials, 7.5% of patients receiving deferoxone experienced elevated serum transaminase levels, and approximately 1% discontinued treatment as a result. In many cases, it is unclear whether the ALT elevation is caused by deferoxone treatment or by spontaneous exacerbations of underlying chronic hepatitis B or C, the latter being more common in patients with transfusion-related iron overload. Furthermore, reports of clinically significant liver injury caused by deferoxone treatment are very rare, and the clinical characteristics of deferoxone-induced liver injury (latency of onset, pattern of serum enzyme elevation, clinical symptoms and laboratory findings, and subsequent disease course) remain unclear. Iron overload itself can lead to liver injury and cause significant liver fibrosis and even cirrhosis. By reducing hepatic iron storage, deferoxone and other iron chelators should improve liver disease and halt the progression of fibrosis. In a controversial open-label study, 19 patients with thalassemia and iron overload received deferoxone treatment for up to 4 years. Results showed that among the 12 subjects who underwent repeat liver biopsies an average of 4 years later, 5 developed fibrosis progression; while none of the 12 subjects treated with deferoxamine developed fibrosis progression. However, subsequent studies failed to show fibrosis progression in patients with thalassemia and iron overload treated with deferoxamine, particularly in patients without hepatitis C. Probability score: E (Unproven but suspected cause of clinically significant liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation Deferoxamine may be actively transported into breast milk by binding to lactoferrin. Since there is currently no information on the use of deferoxamine during lactation, and deferoxamine is an orally absorbed drug, alternative medications are recommended, especially for breastfed newborns or premature infants. Australian guidelines recommend avoiding breastfeeding during deferoxamine treatment. The US manufacturer recommends discontinuing breastfeeding for 2 weeks after the last dose.
◉ Effects on breastfed infants
No relevant published information was found as of the revision date.
◉ Effects on lactation and breast milk
No relevant published information was found as of the revision date.

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Protein binding
Plasma protein binding was less than 10%.

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This study indicates that deferone has good clinical efficacy and has been used in patients with thalassemia for a long time (more than 15 years) without significant side effects affecting quality of life. It has been reported that the drug is well tolerated in non-iron overload diseases at daily doses of 20-75 mg/kg. [1]
No cytotoxicity (cell death) was observed at concentrations up to 660 µM used in proliferation assays because cell viability was assessed by trypan blue exclusion method. [1]

[1]. Rui V. Simões, Inhibition of prostate cancer proliferation by Deferiprone. NMR Biomed 2017 Jun;30(6):10.1002/nbm.3712.

[2]. Deferiprone (L1) Chelates Pathologic Iron Deposits From Membranes of Intact Thalassemic and Sickle Red Blood Cells Both In Vitro and In Vivo. Blood. 1995 Sep 1;86(5):2008-13.

[3]. Antiplatelet activity of deferiprone through cyclooxygenase-1 inhibition. Platelets 2020 May 18;31(4):505-512.

[4]. Deferiprone Stimulates Aged Dermal Fibroblasts via HIF-1α Modulation.Pathog Dis. 2018 Jul 1;76(5).

[5]. Iron chelation destabilizes bacterial biofilms and potentiates the antimicrobial activity of antibiotics against coagulase-negative Staphylococci. Pathogens and Disease, Volume 76, Issue 5, July 2018, fty052

[6]. Deferiprone Treatment in Aged Transgenic Tau Mice Improves Y-Maze Performance and Alters Tau Pathology. Neurotherapeutics. 2021 Apr;18(2):1081-1094.

Deferiprone belongs to the 4-pyridone class of compounds, with the structure pyridin-4(1H)-one, where methyl groups are substituted at positions 1 and 2, and a hydroxyl group is substituted at position 3. It is a lipid-soluble iron chelator used to treat thalassemia. It both chelates and protects against iron. Deferiprone is an oral iron chelator used as a second-line treatment in thalassemia syndrome caused by transfusion-induced iron overload. Thalassemia is a hereditary anemia caused by a defect in hemoglobin production. Therefore, erythropoiesis (the production of new red blood cells) is impaired. This drug was approved by the U.S. Food and Drug Administration (FDA) on October 14, 2011. Deferiprone is an iron chelator. Its mechanism of action is iron chelation. Deferiprone is an oral iron chelator used to treat transfusion-related chronic iron overload. The incidence of transient elevations in serum transaminases during Deferiprone treatment is low, and clinically significant liver damage is rare.
Deferiprone is a bidentate ligand with high oral bioavailability and iron-chelating activity. The molar ratio of Deferiprone to iron is 3:1 (ligand: iron). Deferiprone removes excess iron from the body by binding to iron.
It is a pyridone derivative and iron chelator used to treat iron overload in patients with thalassemia.

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Drug Indications>
Deferiprone is indicated for patients with thalassemia syndrome when first-line chelators are insufficient to treat transfusion-induced iron overload.
FDA Label
Ferriprox monotherapy is indicated for the treatment of iron overload in patients with severe thalassemia when existing chelating therapies are contraindicated or ineffective. Ferriprox may be used in combination with other chelators in patients with severe thalassemia when any iron chelator monotherapy is ineffective, or when rapid or intensive treatment is required to prevent or treat life-threatening consequences of iron overload (primarily cardiac iron overload).
When existing chelation therapies are contraindicated or ineffective, Deferiprone Lipomed can be used as monotherapy to treat iron overload in patients with severe thalassemia. For patients with severe thalassemia, Deferiprone Lipomed can be used in combination with other chelators when monotherapy with any iron chelator is ineffective, or when rapid or intensive treatment is required to prevent or treat life-threatening consequences of iron overload.
Treatment of Chronic Iron Overload

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Mechanism of Action>
Deferiprone is an iron chelator that binds to ferric (III) ions to form a stable 3:1 (Deferiprone:iron) complex, which is then excreted in the urine. Deferiprone has a higher selectivity for iron, while other metals (such as zinc, copper, and aluminum) have a lower affinity for it.
Deferiprone is a chelator with an affinity for ferric (III) ions. Deferiprone binds to ferric ions to form a neutral 3:1 (deferiprone:iron) complex, which remains stable over a wide pH range. Deferiprone has a lower affinity for binding other metals (such as copper, aluminum, and zinc) than for binding iron. Deferiprone is an oral iron chelator used clinically to treat thalassemia, Friedreich ataxia, and kidney disease. It readily enters cells and reaches sites of intracellular iron accumulation, particularly mitochondria. [1] This study suggests that Deferiprone, by chelating intracellular iron and inhibiting the iron-dependent enzyme mitochondrial aconitase (m-Acon), could inhibit the metabolism, proliferation, and migration of cancer cells at clinically achievable concentrations, thus making it a potential candidate drug for the treatment of prostate cancer. [1]

C7H9NO2

139.15186

139.063

C, 60.42; H, 6.52; N, 10.07; O, 23.00

30652-11-0

Deferiprone-d3;1346601-82-8

2972

White to off-white solid powder

1.2±0.1 g/cm3

232.7±40.0 °C at 760 mmHg

272-275 °C(lit.)

94.5±27.3 °C

0.0±1.0 mmHg at 25°C

1.565

-0.22

1

3

0

10

228

0

O=C1C(O)=C(C)N(C)C=C1

TZXKOCQBRNJULO-UHFFFAOYSA-N

InChI=1S/C7H9NO2/c1-5-7(10)6(9)3-4-8(5)2/h3-4,10H,1-2H3

3-hydroxy-1,2-dimethylpyridin-4(1H)-one

Ferriprox

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)

Water : 3.33~27 mg/mL(~23.93 mM)
DMSO : ~7.14 mg/mL (~51.31 mM)

Solubility in Formulation 1: ≥ 0.71 mg/mL (5.10 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 7.1 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: ≥ 0.71 mg/mL (5.10 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 7.1 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: ≥ 0.71 mg/mL (5.10 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 7.1 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 0.71 mg/mL (5.10 mM)

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Solubility in Formulation 5: 10 mg/mL (71.86 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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