Free iron chelating agent

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].

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

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]

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.

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.

[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.

Red blood cell (RBC) membranes from patients with the thalassemic and sickle hemoglobinopathies carry abnormal deposits of iron presumed to mediate a variety of oxidative-induced membrane dysfunctions. We hypothesized that the oral iron chelator deferiprone (L1), which has an enhanced capacity to permeate cell membranes, might be useful in chelating these pathologic iron deposits from intact RBCs. We tested this hypothesis in vitro by incubating L1 with RBCs from 15 patients with thalassemia intermedia and 6 patients with sickle cell anemia. We found that removal of RBC membrane free iron by L1 increased both as a function of time of incubation and L1 concentration. Thus, increasing the time of incubation of thalassemic RBCs with 0.5 mmol/L L1 from 0.5 to 6 hours, enhanced removal of their membrane free iron from 18% +/- 9% to 96% +/- 4%. Dose-response studies showed that incubating thalassemic RBC for 2 hours with L1 concentrations ranging from 0.125 to 0.5 mmol/L resulted in removal of membrane free iron from 28% +/- 15% to 68% +/- 11%. Parallel studies with sickle RBCs showed a similar pattern in time and dose responses. Deferoxamine (DFO), on the other hand, was ineffective in chelating membrane free iron from either thalassemic or sickle RBCs regardless of dose (maximum, 0.333 mmol/L) or time of incubation (maximum, 24 hours). In vivo efficacy of L1 was shown in six thalassemic patients whose RBC membrane free iron decreased by 50% +/- 29% following a 2-week course of L1 at a daily dose of 25 mg/kg. As the dose of L1 was increased to 50 mg/kg/d (n = 5), and then to 75 mg/kg/d (n = 4), 67% +/- 14% and 79% +/- 11%, respectively, of their RBC membrane free iron was removed. L1 therapy--both in vitro and in vivo--also significantly attenuated the malondialdehyde response of thalassemic RBC membranes to in vitro stimulation with peroxide. Remarkably, the heme content of RBC membranes from L1-treated thalassemic patients decreased by 28% +/- 10% during the 3-month study period. These results indicate that L1 can remove pathologic deposits of chelatable iron from thalassemic and sickle RBC membranes, a therapeutic potential not shared by DFO. Furthermore, membrane defects possibly mediated by catalytic iron, such as lipid peroxidation and hemichrome formation, may also be alleviated, at least in part, by L1.[2]

C7H9NO2

139.15186

139.06

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

94.5±27.3 °C

0.0±1.0 mmHg at 25°C

1.565

-0.22

42.23

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.)