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Purity: ≥98%
UAMC-3203 (UAMC3203) is a novel and selective Ferroptosis inhibitor with an IC50 value of 12 nM. It has anti-inflammatory and antioxidant properties. The radical-sequestering antioxidant Ferrostatin-1 (Fer-1) can prevent the iron-catalyzed, nonapoptotic form of controlled necrosis known as ferroptosis from damaging cell membranes. Novel inhibitors derived from the Fer-1 scaffold effectively inhibited ferroptosis but had solubility problems. After daily injections of UAMC-3203 for 4 weeks, no toxicity was seen in mice. In silico, UAMC-3203 inserts quickly into a phospholipid bilayer, which is consistent with the way these drugs currently work. In conclusion, these analogs are novel lead compounds with therapeutic potential in relevant ferroptosis-driven disease models. They exhibit in vivo efficacy, have better properties than Fer-1, and have superior properties to Fer-1.
| Targets |
Ferroptosis (IC50 = 12 nM)
UAMC-3203 has a remarkable t1/2 when incubated with human and rat microsomes (t1/2 = 20.5 h and t1/2 = 16.5 h, respectively), but it is discovered to be relatively less stable when incubated with murine microsomes (t1/2 = 3.46 h)[1]. |
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| ln Vitro |
UAMC-3203 has a remarkable t1/2 when incubated with human and rat microsomes (t1/2 = 20.5 h and t1/2 = 16.5 h, respectively), but it is discovered to be relatively less stable when incubated with murine microsomes (t1/2 = 3.46 h)[1].
UAMC-3203 (compound 39) inhibited erastin-induced ferroptosis in IMR-32 neuroblastoma cells with an IC50 of 10 nM, which is more potent than ferrostatin-1 (IC50 = 33 nM). It also inhibited ferroptosis induced by ferrous ammonium sulfate [(NH4)2Fe(SO4)2] with similar or lower IC50 values compared to ferrostatin-1 . The kinetic solubility of UAMC-3203 was determined to be >200 µM. [1] |
| ln Vivo |
UAMC-3203 significantly lowers the plasma levels of lactate dehydrogenase (LDH) in mice. As is typical for lipophilic basic compounds, it leaves the bloodstream quickly and is distributed again throughout the body's tissues. All of the tissues that were examined (liver, kidney, and lungs) contained significant levels of UAMC-3203[1].
In an acute iron poisoning model in mice, intravenous pretreatment with UAMC-3203 (20 µmol/kg) 15 minutes before intraperitoneal iron sulfate injection (300 mg/kg) significantly reduced plasma lactate dehydrogenase (LDH) levels compared to the vehicle-treated group (2346 ± 99 U/L vs. 3572 ± 185 U/L). This protective effect was significantly greater than that of ferrostatin-1. [1] |
| Cell Assay |
The potency of compounds for inhibiting ferroptosis was assessed using IMR-32 human neuroblastoma cells. Cells were seeded in 96-well plates. The following day, they were pre-treated for 1 hour with a dilution series of the test compound (ranging from 200 nM to 0.78 nM for the ferrous ammonium sulfate assay) along with Sytox Green dye. Subsequently, cell death was induced by adding either erastin (10 µM) or ferrous ammonium sulfate (600 µM). The plates were then placed in a fluorescence plate reader, and Sytox Green intensity (indicative of cell death) was measured after 13 hours. Cell death percentage was calculated relative to background and Triton-X-100-induced lysis controls. IC50 values were determined by fitting the dose-response data using appropriate software. [1]
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| Animal Protocol |
Acute Iron Poisoning Model: C57BL/6N mice received an intravenous injection of UAMC-3203 (2 mM solution in 0.9% NaCl containing 2% DMSO, at 20 µmol/kg body weight) or vehicle 15 minutes prior to an intraperitoneal injection of iron sulfate (300 mg/kg body weight in 0.9% NaCl). Blood was collected 2 hours after iron injection under anesthesia, and plasma LDH levels were measured. [1]
Repeated Dose Toxicity Study: Wild-type mice received daily intraperitoneal injections of UAMC-3203 (2 mM solution in 0.9% NaCl containing 2% DMSO, at 20 µmol/kg body weight) or vehicle for 4 weeks. Body weight and temperature were monitored daily. On day 28, blood was collected under anesthesia for analysis of clinical chemistry parameters (ALT, AST, LDH, CK, creatinine, urea, troponin T). [1] Pharmacokinetic Study: Male Wistar rats received a single intravenous dose of UAMC-3203 at 5 mg/kg. Blood samples were collected at various time points up to 24 hours. At 24 hours, animals were sacrificed, and organs (liver, kidney, lungs) were collected, homogenized, and analyzed for compound concentration. [1] |
| ADME/Pharmacokinetics |
The in vitro microsomal stability half-life (t1/2) of UAMC-3203 was: 20.53 ± 5.49 h in humans, 16.48 ± 4.66 h in rats, and 3.46 ± 1.37 h in mice. After 6 hours of in vitro plasma stability, the recoveries of the parent compound were: 84.2% in humans, 85.8% in rats, and 100% in mice. The calculated in vitro intrinsic clearance (CLint) was: 1.1 ± 0.3 µL/min/mg protein in humans, 3.4 ± 1.0 µL/min/mg protein in rats, and 18.0 ± 7.1 µL/min/mg protein in mice. Following a single intravenous injection of 5 mg/kg in rats, the plasma concentration of UAMC-3203 rapidly decreased below the detection limit, indicating rapid distribution of the drug from the bloodstream.
Tissue distribution analysis 24 hours after administration showed that the compound accumulated in the liver (0.15–0.23 mg/kg organ), kidney (0.20–0.38 mg/kg organ), and lung (0.19–0.53 mg/kg organ). [1] |
| Toxicity/Toxicokinetics |
Mice were intraperitoneally injected daily for 4 weeks with UAMC-3203 (20 µmol/kg), and no toxic reactions were observed. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase (CK), creatinine, urea, and troponin T in plasma were comparable to those in the solvent control group. No significant differences in body temperature or weight gain were observed. [1]
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| References | |
| Additional Infomation |
UAMC-3203 is a novel ferroptosis inhibitor derived from ferroptosis inhibitor-1. Key modifications include replacing the unstable ester group with a sulfonamide group and introducing a piperazine group to improve solubility and metabolic stability. Molecular dynamics simulations show that UAMC-3203 can rapidly insert into the phospholipid bilayer model (POPC), with its solubilized piperazine group forming hydrogen bonds with the lipid head and its lipophilic core interacting with the lipid tail. This shallow insertion mode contrasts with deeply inserted antioxidants such as α-tocopherol, which may contribute to its efficacy as a free radical scavenger. Compared with ferrostatin-1 and earlier sulfonamide analogs, this compound exhibits superior potency, solubility, and metabolic stability in vitro, and has shown in vivo efficacy in acute injury models and good safety in subchronic studies, highlighting its potential as a lead compound for studying ferroptosis in disease models. [1]
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| Molecular Formula |
C25H37N5O2S
|
|---|---|
| Molecular Weight |
471.6586
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| Exact Mass |
471.27
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| Elemental Analysis |
C, 63.66; H, 7.91; N, 14.85; O, 6.78; S, 6.80
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| CAS # |
2271358-64-4
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| Related CAS # |
UAMC-3203 hydrochloride;2271358-65-5
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| PubChem CID |
137701965
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| Appearance |
White to off-white a solution in ethanol
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| LogP |
3.5
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
33
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| Complexity |
652
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
HSYSVXKJIVUNBR-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H37N5O2S/c31-33(32,28-15-18-30-16-13-26-14-17-30)23-11-12-24(29-22-9-5-2-6-10-22)25(19-23)27-20-21-7-3-1-4-8-21/h1,3-4,7-8,11-12,19,22,26-29H,2,5-6,9-10,13-18,20H2
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| Chemical Name |
3-(benzylamino)-4-(cyclohexylamino)-N-(2-piperazin-1-ylethyl)benzenesulfonamide
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| Synonyms |
UAMC-3203 free base; UAMC-3203; UAMC3203; UAMC 3203
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: 94~250 mg/mL (199.3~530 mM)
Ethanol: ~94 mg/mL (~199.3 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.41 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 20.8 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. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.41 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 20.8 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.41 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1202 mL | 10.6009 mL | 21.2017 mL | |
| 5 mM | 0.4240 mL | 2.1202 mL | 4.2403 mL | |
| 10 mM | 0.2120 mL | 1.0601 mL | 2.1202 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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