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Purity: ≥98%
ML228 (ML-228; CID-46742353) is an activator of the Hypoxia Inducible Factor (HIF) which potently activate HIF in vitro as well as its downstream target VEGF. Hypoxia and ischemia are related to numerous public health problems affecting most major organ systems. Examples include the cardiovascular, pulmonary, renal, neurologic, and musculoskeletal systems. Furthermore, angiogenesis is required for tissue repair and regeneration. In cases of ischemia, whether due to injury or disease, enhancing blood supply is a common goal. The most significant pathway for cellular response to hypoxia is the hypoxia inducible factor (HIF) pathway. HIFs are transcription factors responsible for the activation of genes which encode proteins that mediate adaptive responses to reduced oxygen availability. The molecular probe ML228 demonstrated activity in a cell-based HIF-mediated gene reporter assay with an EC50 around 1 μM. This probe did not inhibit the proteasome, activated HIF stabilization and nuclear translocation, and induced expression of a HIF specific downstream gene (VEGF). It had no apparent toxicity below 30 μM and appeared to be an iron chelator.
ln Vitro |
The research community is using ML228 (CID-46742353) as a new chemotype to investigate HIF activation and its possible therapeutic applications. In addition to having a highly different structure from well-known HIF activators, ML228 is devoid of the nearly universally present acidic functional groups seen in PHD inhibitors, which could be crucial for the treatment of specific diseases [1][2].
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ln Vivo |
Following spinal cord injury (SCI), treatment with ML228 (injection; 1 µg/kg; 7 days) can enhance the local hypoxic-ischemic environment, lessen subsequent SCI damage, and encourage neurological recovery [3].
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Animal Protocol |
Animal/Disease Models: SD rats [3]
Doses: 1 µg/kg Route of Administration: injection; 7-day Experimental Results: Central nervous system SCI was diminished and related symptoms were relieved. |
References |
[1]. Theriault JR, et al. Discovery of a Small Molecule Activator of the Hypoxia Inducible Factor Pathway. Probe Reports from the NIH Molecular Libraries Program.
[2]. Theriault JR, et al. Discovery of a new molecular probe ML228: an activator of the hypoxia inducible factor (HIF) pathway. Bioorg Med Chem Lett. 2012 Jan 1;22(1):76-81. [3]. Chen H, et al. Effect of hypoxia-inducible factor-1/vascular endothelial growth factor signaling pathway on spinal cord injury in rats.Exp Ther Med. 2017 Mar;13(3):861-866. |
Molecular Formula |
C₂₇H₂₁N₅
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Molecular Weight |
415.49
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CAS # |
1357171-62-0
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Appearance |
Typically exists as solids (or liquids in special cases) at room temperature
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SMILES |
C1(C2=NC=CC=C2)=NC(NCC3=CC=C(C4=CC=CC=C4)C=C3)=C(C5=CC=CC=C5)N=N1
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Chemical Name |
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Synonyms |
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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 |
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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) |
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Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.02 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 25.0 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: ≥ 2.5 mg/mL (6.02 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 25.0 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: ≥ 2.5 mg/mL (6.02 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 | 2.4068 mL | 12.0340 mL | 24.0680 mL | |
5 mM | 0.4814 mL | 2.4068 mL | 4.8136 mL | |
10 mM | 0.2407 mL | 1.2034 mL | 2.4068 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.
Complete response curves forML228.Bioorg Med Chem Lett.2012 Jan 1;22(1):76-81. td> |
Effects of metals on HRE luciferase activity ofML228.Bioorg Med Chem Lett.2012 Jan 1;22(1):76-81. td> |
Shape based molecular graphics aligned with the SurflexSim conformational ensemble illustrate the large dissimilarity in shape and volume ofML228(green surface) with the composite shape of the published PHD2 ligands. td> |