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RIP1/RIP3/MLKL activator 1 (Compound 6i) is a novel and potent anti-glioma agent acting as an agpnist of RIP1/RIP3/MLKL pathway. It induces necroptosis through activating RIP1/RIP3/MLKL pathway.
| ln Vitro |
In human glioma cell lines, RIP1/RIP3/MLKL activator 1 (compound 6i) (96 hours) demonstrated antiproliferative action [1]. On U251 cells, RIP1/RIP3/MLKL activator 1 (0–4 µM, 0-72 hours) demonstrates strong anti-proliferative activity in a concentration- and time-dependent way [1]. Acceptable stability is demonstrated by RIP1/RIP3/MLKL activator 1 (10 µM, 0-72 hours) [1]. It has been observed that RIP1/RIP3/MLKL activator 1 (0–2 µM, 24 hours) efficiently prevents U251 cell migration [1]. In U251 cells, RIP1/RIP3/MLKL activator 1 causes mitochondrial depolarization and necroptosis via the RIP1/RIP3/MLKL pathway [1]. In U251 cells, RIP1/RIP3/MLKL activator 1 is unable to cause apoptosis [1].
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|---|---|
| ln Vivo |
Compound 6i, RIP1/RIP3/MLKL activator 1 (2.50 ng/tail; intravenous injection; 48 hours), exhibits acceptable BBB permeability while inhibiting U251 cell proliferation in vivo [1].
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| Cell Assay |
Cell proliferation assay[1]
Cell Types: A172, LN229, U87, U251 and L02 Cell lines Tested Concentrations: 0-4 µM for U251 cells Incubation Duration: 96 hrs (hours); 24, 48 and 72 hrs (hours) for U251 cells Experimental Results: For A172, LN229, U87, U251 and L02 demonstrated antiproliferative activity with IC50 values of 3.03 ± 0.70, 1.78 ± 0.79, 1.22 ± 0.89, 0.94 ± 0.45 and 0.99 ± 0.46 µM cells, respectively. Inhibits the growth of U251 cells in a time- and concentration-dependent manner. Western Blot Analysis[1] Cell Types: U251 Tested Concentrations: 0, 0.5, 1, 2 and 4 µM Incubation Duration: 24 or 48 hrs (hours) Experimental Results: Concentration-dependent upregulation of the expression of p-RIP1, RIP1, p-RIP3, RIP3, p -MLKL and MLKL at 24 or 48 hrs (hours). |
| Animal Protocol |
Animal/Disease Models: Zebrafish broad AB strain; 200 CM-DiI labeled U251 cells were transplanted into the yolk sac of each wild-type zebrafish embryo at 2 dpf (2 days after fertilization) [1]
Doses: 2.50 ng/tail Route of Administration: microinjection; 48-hour Experimental Results: The fluorescence intensity of U251 xenografts was Dramatically diminished. |
| References |
| Molecular Formula |
C43H56N4O3
|
|---|---|
| Molecular Weight |
676.929751396179
|
| Exact Mass |
676.435
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| CAS # |
2682850-41-3
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| PubChem CID |
163322291
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| Appearance |
Orange to red solid powder
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| Density |
1.19±0.1 g/cm3(Predicted)
|
| LogP |
8.3
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| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
50
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| Complexity |
1560
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| Defined Atom Stereocenter Count |
5
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| SMILES |
CC1=C(C(=O)C=C2C1=CC=C3[C@]2(CC[C@@]4([C@@]3(CC[C@@]5(C4C[C@](CC5)(C)C(=O)NCC6=CN(N=N6)CC7=CC=C(C=C7)C(C)(C)C)C)C)C)C)O
|
| InChi Key |
QLFCJGYFBTYJGC-RSWNTZNOSA-N
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| InChi Code |
InChI=1S/C43H56N4O3/c1-27-31-14-15-34-41(7,32(31)22-33(48)36(27)49)19-21-43(9)35-23-40(6,17-16-39(35,5)18-20-42(34,43)8)37(50)44-24-30-26-47(46-45-30)25-28-10-12-29(13-11-28)38(2,3)4/h10-15,22,26,35,49H,16-21,23-25H2,1-9H3,(H,44,50)/t35?,39-,40-,41+,42-,43+/m1/s1
|
| Chemical Name |
(2R,4aS,6aR,6aS,14aS)-N-[[1-[(4-tert-butylphenyl)methyl]triazol-4-yl]methyl]-10-hydroxy-2,4a,6a,6a,9,14a-hexamethyl-11-oxo-1,3,4,5,6,13,14,14b-octahydropicene-2-carboxamide
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| 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 : ~100 mg/mL (~147.73 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (3.69 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), suspension 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. Solubility in Formulation 2: 2.5 mg/mL (3.69 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.4773 mL | 7.3863 mL | 14.7726 mL | |
| 5 mM | 0.2955 mL | 1.4773 mL | 2.9545 mL | |
| 10 mM | 0.1477 mL | 0.7386 mL | 1.4773 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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