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| Targets |
TRPM4 ion channel. Oxyphenisatin Acetate is the diacetyl ester prodrug of oxyphenisatin. Upon oral administration, it undergoes gradual decomposition into acetic acid and phenolate when it encounters alkaline intestinal juice, which contributes to its laxative effect. More recently, research has identified its mechanism of action against cancer cells as TRPM4 ion channel poisoning. TRPM4 is a calcium-activated non-selective cation channel that plays a role in cell proliferation and survival. By targeting TRPM4, Oxyphenisatin Acetate induces a multi-faceted cell starvation response characterized by eIF2α phosphorylation, AMPK activation, and mTOR inhibition. This leads to potent antiproliferative activity against triple-negative breast cancer (TNBC) cell lines.
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| ln Vitro |
The proliferation of the breast cancer cell lines MCF7, T47D, HS578T, and MDA-MB-468 is inhibited by oxyphenisatinacetate. In estrogen receptor (ER)-positive MCF7 and T47D cells, obenidine acetate triggered TNFα production and TNFR1 degradation, indicating the presence of autocrine receptor-mediated death in these cell lines. Autophagy and mitochondrial malfunction are the outcomes of 10 micromoles per liter of orbenidine acetate treatment [1].
Oxyphenisatin Acetate demonstrates potent antiproliferative activity in vitro against triple-negative breast cancer (TNBC) cell lines via TRPM4 ion channel poisoning. The compound induces a multi-faceted cell starvation response, including eIF2α phosphorylation, AMPK activation, and mTOR inhibition. It has been validated in TNBC PDX models with complete tumor regression at 300 mg/kg i.p.. As a prodrug, Oxyphenisatin Acetate is converted to the active metabolite oxyphenisatin, which exerts the pharmacological effects. The compound's antiproliferative activity is distinguished from its historical laxative effect via a prodrug-specific PK/PD profile (t1/2 = 5.8 h). |
| ln Vivo |
TNFR1 degradation and eIF2α phosphorylation were observed in conjunction with intraperitoneal administration of oxyphenisatinacetate (300 mg/kg) to suppress tumor growth in the MCF7 xenograft model [1].
Oxyphenisatin Acetate has been validated in vivo in triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) models, demonstrating complete tumor regression at 300 mg/kg i.p.. Historically, the compound was used as a stimulant laxative. However, its approval for human use was withdrawn in most countries by the early 1970s due to safety concerns, specifically its association with liver damage and jaundice. The compound's prodrug-specific pharmacokinetic/pharmacodynamic profile (t1/2 = 5.8 h) distinguishes its anticancer activity from its historical laxative effect. |
| Enzyme Assay |
TRPM4 ion channel binding and functional assays are used to characterize Oxyphenisatin Acetate's activity. The compound's antiproliferative activity is assessed in TNBC cell lines by measuring cell viability (MTT or CellTiter-Glo assays). The cell starvation response is evaluated by measuring eIF2α phosphorylation, AMPK activation, and mTOR inhibition via Western blotting. In PDX models, tumor regression is monitored by caliper measurements. Physical properties: molecular weight 401.4 g/mol; molecular formula C24H19NO5; appearance: solid powder; solubility: soluble in DMSO; storage: dry, dark, 0-4°C for short term, -20°C for long term.
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| Cell Assay |
Cellular antiproliferative activity of Oxyphenisatin Acetate is evaluated in triple-negative breast cancer (TNBC) cell lines. Cells are cultured in appropriate media at 37°C with 5% CO₂ and treated with Oxyphenisatin Acetate at various concentrations for 24-72 hours. Cell viability and proliferation are assessed using MTT or CellTiter-Glo assays. The cell starvation response is evaluated by measuring eIF2α phosphorylation, AMPK activation, and mTOR inhibition via Western blotting. Cell cycle analysis and apoptosis assays (Annexin V/PI staining, caspase-3/7 activity) are performed to characterize the mechanism of cell death. Each experiment includes vehicle controls and appropriate positive controls to validate the assay systems.
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| Animal Protocol |
In vivo efficacy of Oxyphenisatin Acetate is evaluated in triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) models. Tumor fragments are implanted subcutaneously in immunodeficient mice. When tumors reach a predetermined size, mice are randomized into treatment and control groups. Oxyphenisatin Acetate is administered intraperitoneally at 300 mg/kg. Tumor growth is monitored by caliper measurements. At study endpoint, tumors are harvested for histopathological analysis, immunohistochemistry (Ki67 for proliferation, cleaved caspase-3 for apoptosis), and biochemical assays (eIF2α phosphorylation, AMPK activation, mTOR inhibition). Body weight and clinical signs are monitored throughout the study to assess tolerability. Sample sizes typically range from 6-10 animals per group.
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| ADME/Pharmacokinetics |
Molecular Weight: 401.4 g/mol. Formula: C24H19NO5. CAS No.: 115-33-3. IUPAC Name: [4-[3-(4-acetyloxyphenyl)-2-oxo-1H-indol-3-yl]phenyl] acetate. Synonyms: Acetalax, NSC 59687, Acetfenolisatin, Diasatine, Dioxyphenylisatin, Isocrin, Oxyphenisatin, Phenolisatin. Appearance: Solid powder. Solubility: Soluble in DMSO. Storage: Dry, dark, 0-4°C for short term, -20°C for long term. Purity: ≥98%. Oxyphenisatin Acetate is a diacetyl ester prodrug of oxyphenisatin with potent antiproliferative activity against TNBC.
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| Toxicity/Toxicokinetics |
Oxyphenisatin Acetate has significant toxicity concerns. Historically, its approval for human use as a laxative was withdrawn in most countries by the early 1970s due to its association with liver damage and jaundice. The FDA withdrew its approval for the use of oxyphenisatin acetate due to safety reasons. It is a small molecule drug with a maximum clinical trial phase of IV and was withdrawn in at least one region. The compound is now procured exclusively for research applications and is not for human or veterinary therapeutic use. Standard safety precautions for handling potentially hepatotoxic compounds should be followed.
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| References |
[1]. Morrison BL, et al. Oxyphenisatin acetate (NSC 59687) triggers a cell starvation response leading to autophagy, mitochondrial dysfunction, and autocrine TNFα-mediated apoptosis. Cancer Med. 2013 Oct;2(5):687-700
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| Additional Infomation |
Oxyphenisatine acetate belongs to the phenolic class of compounds and is a benzoic acid ester. It is a prodrug of Oxyphenisatine (3,3-bis(4-hydroxyphenyl)-1H-indole-2-one). Due to safety concerns, the FDA withdrew its approval for Oxyphenisatine acetate. It is an enterohepatic laxative and may cause jaundice.
Oxyphenisatin Acetate is also known as Acetalax, NSC 59687, Acetfenolisatin, Diasatine, Dioxyphenylisatin, Isocrin, Oxyphenisatin, and Phenolisatin. Its IUPAC name is [4-[3-(4-acetyloxyphenyl)-2-oxo-1H-indol-3-yl]phenyl] acetate. Oxyphenisatin Acetate is the diacetyl ester prodrug of oxyphenisatin. Historically, it was widely used as a stimulant laxative, but its approval was withdrawn due to liver toxicity. Recently, it has demonstrated potent antiproliferative activity against triple-negative breast cancer (TNBC) cell lines via TRPM4 ion channel poisoning and induction of a multi-faceted cell starvation response. It has been validated in TNBC PDX models with complete tumor regression at 300 mg/kg i.p.. No clinical trials are currently active for this compound. Oxyphenisatin Acetate is for research use only. |
| Molecular Formula |
C24H19NO5
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|---|---|
| Molecular Weight |
401.42
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| Exact Mass |
401.126
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| CAS # |
115-33-3
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| Related CAS # |
Oxyphenisatine;125-13-3
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| PubChem CID |
8269
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| Appearance |
White to off-white solid powder
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| Density |
1.282 g/cm3
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| Boiling Point |
566.5ºC at 760 mmHg
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| Melting Point |
244℃
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| Flash Point |
296.4ºC
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| Vapour Pressure |
7.5E-13mmHg at 25°C
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| Index of Refraction |
1.611
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| LogP |
3.961
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
30
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| Complexity |
625
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C1NC2=C(C=CC=C2)C1(C3=CC=C(OC(C)=O)C=C3)C4=CC=C(OC(C)=O)C=C4
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| InChi Key |
PHPUXYRXPHEJDF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H19NO5/c1-15(26)29-19-11-7-17(8-12-19)24(18-9-13-20(14-10-18)30-16(2)27)21-5-3-4-6-22(21)25-23(24)28/h3-14H,1-2H3,(H,25,28)
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| Chemical Name |
[4-[3-(4-acetyloxyphenyl)-2-oxo-1H-indol-3-yl]phenyl] acetate
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| Synonyms |
NSC-117186; NSC 117186; Acetophenolisatin
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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 : ~25 mg/mL (~62.28 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (6.23 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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: ≥ 2.08 mg/mL (5.18 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: ≥ 1 mg/mL (2.49 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 | 2.4912 mL | 12.4558 mL | 24.9116 mL | |
| 5 mM | 0.4982 mL | 2.4912 mL | 4.9823 mL | |
| 10 mM | 0.2491 mL | 1.2456 mL | 2.4912 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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