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| ln Vitro |
When (2R)-octyl-α-hydroxyglutarate, a modified form of 2-hydroxyglutarate with high cellular uptake, was added to IDH1-WT HeLa cells, it caused a dose-dependent DSB in log-phase cells and increased sex. It has been applied to investigate D-2-hydroxyglutarate's role in mitochondrial oxidative processes in cancer cells with IDH1 mutations [1].
Treatment of IDH1-WT HeLa cells with (2R)-Octyl-α-hydroxyglutarate resulted in a dose-dependent increase in DNA double-strand breaks (DSBs) in log-phase cells, as measured by neutral comet assay. A concentration of 900 µM induced the highest amount of DSBs, similar to the level caused by 5 Gy of ionizing radiation. This effect was rapid, occurring within 2 hours of exposure. [1] Exposure of IDH1-WT U2OS DR-GFP reporter cells to (2R)-Octyl-α-hydroxyglutarate caused a dose-dependent suppression of homologous recombination (HR) activity. Similar HR suppression was observed with the (S) enantiomer (octyl ester), but not with the octyl-α-ketoglutarate control. [1] Pre-treatment of IDH1-WT HCT116 cells with 900 µM (2R)-Octyl-α-hydroxyglutarate for 4 days conferred increased sensitivity to the PARP inhibitor BMN-673 in short-term growth delay assays. [1] Treatment with (2R)-Octyl-α-hydroxyglutarate (900 µM and 300 µM) was able to phenocopy the HR defect (measured by plasmid-based HR reporter assay) seen in IDH1-mutant cells or in BRCA2-deficient cells, when applied to various wild-type cell lines (HeLa, HCT116, DLD1, PEO1 C4-2). [1] Treatment of IDH1-WT primary patient-derived glioma cell lines with 300 µM (2R)-Octyl-α-hydroxyglutarate for 7 days recapitulated the phenotype of IDH1-mutant lines: it increased baseline DSBs (comet assay), increased γH2AX/53BP1 foci, and conferred sensitivity to the PARP inhibitor BMN-673 in clonogenic survival assays. [1] |
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| Cell Assay |
Neutral Comet Assay: To assess DNA double-strand breaks (DSBs), cells were trypsinized, washed with PBS, and suspended in LM Agarose. Neutral electrophoresis was conducted at 21 V for 1 hour. Data were collected with a fluorescence microscope and analyzed using Open Comet software. Data are presented as the mean tail moment +/- SEM from at least 3 biological replicates with more than 100 cells analyzed per replicate. For experiments with (2R)-Octyl-α-hydroxyglutarate, cells were typically treated with the indicated concentrations for 24 hours before assay, unless otherwise specified. [1]
U2OS DR-GFP Reporter Assay: To test the effect on homologous recombination (HR), U2OS DR-GFP cells were treated with (2R)-Octyl-α-hydroxyglutarate for the indicated times (e.g., 24 hours). Then, 10^6 cells were transfected in triplicate with 4 µg of the I-SceI expression plasmid (pI-Scel) using nucleofection. Seventy-two hours after transfection, cells were analyzed for GFP expression by flow cytometry. The percentage of GFP-positive cells was calculated and normalized to controls to determine relative HR efficiency. [1] Short-term Growth Delay Assay: For synergy or sensitivity tests, cells were plated in 96-well plates. After 24 hours, media were changed, and drugs (e.g., BMN-673) were added at varying concentrations. For experiments involving pre-treatment with (2R)-Octyl-α-hydroxyglutarate, cells were cultured with the indicated concentration (e.g., 900 µM) for several days (e.g., 4-10 days) before plating and drug addition. At 96 hours after drug addition, cells were fixed, stained with Hoechst, imaged, and counted. [1] |
| References | |
| Additional Infomation |
(2R)-octyl-α-hydroxyglutarate is a cell-permeable octyl ester derivative of (R)-2-hydroxyglutarate (R-2HG). In this study, it was used as a pharmacological tool to deliver 2HG into cells, and the results showed that 2HG itself was sufficient to induce homologous recombination (HR) deficiency and confer sensitivity to PARP inhibitors, thereby mimicking the “BRCA-like” phenotype caused by IDH1/2 mutations. [1] The study found that both the (R)- and (S)-enantiomers of 2HG (in the form of octyl ester) could induce this HR deficiency, suggesting that the effect is mediated by the inhibition of α-ketoglutarate-dependent dioxygenase by 2HG, rather than enantiomer-specific. [1] The commonly used working concentration range in cell culture experiments is 300 µM to 900 µM. [1]
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| Molecular Formula |
C13H24O5
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|---|---|
| Molecular Weight |
260.3267
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| Exact Mass |
260.162
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| CAS # |
1391194-67-4
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| PubChem CID |
71749054
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| Appearance |
White to off-white solid powder
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| Density |
1.1±0.1 g/cm3
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| Boiling Point |
420.5±35.0 °C at 760 mmHg
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| Flash Point |
152.3±19.4 °C
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| Vapour Pressure |
0.0±2.2 mmHg at 25°C
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| Index of Refraction |
1.473
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| LogP |
3.03
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
12
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| Heavy Atom Count |
18
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| Complexity |
240
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CCCCCCCCOC(=O)[C@@H](CCC(=O)O)O
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| InChi Key |
UJZOKTKSGUOCCM-LLVKDONJSA-N
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| InChi Code |
InChI=1S/C13H24O5/c1-2-3-4-5-6-7-10-18-13(17)11(14)8-9-12(15)16/h11,14H,2-10H2,1H3,(H,15,16)/t11-/m1/s1
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| Chemical Name |
(4R)-4-hydroxy-5-octoxy-5-oxopentanoic acid
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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, 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 (~384.13 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (9.60 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 (9.60 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 (9.60 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 | 3.8413 mL | 19.2064 mL | 38.4128 mL | |
| 5 mM | 0.7683 mL | 3.8413 mL | 7.6826 mL | |
| 10 mM | 0.3841 mL | 1.9206 mL | 3.8413 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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