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Purity: ≥98%
S-Gboxin is an analogue of Gboxin with anticancer activity by potently inhibiting growth of mouse and human glioblastoma (GBM) (IC50 = 470 nM). S-Gboxin is a novel and potent small molecule that specifically inhibits the growth of primary mouse and human glioblastoma cells but not that of mouse embryonic fibroblasts or neonatal astrocytes. Gboxin rapidly and irreversibly compromises oxygen consumption in glioblastoma cells. Gboxin relies on its positive charge to associate with mitochondrial oxidative phosphorylation complexes in a manner that is dependent on the proton gradient of the inner mitochondrial membrane, and it inhibits the activity of F0F1 ATP synthase. Gboxin-resistant cells require a functional mitochondrial permeability transition pore that regulates pH and thus impedes the accumulation of Gboxin in the mitochondrial matrix. Administration of a metabolically stable Gboxin analogue inhibits glioblastoma allografts and patient-derived xenografts. Gboxin toxicity extends to established human cancer cell lines of diverse organ origin, and shows that the increased proton gradient and pH in cancer cell mitochondria is a mode of action that can be targeted in the development of antitumour reagents.
| ln Vitro |
S-Gboxin exhibited an IC₅₀ of 470 nM against primary glioblastoma (GBM) high-throughput tumor sphere (HTS) cells in cell viability assays.[1]
Western blot analysis showed that S-Gboxin (1 μM, 12 hours), like its parent compound Gboxin, upregulated ATF4 expression and suppressed phospho-S6 (p-S6) levels in HTS GBM cells.[1] |
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| ln Vivo |
Excellent metabolic stability, improved plasma stability, and PK characteristics appropriate for in vivo research are all retained by S-Gboxin. Intraperitoneally administered S-Gboxin (10 mg/kg/day) suppresses the growth of glioblastoma (GBM) in vivo [1].
S-Gboxin inhibited the growth of mouse GBM (HTS cells) allografts in nude mice. Daily intraperitoneal (IP) administration of S-Gboxin (10 mg/kg/day), starting 3 days after subcutaneous flank implantation, significantly reduced tumor volume compared to vehicle controls. Treated tumors showed reduced cellular density, decreased proliferation (Ki67+ cells), and reduced expression of high-grade glioma markers (GFAP and Olig2). In a separate experiment where treatment began 14 days post-implantation, S-Gboxin similarly inhibited tumor growth and extended mouse survival.[1] S-Gboxin also inhibited the growth of primary human GBM patient-derived xenograft (PDX) cells (ts1156) subcutaneously implanted in immunocompromised mice. Daily IP administration (10 mg/kg/day) starting 3 days post-implantation resulted in significant tumor growth attenuation and reduced cellularity.[1] For intracranial tumors, S-Gboxin was delivered locally via subcutaneous minipumps connected to an intracranial catheter (2.16 µg/day/mouse), starting two weeks after orthotopic transplantation of primary mouse GBM cells. This treatment inhibited tumor growth, reduced hemorrhage and cellular density, and decreased proliferation and glioma marker expression.[1] S-Gboxin was also tested in two independent orthotopic patient-derived xenograft (PDX) models (PDX-170620 and PDX-170404). Local delivery via minipumps after tumor establishment inhibited GBM PDX growth, as evidenced by improved general health, reduced tumor cellularity, decreased proliferation, and lower GBM marker expression in treated mice compared to vehicle controls.[1] |
| Cell Assay |
Cell viability assays were performed to determine the sensitivity of cells to S-Gboxin. Cells were treated with increasing doses of the compound for 96 hours, and viability was assessed using a Cell-Titer-Glo® luminescent cell viability assay protocol. The IC₅₀ value was calculated from dose-response curves.[1]
For molecular analysis, cells were treated with S-Gboxin (e.g., 1 μM) for specified durations (e.g., 12 hours). Cells were then lysed, and proteins were extracted for western blot analysis to detect changes in markers such as ATF4 and phospho-S6.[1] |
| Animal Protocol |
Animal/Disease Models: Female nude mice (6 to 9 weeks) [1]
Doses: 10 mg/kg/day Route of Administration: intraperitoneal (ip) injection; daily; 3 or 14 days Experimental Results: Caused Dramatically attenuated growth and Cell density decreases. Subcutaneous Allograft Model (Mouse GBM): 10^5 primary mouse GBM (HTS) cells were injected subcutaneously into the flanks of nude mice. Mice were treated daily via intraperitoneal (IP) injection with either vehicle or S-Gboxin at a dose of 10 mg/kg/day. Treatment commenced either 3 days or 14 days after cell implantation. Tumor dimensions were measured every 2 days to calculate volume (Width x Length x Height). Mice were monitored for survival or sacrificed for tumor analysis.[1] Subcutaneous Xenograft Model (Human GBM PDX): 2×10^5 primary human GBM PDX cells (ts1156) were mixed with Matrigel and injected subcutaneously into the flanks of immunocompromised mice. Daily IP treatment with vehicle or S-Gboxin (10 mg/kg/day) began 3 days after implantation. Tumor growth was monitored by measuring volume every 2 days.[1] Intracranial Orthotopic Models: For local delivery, primary mouse GBM cells or freshly harvested human GBM PDX tumor cells were orthotopically implanted into the brains of mice. After a recovery/tumor establishment period (2 weeks for mouse cells, 2-4 weeks for PDX models), an intracranial catheter connected to a subcutaneous osmotic minipump was implanted at the injection site. The minipumps delivered vehicle or S-Gboxin continuously. For the mouse GBM model, the delivery rate was 2.16 µg of S-Gboxin per day per mouse. Mice were monitored for symptoms and sacrificed for brain analysis.[1] |
| ADME/Pharmacokinetics |
Structure-activity relationship (SAR) studies have shown that S-Gboxin is a functional analog with better metabolic stability and pharmacokinetic properties, making it suitable for in vivo studies. Plasma pharmacokinetic (PK) data show that S-Gboxin has enhanced plasma stability compared to the original Gboxin compound. Tumor PK data show that S-Gboxin can be detected in tumors after administration. [1] Specific parameters of S-Gboxin, such as half-life, Cmax, AUC, oral bioavailability, absorption, distribution, metabolism, and excretion, are not provided in the text and extended data figures. [1]
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| Toxicity/Toxicokinetics |
In in vivo studies, mice were treated daily with S-Gboxin (10 mg/kg/day, intraperitoneal injection) for up to 32 days and did not experience weight loss compared to the control group treated with the carrier. No significant health defects were detected in the treated mice during the study period. [1] Specific toxicity parameters, such as LD₅₀, hepatotoxicity, nephrotoxicity, drug interactions, or plasma protein binding, were not reported. [1]
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| References | |
| Additional Infomation |
S-Gboxin is a pharmacologically stable analogue of Gboxin, a novel small-molecule oxidative phosphorylation (OxPhos) inhibitor that selectively targets glioblastoma and other cancer cells. The activity of S-Gboxin is associated with an elevated proton gradient across the inner mitochondrial membrane of cancer cells. Its positive charge promotes its accumulation in the mitochondrial matrix and interacts with and inhibits the activity of OxPhos complexes, particularly complex V (F0F1 ATP synthase). Resistance to Gboxin/S-Gboxin in normal wild-type cells is mediated by the functional mitochondrial permeability transition pore (mPTP), which regulates matrix pH and limits compound accumulation. Many cancer cells, including glioblastoma (GBM), exhibit reduced mPTP activity, making them selectively sensitive to drugs. Primary cultures established from residual S-Gboxin-treated tumors remained sensitive to both Gboxin and S-Gboxin, suggesting that in vivo treatment failure may be due to decreased efficiency of drug entry into cells over time rather than acquired resistance. [1]
|
| Molecular Formula |
C27H32F3IN2O2
|
|---|---|
| Molecular Weight |
600.454870223999
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| Exact Mass |
600.146
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| Elemental Analysis |
C, 54.01; H, 5.37; F, 9.49; I, 21.13; N, 4.67; O, 5.33
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| CAS # |
2101317-21-7
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| Related CAS # |
2101317-20-6 (cation);2101317-21-7 (iodide);
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| PubChem CID |
137628665
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| Appearance |
Solid powder
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
35
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| Complexity |
700
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| Defined Atom Stereocenter Count |
3
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| SMILES |
C[C@@H]1CC[C@H]([C@@H](C1)OC(=O)CN2C3=CC=CC=C3[N+](=C2C4=CC(=CC=C4)C(F)(F)F)C)C(C)C.[I-]
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| InChi Key |
DCAJNAWCJSUZDG-DZJKTSMVSA-M
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| InChi Code |
InChI=1S/C27H32F3N2O2.HI/c1-17(2)21-13-12-18(3)14-24(21)34-25(33)16-32-23-11-6-5-10-22(23)31(4)26(32)19-8-7-9-20(15-19)27(28,29)30;/h5-11,15,17-18,21,24H,12-14,16H2,1-4H3;1H/q+1;/p-1/t18-,21+,24-;/m1./s1
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| Chemical Name |
3-(2-(((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)-2-oxoethyl)-1-methyl-2-(3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-3-ium iodide
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| Synonyms |
S-Gboxin; S Gboxin
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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 : ~93.33 mg/mL (~155.43 mM)
H2O : ~1 mg/mL (~1.67 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 9.33 mg/mL (15.54 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 93.3 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: ≥ 9.33 mg/mL (15.54 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 93.3 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: ≥ 9.33 mg/mL (15.54 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 | 1.6654 mL | 8.3271 mL | 16.6542 mL | |
| 5 mM | 0.3331 mL | 1.6654 mL | 3.3308 mL | |
| 10 mM | 0.1665 mL | 0.8327 mL | 1.6654 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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