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| 5mg |
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| Targets |
Digeranyl bisphosphonate targets geranylgeranylpyrophosphate (GGPP) synthase, a key enzyme in the mevalonate pathway responsible for the synthesis of GGPP. This leads to the inhibition of the geranylgeranylation of small GTPases, including Rac1. By inhibiting this post-translational modification, DGBP disrupts the membrane localization and function of these proteins, affecting cell signaling, proliferation, and survival.
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| ln Vitro |
Geranylgeranylation is hampered by digeranyl bisphosphonate (DGBP). Cells were treated to either vehicle or digeranyl diphosphonate in order to investigate if the latter affects Rac1 activity. Chrysotile exposure markedly enhanced Rac1 activation, while geranylbisphosphonate-treated cells showed a return to control levels of activity. Moreover, digeranyl bisphosphonate decreases the generation of H2O2 in macrophages exposed to chrysotile [1].
In vitro, Digeranyl bisphosphonate is characterized by its potent inhibition of GGPP synthase. This results in the inhibition of Rac1 geranylgeranylation. The compound's activity is confirmed in cell-based assays, where it inhibits the prenylation of Rac1, as measured by a decrease in the membrane-bound fraction of the protein and an accumulation of the unprenylated form in the cytosol. |
| ln Vivo |
To further examine the role of digeranyl bisphosphonate (DGBP; 0.2 mg/kg/day) in protecting mice from chrysotile-induced lung fibrosis, animals were subcutaneously injected with vehicle or digeranyl bisphosphonate in an osmotic pump. geranyl bisphosphonate and being exposed to chlorotile or saline the following day. Mice exposed to saline exhibited normal lung anatomy after treatment with vehicle and digeranyl diphosphonate. Chrysotile-exposed animals that received vehicle displayed severe structural abnormalities in the lung parenchyma and had extensive collagen deposition, whereas the lungs of geranylbisphosphonate-treated mice were largely normal. To study the role of digeranyl diphosphonate in bleomycin-induced fibrosis, osmotic pumps containing vehicle or digeranyl diphosphonate were implanted subcutaneously in WT mice. Mice were exposed to saline or bleomycin the next day. Mice treated with diceranyl bisphosphonate (0.2 mg/kg/day) displayed significantly less hydroxyproline compared to vehicle-treated mice exposed to bleomycin [1].
In vivo, Digeranyl bisphosphonate is used as a pharmacological tool to study the role of protein geranylgeranylation in various physiological and pathological processes. By inhibiting Rac1 geranylgeranylation, DGBP can affect cell migration, angiogenesis, and osteoclast function. It has been used in preclinical models of cancer, inflammation, and bone diseases to explore the therapeutic potential of targeting this pathway. |
| Enzyme Assay |
The in vitro enzyme assay for Digeranyl bisphosphonate involves measuring the activity of GGPP synthase. The enzyme is incubated with its substrates, isopentenyl pyrophosphate (IPP) and farnesyl pyrophosphate (FPP), in the presence of varying concentrations of the inhibitor. The production of GGPP is measured, typically by using radiolabeled substrates or by HPLC, and the IC50 is calculated from the inhibition curve.
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| Cell Assay |
In vitro cell culture studies using Digeranyl bisphosphonate involve treating cells (e.g., cancer cells, endothelial cells, or osteoclasts) with the compound. The effect on Rac1 geranylgeranylation is assessed by Western blotting to detect the prenylated and unprenylated forms of the protein. Functional assays, such as cell migration (scratch assay), angiogenesis (tube formation assay), or osteoclast resorption assays, are performed to assess the biological consequences of this inhibition.
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| Animal Protocol |
In vivo animal experiments for Digeranyl bisphosphonate are not extensively documented. As a research tool, it would be administered to rodents, typically via intraperitoneal injection. Its effects on tumor growth in xenograft models or on bone resorption in models of osteoporosis could be assessed. Endpoints would include tumor volume, bone density (micro-CT), and histopathological analysis of tissues.
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| ADME/Pharmacokinetics |
Digeranyl bisphosphonate has a molecular weight of 536.40 g/mol and a purity of >98.0%. It is a solid powder that is soluble in water and DMSO. It is typically stored in a cool, dry place for long-term stability. Its sodium salt form enhances its aqueous solubility, making it suitable for in vivo administration.
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| Toxicity/Toxicokinetics |
Toxicological data for Digeranyl bisphosphonate are limited, as it is a research compound. It is not intended for human use. Given its mechanism of inhibiting protein prenylation, it could have significant biological effects at higher doses. Standard safety precautions for handling chemical research reagents should be followed.
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| References | |
| Additional Infomation |
Digeranyl bisphosphonate is a research compound used as a tool to study the mevalonate pathway and protein prenylation. It is not approved for clinical use. It is particularly valuable for investigating the role of Rac1 and other geranylgeranylated proteins in cancer, inflammation, and bone metabolism, and serves as a lead for the development of new therapeutic agents that target this pathway.
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| Molecular Formula |
C21H38NAO6P2
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| Molecular Weight |
471.460119724274
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| Exact Mass |
536.142
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| CAS # |
878143-03-4
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| PubChem CID |
11606262
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| Appearance |
White to off-white 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 |
10
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| Heavy Atom Count |
33
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| Complexity |
654
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C(P(O)(O)=O)(P(O)(O)=O)(C/C=C(\C)/CC/C=C(\C)/C)C/C=C(\C)/CC/C=C(\C)/C.[Na]
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| InChi Key |
MPGGMSSLQRFXRP-DRLFUFNGSA-J
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| InChi Code |
InChI=1S/C21H38O6P2.4Na/c1-17(2)9-7-11-19(5)13-15-21(28(22,23)24,29(25,26)27)16-14-20(6)12-8-10-18(3)4;;;;/h9-10,13-14H,7-8,11-12,15-16H2,1-6H3,(H2,22,23,24)(H2,25,26,27);;;;/q;4*+1/p-4/b19-13+,20-14+;;;;
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| Chemical Name |
tetrasodium;dioxido-oxo-[(6E,11E)-2,6,12,16-tetramethyl-9-phosphonatoheptadeca-2,6,11,15-tetraen-9-yl]-λ5-phosphane
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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: (1). This product requires protection from light (avoid light exposure) during transportation and storage. (2). 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 : ~2 mg/mL (~3.73 mM)
H2O : ~2 mg/mL (~3.73 mM) |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1211 mL | 10.6054 mL | 21.2107 mL | |
| 5 mM | 0.4242 mL | 2.1211 mL | 4.2421 mL | |
| 10 mM | 0.2121 mL | 1.0605 mL | 2.1211 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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