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| Targets |
NCI172112 targets DNA, acting as a DNA crosslinker. As a bifunctional alkylating agent, it forms covalent crosslinks between DNA strands, preventing DNA replication and transcription. This DNA damage activates cellular DNA damage responses and can lead to cell death, particularly in rapidly dividing cancer cells. The compound's spirohydantoin moiety may serve as a carrier to cross the blood-brain barrier.
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| ln Vitro |
In vitro, NCI172112 is a classical bifunctional alkylating agent that acts as a DNA crosslinker. Its antitumor activity has been demonstrated in various cancer cell lines. The compound's ability to form DNA crosslinks and induce DNA damage responses has been characterized in biochemical and cell-based assays. Its activity against CNS tumors has been of particular interest due to its potential to cross the blood-brain barrier.
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| ln Vivo |
Spirohydantoin mustard, or NCI172112, has the potential to pass through the blood-brain barrier as a carrier [1]. Following the administration of [2-chloroethyl-U-14C]NCI172112 or [hydantoin-4-14C]NCI172112 (3.13 mg/kg.iv), the total excretion of radioactivity in the urine and feces of the rats was measured. Rats treated with [hydantoin-14C]NCI172112 had considerably higher urinary radioactivity four hours after dose (P<0.005) than rats treated with [ethyl-14C]NCI172112. But after a day, for both labeling materials, about half of the dose was found in the urine. Radioactivity excreted from feces is slowly cleared, whereas renal excretion of the hydantoin-14C component is much higher. Rats given a single dosage of [hydantoin-14C]NCI17212 did not exhibit any radioactivity in their exhaled breath, and when [ethyl-14C]NCI172112 was administered, the radioactivity was measured at a level of less than 1%. Renal radioactive clearance was comparable four hours after [14C]NCI172112 was administered to rats with bile duct cannulation: 14.1±2.9 and 17.5±2.1% for ethyl-14C and 34.5±2.5 and 33.1±6.3% for hydantoin-14C. Urine doses after 3.13 and 6.25 mg/kg, respectively, were taken. There were variations in the two indicators' 4-hour urine excretion in dogs who received [14C]NCI172112 (1 mg/kg, i.v.). Hydantoin-14C and ethyl-14C elimination percentages were 29.4±2.7% and 17.2±3.5%, respectively (P<0.05) [2].
In vivo, NCI172112 was synthesized for the development of effective antitumor agents against CNS tumors. The spirohydantoin mustard (SHM) moiety may serve as a carrier to cross the blood-brain barrier. The cumulative excretion of radioactivity in the urine and feces of rats after administration of radiolabeled NCI172112 (3.13 mg/kg, i.v.) has been measured. The compound demonstrates significant antitumor activity, particularly against central nervous system (CNS) tumors. |
| Enzyme Assay |
The in vitro DNA crosslinking assay for NCI172112 involves incubating the compound with plasmid DNA or genomic DNA. Varying concentrations of NCI172112 (typically 0.1-1000 uM) are incubated with DNA in appropriate buffer at 37degC for 1-24 hours. DNA crosslinking is assessed by agarose gel electrophoresis, where crosslinked DNA migrates more slowly than uncrosslinked DNA. Alternatively, the alkaline elution assay or comet assay can be used to measure DNA crosslinks and strand breaks. The compound's alkylating activity can also be assessed by measuring the formation of DNA adducts using mass spectrometry or by measuring the inhibition of DNA synthesis using radioactive thymidine incorporation.
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| Cell Assay |
In vitro cellular assays for NCI172112 are conducted using cancer cell lines, particularly those derived from CNS tumors. Cells are seeded in 96-well plates and treated with varying concentrations of NCI172112 (typically 0.01-100 uM) for 24-72 hours. Cell viability is assessed using MTT, CellTiter-Glo, or crystal violet staining assays. DNA damage is assessed by measuring gamma-H2AX foci formation by immunofluorescence or by Western blotting. Cell cycle analysis is performed by flow cytometry using propidium iodide staining. Apoptosis is evaluated using Annexin V-FITC/PI double staining or by measuring caspase-3/7 activity.
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| Animal Protocol |
In vivo animal studies for NCI172112 typically involve administration to rodents bearing CNS tumor xenografts. The compound is administered by intravenous injection at doses determined from preliminary pharmacokinetic and tolerability studies. Tumor growth inhibition is assessed by measuring tumor volumes. The compound's ability to cross the blood-brain barrier is of particular interest. In pharmacokinetic studies, radiolabeled NCI172112 (3.13 mg/kg, i.v.) is administered to rats, and cumulative excretion of radioactivity in urine and feces is measured.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of NCI172112 have been partially characterized. The compound has a molecular weight of 336.26 and a molecular formula of C14H23Cl2N3O2. It is also known as NSC 172112 and NSC 268497. The spirohydantoin moiety may facilitate crossing the blood-brain barrier. In radiolabeled studies in rats, the cumulative excretion of radioactivity in urine and feces after intravenous administration (3.13 mg/kg) has been measured. Detailed ADME parameters are available in the primary literature on nitrosourea alkylating agents.
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| Toxicity/Toxicokinetics |
The toxicological profile of NCI172112 is characteristic of alkylating agents. As a DNA crosslinker, the compound can cause bone marrow suppression, gastrointestinal toxicity, and other side effects associated with alkylating chemotherapy agents. The compound is for research use only and is not intended for human therapeutic use. Standard safety precautions should be followed when handling the compound in a laboratory setting. No specific LD50 values have been reported.
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| References | |
| Additional Infomation |
Spiromustine is a bifunctional nitrogen alkylating agent with antitumor activity and lipophilic properties. Its molecular structure contains a lipophilic hydantoin group, which can act as a carrier to cross the blood-brain barrier. Spiromustine forms covalent bonds with nucleophilic centers in DNA, leading to depurination, base mismatches, strand breaks, and DNA-DNA cross-linking, potentially resulting in cytotoxicity. (NCI04)
NCI172112 (CAS 56605-16-4) is a bifunctional alkylating agent also known as spiromustine, spirohydantoin mustard (SHM), or NSC 172112. It was synthesized for the development of antitumor agents against CNS tumors. The compound acts as a DNA crosslinker and demonstrates significant antitumor activity. It is available for research purposes only. |
| Molecular Formula |
C14H23CL2N3O2
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| Molecular Weight |
336.25700
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| Exact Mass |
335.117
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| CAS # |
56605-16-4
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| PubChem CID |
41945
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| Appearance |
White to off-white solid powder
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| Density |
1.29g/cm3
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| Melting Point |
125.5°C
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| Index of Refraction |
1.56
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| LogP |
2.287
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
21
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| Complexity |
380
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
QNKJFXARIMSDBR-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C14H23Cl2N3O2/c15-6-8-18(9-7-16)10-11-19-12(20)14(17-13(19)21)4-2-1-3-5-14/h1-11H2,(H,17,21)
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| Chemical Name |
3-[2-[bis(2-chloroethyl)amino]ethyl]-1,3-diazaspiro[4.5]decane-2,4-dione
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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 : ~100 mg/mL (~297.39 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 | 2.9739 mL | 14.8694 mL | 29.7389 mL | |
| 5 mM | 0.5948 mL | 2.9739 mL | 5.9478 mL | |
| 10 mM | 0.2974 mL | 1.4869 mL | 2.9739 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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