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| Targets |
Pyrazoloacridine targets DNA and the enzymes topoisomerase I and II (TOP2). It appears to intercalate into DNA, which disrupts the DNA structure. By intercalating, it inhibits both RNA and DNA synthesis. It also inhibits the activities of topoisomerases I and II, which are enzymes that relieve torsional stress in DNA during replication and transcription. This dual mechanism leads to DNA damage and cell death.
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| ln Vitro |
Pyrazoloacridine (NSC 366140, PD 115934) had IC50 values of 10.7 μM and 4.5 μM on aerobic and hypoxic HCT-8 cells, respectively [1]. In vitro, topoisomerase I and II lose their catalytic activity when exposed to pyrazoloacridine (NSC 366140, 2-4 μM) [2]. Pyrazoloacridine (NSC 366140) exhibits efficacy against ovarian cancer that is resistant to paclitaxel and cisplatin [2]. In MCF-7 breast cancer cells, pyrazoleacridine (NSC 366140) has been demonstrated to produce delayed DNA fragmentation [2]. Human hepatoma cells lacking the protein kinase P53 can undergo apoptosis when exposed to pyrazoloacridine (NSC 366140) [2].
In vitro, Pyrazoloacridine exhibits cytotoxic activity against various cancer cell lines. Its mechanism of action, involving DNA intercalation and topoisomerase inhibition, leads to the disruption of DNA replication and transcription, causing cell death. It has been studied in vitro to determine its potency and efficacy against different tumor types. However, specific IC50 values for different cell lines are not detailed in the available literature. |
| ln Vivo |
In vivo, Pyrazoloacridine has been evaluated in clinical trials for the treatment of various cancers, including metastatic skin or eye melanoma, lung cancer, liver cancer, and breast cancer. These trials indicate that the compound has been administered to patients to assess its therapeutic potential. However, the specific outcomes of these trials are not provided in the available summaries.
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| Enzyme Assay |
Cell-free assays for Pyrazoloacridine focus on its ability to inhibit its targets. The compound's ability to intercalate into DNA can be measured using various biophysical techniques, such as UV-Vis spectroscopy or fluorescence spectroscopy. Its inhibition of topoisomerase activity can be assessed in a cell-free system. In this assay, the topoisomerase enzyme is incubated with a DNA substrate and ATP in the presence of varying concentrations of Pyrazoloacridine. The relaxation of supercoiled DNA is then measured by gel electrophoresis. This assay allows the direct quantification of topoisomerase inhibition.
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| Cell Assay |
Cytotoxicity assay[2]
Cell Types: K562 myeloid leukemia cells. Tested Concentrations: 0-500 μM. Incubation Duration: 1 hour or 24 hrs (hours). Experimental Results: When K562 cells were incubated with PA for 1 hour and then plated on soft agar, an IC50 of -50 μM was observed. In contrast, when cells were incubated with PA for 24 hrs (hours), the IC50 was 1.25 μM. In vitro cell-based assays for Pyrazoloacridine are performed to evaluate its cytotoxic and antiproliferative effects. Cancer cell lines from various origins (e.g., lung, breast, melanoma) are cultured and treated with varying concentrations of the compound for a defined period. Cell viability is then measured using standard assays like MTT or CellTiter-Glo. The compound's ability to induce apoptosis can also be assessed by staining cells with Annexin V and propidium iodide, followed by flow cytometry. These assays help to determine the compound's potency and efficacy. |
| Animal Protocol |
In vivo animal experiments for Pyrazoloacridine would involve xenograft models using immunodeficient mice implanted with human tumor cells. The compound would be administered, and tumor growth would be monitored. However, specific protocols for Pyrazoloacridine are not detailed in the available literature. The compound has advanced to clinical trials, suggesting that it has been studied in animal models prior to human testing.
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| ADME/Pharmacokinetics |
Metabolism / Metabolites
Pyrazoloacridine's known metabolites include N-demethylpyrazoloacridine. Pharmacokinetic (PK) data for Pyrazoloacridine is not detailed in the available literature. As a compound that has been in clinical trials, its PK properties would have been studied. However, specific parameters such as bioavailability, half-life, and metabolism are not provided. For storage, the compound is typically kept as a powder. |
| Toxicity/Toxicokinetics |
Toxicological data for Pyrazoloacridine is not available in the public literature. As an anticancer agent that has been in clinical trials, its toxicity profile would have been evaluated. However, specific data such as common adverse effects or dose-limiting toxicities are not reported here. Its use is for research purposes, and it is not a clinically approved drug.
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| References | |
| Additional Infomation |
Pyrazoloacridine has been used in clinical trials for the treatment of various cancers, including lung cancer, liver cancer, breast cancer, melanoma (skin), and metastatic cancer. Pyrazoloacridine is a 9-methoxyacridine compound containing a reducible 5-nitro substituent. Pyrazoloacridine appears to intercalate into DNA, inhibiting RNA synthesis, DNA synthesis, and the activity of topoisomerases I and II, thereby leading to cytotoxicity. (NCI04)
Pyrazoloacridine is an investigational anticancer agent that has been studied in clinical trials for various cancers. Its mechanism of action, involving DNA intercalation and topoisomerase inhibition, is characteristic of several established chemotherapeutic agents. It belongs to the acridine family of drugs, which are known for their DNA-intercalating properties. However, it has not received FDA approval for marketing. All information is for research reference and not for diagnostic or clinical use. |
| Molecular Formula |
C19H21N5O3
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|---|---|
| Molecular Weight |
367.41
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| Exact Mass |
367.164
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| CAS # |
99009-20-8
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| Related CAS # |
99009-21-9 (methanesulfonate salt)
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| PubChem CID |
339455
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| Appearance |
Light brown to orange solid powder
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| Density |
1.314g/cm3
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| Boiling Point |
595.6ºC at 760 mmHg
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| Flash Point |
314ºC
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| Index of Refraction |
1.678
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| LogP |
4.062
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
27
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| Complexity |
542
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
HZCWPKGYTCJSEB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H21N5O3/c1-22(2)9-4-10-23-15-7-8-16(24(25)26)19-17(15)18(21-23)13-11-12(27-3)5-6-14(13)20-19/h5-8,11,20H,4,9-10H2,1-3H3
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| Chemical Name |
3-(4-methoxy-10-nitro-8,14,15-triazatetracyclo[7.6.1.02,7.013,16]hexadeca-1(15),2(7),3,5,9,11,13(16)-heptaen-14-yl)-N,N-dimethylpropan-1-amine
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| Synonyms |
PD-115934; PD 115934; Pyrazoloacridine
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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 : ~16.67 mg/mL (~45.37 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 | 2.7218 mL | 13.6088 mL | 27.2175 mL | |
| 5 mM | 0.5444 mL | 2.7218 mL | 5.4435 mL | |
| 10 mM | 0.2722 mL | 1.3609 mL | 2.7218 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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