Pixantrone (formerly known as BBR 2778), is a novel, potent aza-anthracenedione analog with anticancer activity with little cardiotoxicity. It functions as a weak inhibitor of topoisomerase II and a DNA intercalator, selectively forming stable DNA adducts at sites of hypermethylation through alkylation. DNA replication is inhibited and tumor cell cytotoxicity is caused when it intercalates into DNA and creates topoisomerase II-mediated DNA strand crosslinks. Despite their importance as oncotherapeutics, anthracene and anthracene derivatives are linked to cumulative and irreversible cardiotoxicity. Pixantrone was created to decrease treatment-related cardiotoxicity without compromising effectiveness. For patients with aggressive non-Hodgkin lymphoma (aNHL), Pixantrone is a less cardiotoxic and more effective treatment than doxorubicin.
Physicochemical Properties
| Molecular Formula | C17H19N5O2 | |
| Molecular Weight | 325.37 | |
| Exact Mass | 325.153 | |
| CAS # | 144510-96-3 | |
| Related CAS # | 144510-96-3;144675-97-8 (dimaleate); 175989-38-5 (HCl) | |
| PubChem CID | 134019 | |
| Appearance | Solid powder | |
| Density | 1.4±0.1 g/cm3 | |
| Boiling Point | 650.0±55.0 °C at 760 mmHg | |
| Flash Point | 346.9±31.5 °C | |
| Vapour Pressure | 0.0±1.9 mmHg at 25°C | |
| Index of Refraction | 1.729 | |
| LogP | -1.13 | |
| Hydrogen Bond Donor Count | 4 | |
| Hydrogen Bond Acceptor Count | 7 | |
| Rotatable Bond Count | 6 | |
| Heavy Atom Count | 24 | |
| Complexity | 472 | |
| Defined Atom Stereocenter Count | 0 | |
| InChi Key | PEZPMAYDXJQYRV-UHFFFAOYSA-N | |
| InChi Code | InChI=1S/C17H19N5O2/c18-4-7-21-12-1-2-13(22-8-5-19)15-14(12)16(23)10-3-6-20-9-11(10)17(15)24/h1-3,6,9,21-22H,4-5,7-8,18-19H2 | |
| Chemical Name | 6,9-bis(2-aminoethylamino)benzo[g]isoquinoline-5,10-dione | |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | Topoisomerase II | ||
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| ln Vivo |
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| Cell Assay | Following seeding into 96-well plates, cells are exposed to escalating doses of either doxorubicin or pixantrone for a full 72 hours. Subsequently, the cells are treated with MTS reagent and allowed to incubate for an additional 4 hours at 37°C. The absorbance at 490 nm is then used to calculate the rate of cell proliferation. Every data point is compared to untreated cells for normalcy. Every treatment is administered in triplicate and at least three times. | ||
| Animal Protocol |
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Intravenous administration results in a rapid distribution followed by a slow elimination. [2] In ex vivo myocardial strips, pixantrone is taken up to a higher degree than mitoxantrone. In myocardial strips which are doxorubicin naive pixantrone displays higher uptake than in DOX-loaded myocardial strips. DOX clearance causes membrane effects which may be responsible for this observation. DOX clearance involves rapid passive diffusion through one side of the membrane followed by "flip flop" reorientation of the lipid bilayer. This disorganization of lipids is believed to impair membrane penetration by pixantrone. [3] Fecally and renally excreted. Urinary elimination of unchanged drug is less than 10%. [2] 9.7-29.7 L/kg. [2] Plasma clearance is 0.75 - 1.31 L/h/kg. [2] Metabolism / Metabolites Pixantrone does not form secondary alcohol metabolites. [2] Pixantrone hydrolyzes extensively to CT-45886 which is believed to inhibit doxol formation by displacing DOX from the active site of reductases. CT4889 and CT-45890 are also formed.[3] Biological Half-Life Half life ranges from 14.7 to 31.9 hours. |
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| Toxicity/Toxicokinetics |
Protein Binding Anthracyclines, which may be effective second line treatments for NHL have limited use in therapy because of cumulative cardiotoxicity which may result in irreversible damage to cardiac tissue. [2] |
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| References |
[1]. BGP-15 Improves Aspects of the Dystrophic Pathology in mdx and dko Mice with Differing Efficacies in Heart and Skeletal Muscle. Am J Pathol. 2016 Dec;186(12):3246-3260. [2]. The chaperone co-inducer BGP-15 alleviates ventilation-induced diaphragm dysfunction. Sci Transl Med. 2016 Aug 3;8(350):350ra103. [3]. The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice. Nat Commun. 2014 Dec 9;5:5705. [4]. Improvement of insulin sensitivity by a novel drug candidate, BGP-15, in different animal studies. Metab Syndr Relat Disord. 2014 Mar;12(2):125-31. [5]. BGP-15, a PARP-inhibitor, prevents imatinib-induced cardiotoxicity by activating Akt and suppressing JNK and p38 MAP kinases. Mol Cell Biochem. 2012 Jun;365(1-2):129-37. [6]. BGP-15, a nicotinic amidoxime derivate protecting heart from ischemia reperfusion injury through modulation of poly(ADP-ribose) polymerase. Biochem Pharmacol. 2000 Apr 15;59(8):937-45. |
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| Additional Infomation |
Pharmacodynamics Pixantrone has a wide range of antitumor activity, especially in terms of treating leukemias and lymphomas [3]. Pixantrone lacks cardio-toxic effects. It has postulated that his is because of its redox inactivity and lack and inhibition of doxorubicinol formation in human myocardium. [3] |
Solubility Data
| Solubility (In Vitro) |
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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 (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *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). 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)] *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. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL 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). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.0734 mL | 15.3671 mL | 30.7342 mL | |
| 5 mM | 0.6147 mL | 3.0734 mL | 6.1468 mL | |
| 10 mM | 0.3073 mL | 1.5367 mL | 3.0734 mL |