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Mitoxantrone HCl (formerly NSC-301739; NSC301739; DHAQ; CL-232325; Mitroxone; Neotalem; Onkotrone; Pralifan; Novantrone), the hydrochloride salt of Mitoxantrone which is an anthracenedione anticancer agent, is a potent type II topoisomerase inhibitor with potential antitumor activity. It has an IC50 of 2.0 μM in HepG2 and 0.42 mM in MCF-7/wt cells for TOPO II inhibition. It is a confirmed treatment for multiple sclerosis and an anti-neoplastic for leukemia and other cancers. By preventing DNA synthesis and the division of cells, mitoxantrone suppressed leukemia. It impacted several immune cells, including macrophages, T cells, and B cells, among others. Numerous DSBs (DNA strand breaks), chromatin structure alterations, and other events were caused by its interference with TOPO-II-mediated DNA cleavage.
Physicochemical Properties
| Molecular Formula | C22H29CLN4O6.HCL |
| Molecular Weight | 517.4 |
| Exact Mass | 516.154 |
| Elemental Analysis | C, 51.07; H, 5.84; Cl, 13.70; N, 10.83; O, 18.55 |
| CAS # | 70476-82-3 |
| Related CAS # | 65271-80-9; 70476-82-3 (HCl salt); 70711-41-0 (diacetate) |
| PubChem CID | 4212 |
| Appearance | Black solid powder |
| Boiling Point | 805.7ºC at 760 mmHg |
| Melting Point | 203-205ºC |
| Flash Point | 441.1ºC |
| LogP | 2.392 |
| Hydrogen Bond Donor Count | 8 |
| Hydrogen Bond Acceptor Count | 10 |
| Rotatable Bond Count | 12 |
| Heavy Atom Count | 32 |
| Complexity | 571 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | Cl[H].Cl[H].O=C1C2=C(C([H])=C([H])C(=C2C(C2=C(C([H])=C([H])C(=C21)N([H])C([H])([H])C([H])([H])N([H])C([H])([H])C([H])([H])O[H])N([H])C([H])([H])C([H])([H])N([H])C([H])([H])C([H])([H])O[H])=O)O[H])O[H] |
| InChi Key | ZAHQPTJLOCWVPG-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C22H28N4O6.2ClH/c27-11-9-23-5-7-25-13-1-2-14(26-8-6-24-10-12-28)18-17(13)21(31)19-15(29)3-4-16(30)20(19)22(18)32;;/h1-4,23-30H,5-12H2;2*1H |
| Chemical Name | 1,4-dihydroxy-5,8-bis[2-(2-hydroxyethylamino)ethylamino]anthracene-9,10-dione;dihydrochloride |
| Synonyms | NSC-301739; CL-232325; NSC301739; CL 232325; NSC 301739; DHAQ; CL232325; Mitozantrone; Mitoxantrone HCl; Mitoxantrone dihydrchloride; US brand name: Novantrone. NSC 301739; DHAQ; CL232325; Foreign brand names: Mitroxone; Neotalem; Onkotrone; Pralifan |
| 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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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 | PKC ( IC50 = 8.5 μM ); Topoisomerase II | ||
| ln Vitro |
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| ln Vivo |
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| Enzyme Assay | Mitoxantrone inhibits PKC in a non-competitive manner with respect to phosphatidylserine and ATP, but in a competitive manner with respect to histone H1, where its Ki value is 6.3 μM. Cell viability is reduced when B-CLL cells are treated with mitoxantrone (0.5 μg/mL) for 48 hours. Poly(ADP-ribose) polymerase (PARP) is subjected to proteolytic cleavage and DNA fragmentation upon induction by mitoxantrone, indicating that the cytotoxic effect of the drug is a result of apoptosis induction. Human breast carcinoma cell lines MDA-MB-231 and MCF-7 exhibit cytotoxicity to mitoxantrone, with IC50 values of 18 and 196 nM, respectively. | ||
| Cell Assay | In standard 96-well plates, the human breast carcinoma cell lines MDA-MB-231 and MCF-7 are seeded. The culture medium is swapped out for one containing varying concentrations of mitoxantrone (10-5 to 5 μM) with or without DHA (30 μM) for a period of seven days following seeding. The tetrazolium salt assay is used to determine the overall viability of cells. | ||
| Animal Protocol |
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Poorly absorbed following oral administration 1000 L/m2 21.3 L/hr/m2 [Elderly patients with breast cancer receiving IV administration of 15-90 mg/m2] 28.3 L/hr/m2 [Non-elderly patients with nasopharyngeal carcinoma receiving IV administration of 15-90 mg/m2] 16.2 L/hr/m2 [Non-elderly patients with malignant lymphoma receiving IV administration of 15-90 mg/m2] Metabolism / Metabolites Hepatic Hepatic Half Life: 75 hours Biological Half-Life 75 hours |
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| Toxicity/Toxicokinetics |
Toxicity Summary Mitoxantrone, a DNA-reactive agent that intercalates into deoxyribonucleic acid (DNA) through hydrogen bonding, causes crosslinks and strand breaks. Mitoxantrone also interferes with ribonucleic acid (RNA) and is a potent inhibitor of topoisomerase II, an enzyme responsible for uncoiling and repairing damaged DNA. It has a cytocidal effect on both proliferating and nonproliferating cultured human cells, suggesting lack of cell cycle phase specificity. Hepatotoxicity Chemotherapy with mitoxantrone alone is associated with serum enzyme elevations in up to 40% of patients, but these elevations are generally mild-to-moderate in severity, transient and not accompanied by symptoms or jaundice. Higher rates of liver enzyme elevations have been reported with combination chemotherapeutic regimens that include mitoxantrone. In high doses, mitoxantrone has been associated with a high rate of jaundice, but the degree of hyperbilirubinemia has been mild, transient and not associated with significant serum enzyme elevations or evidence of hepatitis. Rare instances of acute liver injury have been reported in patients taking mitoxantrone, including a single case of drug-rash with eosinophilia and systemic symptoms (DRESS). The latency to onset was 8 weeks and the pattern of serum enzyme elevations was cholestatic and later mixed. Immunoallergic features were prominent and appeared to respond to corticosteroid therapy. Other drugs were being taken and the association with mitoxantrone was not definite (Case 1). Thus, idiosyncratic and clinically apparent liver injury from mitoxantrone may occur but is quite rare. Likelihood score: D (possible rare cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy, such as mitoxantrone. It might be possible to breastfeed safely during intermittent therapy with an appropriate period of breastfeeding abstinence, but the duration of abstinence is not clear. In one patient, mitoxantrone was still detectable in milk 28 days after a dose of 6 mg per square meter. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk. Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant. ◉ Effects in Breastfed Infants One mother received 3 daily doses of 6 mg/sq. m. of mitoxantrone intravenously along with 5 daily doses of etoposide 80 mg/sq. m. and cytarabine 170 mg/sq. m. intravenously. She resumed breastfeeding her infant 3 weeks after the third dose of mitoxantrone at a time when mitoxantrone was still detectable in milk. The infant had no apparent abnormalities at 16 months of age. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding 78% |
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| References |
[1]. Antiviral Res. 2011 Dec 11;93(2):305–308. Inhibition of cowpox virus and monkeypox virus infection by mitoxantrone [2]. Mechanism of action of mitoxantrone. Neurology.2004 Dec 28;63(12 Suppl 6):S15-8. |
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| Additional Infomation |
Pharmacodynamics Mitoxantrone has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation and impair antigen presentation, as well as the secretion of interferon gamma, TNFa, and IL-2. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.83 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 25.0 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: ≥ 2.5 mg/mL (4.83 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 25.0 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. Solubility in Formulation 3: Saline: 30 mg/mL Solubility in Formulation 4: 2 mg/mL (3.87 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C). (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9327 mL | 9.6637 mL | 19.3274 mL | |
| 5 mM | 0.3865 mL | 1.9327 mL | 3.8655 mL | |
| 10 mM | 0.1933 mL | 0.9664 mL | 1.9327 mL |