65271-80-9

Basic information

• Product Name: Mitoxantrone
• Synonyms: MITOXANTRONE;1,4-dihydroxy-5,8-bis(2-((2-hydroxyethyl)amino)ethylamino)-9,10-anthracenedi;5,8-bis((2-((2-hydroxyethyl)amino)ethyl)amino)-1,4-dihydroxy-anthraquinon;5,8-bis((2-((2-hydroxyethyl)amino)ethyl)amino)-1,4-dihydroxyanthraquinone;9,10-anthracenedione,1,4-dihydroxy-5,8-bis((2-((2-hydroxyethyl)amino)ethyl)a;dihydroxyanthraquinone;mitoxanthrone;nsc279836
• CAS NO: 65271-80-9
• Molecular Formula: C₂₂H₂₈N₄O₆
• Molecular Weight: 444.48
• EINECS: 1533716-785-6
• Product Categories: Pharmaceutical material and intermeidates;Intermediates & Fine Chemicals;Pharmaceuticals;Anti-cancer&immunity;Inhibitors
• Mol File: 65271-80-9.mol
• Article Data: 11

Chemical Properties

• Melting Point: 170-1740C
• Boiling Point: 554.47°C (rough estimate)
• Flash Point: 441.098 °C
• Appearance: Dark blue crystalline solid
• Density: 1.3049 (rough estimate)
• Vapor Pressure: 2.05E-27mmHg at 25°C
• Refractive Index: 1.6500 (estimate)
• Storage Temp.: -20°C Freezer
• Solubility: DMSO (Slightly), Methanol (Sparingly), Water (Slightly)
• PKA: pKa 5.99 (Uncertain);8.13 (Uncertain)
• CAS DataBase Reference: Mitoxantrone(CAS DataBase Reference)
• NIST Chemistry Reference: Mitoxantrone(65271-80-9)
• EPA Substance Registry System: Mitoxantrone(65271-80-9)

Safety Data

• Hazard Codes: T,T+
• Statements: 46-61-26/27/28
• Safety Statements: 53-36/37/39-45-22
• WGK Germany: 3
• RTECS: CB5748500
• Hazardous Substances Data: 65271-80-9(Hazardous Substances Data)

Usage

Chemical Properties

Dark Blue Crystalline Solid

Originator

Novantrone,Immunex Corporation

Uses

Mitoxantrone is a DNA intercalating drug. Mitoxantrone inhibits DNA synthesis. Mitoxantrone is used as an anti-cancer agent.

Indications

Mitoxantrone (Novantrone) is a synthetic anthraquinone that is structurally and mechanistically related to the anthracyclines. It intercalates with DNA and produces single- strand DNA breakage. It is cross-resistant with doxorubicin in multidrug-resistant cells and in patients who have failed to respond to doxorubicin therapy. Mitoxantrone is active against breast carcinomas, leukemias, and lymphomas. Its antitumor efficacy in patients with breast cancer is slightly lower than that of doxorubicin. Its major toxicity is myelosuppression; mucositis and diarrhea also may occur. Mitoxantrone produces less nausea, alopecia, and cardiac toxicity than does doxorubicin.

Manufacturing Process

A suspension of 12.5 g of 2-(2-aminoethylamino)ethanol in 40 ml of N,N,N',N'-tetramethylethylenediamine is stirred and de-aerated by bubbling nitrogen in for 15 min. A 10.97 g of leuco-1,4,5,8-tetrahydroxyanthraquinone is gradually added with stirring. The suspension is heated and stirred under nitrogen at 50-52°C for 5 hours. The mixture is allowed to stand and cool under nitrogen for 12 hours. The solid is collected by decantation, macerated in ethanol, collected and washed with ethanol giving 15.06 g of the desired product leuco-1,4-bis[2-(2-hydroxyethylamino)ethylamino]-5,8- dihydroxyanthraquinone as a green-gray solid, melting point 129-131°C.Chloranil oxidation. To 17.86 g of a suspension of the leuco-1,4-bis[2-(2- hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone (0.03 mole) in 2- methoxyethanol was added gradually with stirring 15 ml of 8 N ethanolic hydrogen chloride. The system was chilled with an ice bath and stirred as 7.50 g (0.0305 mole) of chloranil powder was gradually added. The mixture was stirred overnight at room temperature and diluted with 600 ml of ether. The solid was collected and washed with tetrahydrofuran. Yield of 1,4-bis[2-(2- hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone dihydrochloride 21.34 g, melting point 203-205°C (without recrystallisation).

Brand name

Novantrone (Serono).

Therapeutic Function

Antineoplastic

Mechanism of action

The mechanism of its action is not completely understood, although it is presumed, that mitoxantrone acts by binding with DNA, thus disturbing the twisting process of the chains. It is used intravenously for treating severe nonlymphatic leukemia, breast cancer, and so on. A synonym of this drug is novantrone.

Clinical Use

#N/A

Synthesis

Mitoxantrone, 1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl) amino) ethyl]amino]]-9,10-anthracendione (30.6.3), is structurally related to the antibiotic doxorubicine. It is synthesized from danthron (1,8-dihydroxyanthraquinone), which when reacted with nitric acid, and then a mixture of sodium sulfide and thiosulfate in a base, is transformed to 1,4,5,8-tetrahydroxyanthraquinone (30.6.2). Reacting this with 2-aminoethylaminoethanol in the presence of chloranyl (2,3,5,6-tetrachlorobenzoquinone-1,4) gives the desired mitoxantrone (30.6.3),

Veterinary Drugs and Treatments

Mitoxantrone may be useful in the treatment of several neoplastic diseases in dogs and cats, including lymphosarcoma mammary adenocarcinoma, squamous cell carcinoma, renal adenocarcinoma, fibroid sarcoma, thyroid or transitional cell carcinomas, and hemangiopericytoma. Because renal clearance of the drug is minimal (10%), it may be administered to cats with renal insufficiency much more safely than doxorubicin.

Drug interactions

Potentially hazardous interactions with other drugs Other antineoplastic agents: enhanced myelosuppression - when used in combination reduce mitoxantrone dose by 2-4 mg/m2. Antipsychotics: avoid with clozapine, increased risk of agranulocytosis. Cardiotoxic drugs: increased risk of cardiac toxicity. Ciclosporin: excretion of mitoxantrone reduced. Live vaccines: risk of generalised infections - avoid.

Metabolism

Extensive metabolism in the liver. Excretion is predominantly via the bile and faeces. 5-10% of a dose is excreted in the urine and 13-25% in the faeces, within 5 days

InChI:InChI=1/C22H28N4O6/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

Synthetic route

1,4-Difluoro-5,8-dihydroxyanthracene-9,10-dione (131401-54-2) + 2-(2-Aminoethylamino)ethanol (111-41-1) → novantrone (65271-80-9)

Conditions	Yield
With pyridine	38%

1,4,5,8-tetrahydroxy-2,3-dihydro-9,10-anthracenedione (81-59-4) + 2-(2-Aminoethylamino)ethanol (111-41-1) → novantrone (65271-80-9)

Conditions	Yield
In 1,4-dioxane at 53℃; for 2.2h; Temperature; Inert atmosphere;	38%

1,4-Difluoro-5,8-dihydroxyanthracene-9,10-dione (131401-54-2) + 2-(2-Aminoethylamino)ethanol (111-41-1) → novantrone (65271-80-9) + 6-Fluoro-8,11-dihydroxy-4-(2-hydroxy-ethyl)-1,2,3,4-tetrahydro-1,4-diaza-benzo[a]anthracene-7,12-dione (134529-38-7)

Conditions	Yield
In pyridine for 50h; Ambient temperature;	A 30% B 11%

5,8-Dihydroxy-1,4-bis-[2-(2-hydroxy-ethylamino)-ethylamino]-2,3-dihydro-anthraquinone (70476-74-3) → novantrone (65271-80-9)

Conditions	Yield
With chloranil In 2-methoxy-ethanol

Daunorubicin+ Mitoxantrone → DNR (20830-81-3) + novantrone (65271-80-9)

Conditions	Yield
In water-d2 at 44.85℃; pH=7.1; Equilibrium constant;

novantrone (65271-80-9) → 8,11-dihydroxy-4-(2-hydroxyethyl)-6-[[2-[(2-hydroxyethyl)amino]ethyl]amino]-1,2,3,4,7,12-hexahydronaphtho-[2,3-f]-chinoxaline-7,12-dione

Conditions	Yield
With potassium hydroxide In methanol for 5h; Heating;	85%
With potassium hydroxide In methanol for 1h; Heating;	82%
With sodium nitrite In water Kinetics; Further Variations:; pH-values; Oxidation;

UDP-glucose (133-89-1) + novantrone (65271-80-9) → mitoxantrone-4'-β-D-glucoside (1295578-41-4)

Conditions	Yield
With OleD ASP enzyme In dimethyl sulfoxide at 20℃; for 27h; pH=8; aq. buffer; Enzymatic reaction;	33%

DNR (20830-81-3) + novantrone (65271-80-9) → Daunorubicin+ Mitoxantrone

Conditions	Yield
In water-d2 at 44.85℃; pH=7.1; Equilibrium constant; Thermodynamic data;

novantrone (65271-80-9) → 1,4-Bis[2-[N-(2-hydroxyethyl)trifluoroacetamido]-ethylamino]-5,8-dihydroxyanthraquinone

Conditions	Yield
In methanol; ethyl trifluoroacetate,
In methanol; ethyl trifluoroacetate,

novantrone (65271-80-9) → C22H24N4O7 + C22H22N4O8 + C22H22N4O7 + 8,11-dihydroxy-4-(2-hydroxyethyl)-6-[[2-[(2-hydroxyethyl)amino]ethyl]amino]-1,2,3,4,7,12-hexahydronaphtho-[2,3-f]-chinoxaline-7,12-dione

Conditions	Yield
With dihydrogen peroxide; horseradish peroxidase at 20℃; for 48h; pH=7.2; aq. phosphate buffer; Enzymatic reaction;

novantrone (65271-80-9) + C66H80N20O24 → C66H80N20O24*C22H28N4O6

Conditions	Yield
In aq. phosphate buffer pH=7.5;

di-tert-butyl dicarbonate (24424-99-5) + novantrone (65271-80-9) → C32H44N4O10

Conditions	Yield
With sodium carbonate In 1,4-dioxane; water at 20℃; for 12h;	435 mg

cyano-4-[(ethylsulfanylthiocarbonyl)sulfanyl]-4-methylbutanoic acid (1137725-46-2) + novantrone (65271-80-9) → C40H50N6O8S6

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide at 30℃; for 24h;

novantrone (65271-80-9) → novantrone (70476-82-3)

Conditions	Yield
With hydrogenchloride In water at 52 - 60℃; for 0.5h; pH=Ca. 2.8 - 3; Temperature; Inert atmosphere;	6.4 g

Upstream product

• 81-59-4 1,4,5,8-tetrahydroxy-2,3-dihydro-9,10-anthracenedione 
• 111-41-1 2-(2-Aminoethylamino)ethanol 
• 131401-54-2 1,4-Difluoro-5,8-dihydroxyanthracene-9,10-dione 
• 70476-74-3 5,8-Dihydroxy-1,4-bis-[2-(2-hydroxy-ethylamino)-ethylamino]-2,3-dihydro-anthraquinone 

Downstream Products

• 70476-82-3 novantrone 

Relevant articles and documents

Exploring the Effects of Glycosylation and Etherification of the Side Chains of the Anticancer Drug Mitoxantrone

Herein we report the synthesis and biological evaluation of symmetric and asymmetric analogues of the DNA intercalating drug mitoxantrone (MTX) in which the side chains of the parent drug were modified through glycosylation or methyl etherification. Several analogues with glycosylated side chains exhibited higher DNA affinity than the parent MTX. The most potent in vitro cytotoxicity was observed for MTX analogue 8 (1,4-dimethoxy-5,8-bis[2-(2-methoxyethylamino)ethylamino]anthracene-9,10-dione) with methoxy ether containing side chains. Treatment of melanoma-bearing mice with MTX or analogue 8 decreased the intraperitoneal tumor burden relative to untreated mice; the effect of 8 was less pronounced than that of MTX. In vitro metabolism assays of MTX with rabbit liver S9 fraction gave rise to several metabolites; almost no metabolites were detected for MTX analogue 8. The results presented indicate that derivatization of the MTX side chain primary hydroxy groups may result in a significant improvement in DNA affinity and lower susceptibility to the formation of potentially toxic metabolites.

THERAPEUTIC FOR HEPATIC CANCER

A novel pharmaceutical composition for treating or preventing hepatocellular carcinoma and a method of treatment are provided. A pharmaceutical composition for treating or preventing liver cancer is obtained by combining a chemotherapeutic agent with an anti-glypican 3 antibody. Also disclosed is a pharmaceutical composition for treating or preventing liver cancer which comprises as an active ingredient an anti-glypican 3 antibody for use in combination with a chemotherapeutic agent, or which comprises as an active ingredient a chemotherapeutic agent for use in combination with an anti-glypican 3 antibody. Using the chemotherapeutic agent and the anti-glypican 3 antibody in combination yields better therapeutic effects than using the chemotherapeutic agent alone, and mitigates side effects that arise from liver cancer treatment with the chemotherapeutic agent.

1H NMR structural and thermodynamical analysis of the hetero-association of daunomycin and novatrone in aqueous solution

The complexation of antitumour antibiotics novatrone (NOV) and daunomycin (DAU) in aqueous solution has been studied by one- and two-dimensional 1H-NMR spectroscopy (500 MHz) in order to elucidate the probable molecular mechanism of the action