65271-80-9

Usage

Uses

Used in Oncology:
Mitoxantrone is used as an anti-cancer agent for the treatment of various malignancies, including acute myeloid leukemia, multiple myeloma, and advanced prostate cancer. Its ability to intercalate into DNA and inhibit topoisomerase II activity results in the suppression of tumor growth and progression, offering a therapeutic option for patients with these life-threatening conditions.
Used in Drug Development:
Mitoxantrone's unique mechanism of action also makes it a valuable compound in the development of novel anticancer drugs. Researchers are exploring its potential in combination therapies and the development of new drug delivery systems to enhance its efficacy and reduce side effects, further expanding its applications in cancer treatment.

Originator

Novantrone,Immunex Corporation

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).

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

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

Downstream Products

• 70476-82-3 novantrone 

Relevant academic research and scientific papers

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.

Semi-synthesis method for mitoxantrone

The invention discloses a semi-synthesis method for mitoxantrone. The semi-synthesis method is characterized in that bulk pharmaceutical chemicals are synthesized through one-step process, and a follow-up refining process is performed to obtain a mitoxantrone hydrochloride drug. The semi-synthesis method is simple in synthesis step, is short in synthesis period, is gentle in reaction condition andis high in product yield.

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.

Anti-Claudin 3 Monoclonal Antibody and Treatment and Diagnosis of Cancer Using the Same

Monoclonal antibodies that bind specifically to Claudin 3 expressed on cell surface are provided. The antibodies of the present invention are useful for diagnosis of cancers that have enhanced expression of Claudin 3, such as ovarian cancer, prostate cancer, breast cancer, uterine cancer, liver cancer, lung cancer, pancreatic cancer, stomach cancer, bladder cancer, and colon cancer. The present invention provides monoclonal antibodies showing cytotoxic effects against cells of these cancers. Methods for inducing cell injury in Claudin 3-expressing cells and methods for suppressing proliferation of Claudin 3-expressing cells by contacting Claudin 3-expressing cells with a Claudin 3-binding antibody are disclosed. The present application also discloses methods for diagnosis or treatment of cancers.

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

Compositions and methods for coating medical implants

Medical implants are provided which release an anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, and/or platinum complex, thereby inhibiting or reducing the incidence of infection associated with the implant.

Synthesis and Antitumor Evaluations of Symmetrically and Unsymmetrically Substituted 1,4-Bisanthracene-9,10-diones and 1,4-Bis-5,8-dihydroxyanthracene-9,10-diones

The ipso bis displacements of fluoride from 1,4-difluoroanthracene-9,10-dione (3) and 1,4-difluoro-5,8-dihydroxyanthracene-9,10-dione (4) by excess of a diamine (or a monoamine) in pyridine at room temperature lead to the symmetrically substituted 1,4-bis-substituted analogues 5 and 6, respectively.The ipso monodisplacements of fluoride from 3 and 4 can be accomplished by treatment with less than 1 molar equiv of a diamine (or a monoamine) to yield 7 and 8, respectively.Treatment of 7 or 8 with a different diamine leads to the unsymmetrically substituted1,4-bisanthracene-9,10-diones 9 and 10, respectively.Many of the synthetic unsymmetrical analogues have been evaluated for their antitumor activity against L1210 in vitro and in vivo.Cross resistance of analogue 10a with mitoxantrone (2) and doxorubicin was evaluated against MDR lines in vitro against human colon carcinoma LOVO and its subline resistant to DOXO (LOVO/DOXO).Potential mechanisms for the observed cytotoxicity are presented and discussed.

Novel 1,4-bis(substituted-amino(-5,8-dihydroxyanthraquinones and leuco bases thereof

This disclosure describes symmetrical 1,4-bis(substituted-amino)-5,8-dihydroxyanthraquinones useful as chelating agents and for inducing regression and/or palliation of cancer diseases in mammals.

Polymeric[[(oxazolidinyl)alkyl]amino]anthraquinones

This disclosure describes novel polymeric 1,4-bis-[(1,3-oxazolidin-3-yl)alkylamino]anthraquinones prepared by condensation of 1,4-bis-[(2-hydroxyalkylamino)alkylamino]anthraquinones with dialdehydes which are useful as anti-cancer agents.

Metal chelates of 1,4-bis(substituted-amino-5,8-dihydroxy-anthraquinones

This disclosure describes metal chelates of symmetrical 1,4-bis(substituted-amino)-5,8-dihydroxy-anthraquinones useful for inhibiting the growth of tumors and as colorants or dyes.