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Mitoxantrone

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Mitoxantrone
File:Mitoxantrone skeletal.svg
File:Mitoxantrone ball-and-stick.png
Systematic (IUPAC) name
1,4-dihydroxy-5,8-bis[2-(2-hydroxyethylamino)
ethylamino]-anthracene-9,10-dione
Clinical data
Trade names Novantrone
AHFS/Drugs.com monograph
MedlinePlus a608019
  • US: D (Evidence of risk)
  • (Prescription only)
Mainly intravenous
Pharmacokinetic data
Bioavailability n/a
Protein binding 78%
Metabolism Hepatic (CYP2E1)
Half-life 75 hours
Excretion Renal
Identifiers
65271-80-9 7pxY
L01DB07
PubChem CID 4212
DrugBank DB01204 7pxY
ChemSpider 4067 7pxY
UNII BZ114NVM5P 7pxY
KEGG D08224 7pxY
ChEBI CHEBI:50729 7pxY
ChEMBL CHEMBL58 7pxY
PDB ligand ID MIX (PDBe, RCSB PDB)
Chemical data
Formula C22H28N4O6
444.481 g/mol
 14pxY (what is this?)  (verify)

Mitoxantrone (INN, BAN, USAN; also known as Mitozantrone in Australia; trade name Novantrone) is an anthracenedione antineoplastic agent.

Uses

It is used in the treatment of certain types of cancer, mostly metastatic breast cancer, acute myeloid leukemia, and non-Hodgkin's lymphoma. It was also shown to improve the survival of children suffering from first relapse of acute lymphoblastic leukemia.[1]

The combination of mitoxantrone and prednisone is approved as a second-line treatment for metastatic hormone-refractory prostate cancer. This combination has been the first line of treatment, until recently, when combination of docetaxel and prednisone has been shown to improve survival and disease-free period.[2]

Mitoxantrone is also used to treat multiple sclerosis (MS), most notably the subset known as secondary progressive MS. Mitoxantrone will not cure multiple sclerosis, but is effective in slowing the progression of secondary progressive MS and extending the time between relapses in relapsing-remitting MS and progressive relapsing MS.[3]

Side effects

As other drugs in its class, mitoxantrone may cause several adverse reactions of varying severity, such as nausea, vomiting, hair loss, heart damage, and immunosuppression. Some side effects may have delayed onset. Cardiomyopathy is a particularly concerning effect as it is irreversible; regular monitoring with echocardiograms or MUGA scans is recommended for people taking mitoxantrone.

Mitoxantrone carries a limit on the cumulative lifetime dose (based on body surface area) in patients with multiple sclerosis due to the risk of cardiomyopathy.[4]

Mechanism of action

File:4g0v mix.png
Human topoisomerase iibeta in complex with DNA and mitoxantrone. PDB entry 4g0v.[5] Detail showing mitoxantrone (spheres) intercalated with DNA.

Mitoxantrone is a type II topoisomerase inhibitor; it disrupts DNA synthesis and DNA repair in both healthy cells and cancer cells, by intercalation[6] between the DNA bases.

Synthesis

Mitoxantrone can be prepared from quinizarin:[7]

Mitoxantrone, 1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl) amino)ethyl]amino]]-9,10-anthracendione, is structurally related to the anthracycline antibiotic doxorubicin. 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. Reacting this with 2-aminoethylaminoethanol in the presence of chloranyl (2,3,5,6-tetrachlorobenzoquinone-1,4) gives the desired mitoxantrone.

800px
  • F.E. Durr, K.C. Murdock, U.S. Patent 4,197,249 (1980).
  • K.C. Murdock, F.E. Durr, R.G. Child, DE 2835661  (1979).
  • Zee-Cheng, R. K. Y.; Cheng, C. C. (1978). "Antineoplastic agents. Structure-activity relationship study of bis(substituted aminoalkylamino)anthraquinones". Journal of Medicinal Chemistry 21 (3): 291–4. PMID 628005. doi:10.1021/jm00201a012.  edit
  • Murdock, K. C.; Child, R. G.; Fabio, P. F.; Angier, R. D.; Wallace, R. E.; Durr, F. E.; Citarella, R. V. (1979). "Antitumor agents. 1. 1,4-Bis[(aminoalkyl)amino]-9,10-anthracenediones". Journal of Medicinal Chemistry 22 (9): 1024–30. PMID 490545. doi:10.1021/jm00195a002.  edit

See also

References

  1. ^ Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, Ancliff P, Morgan M, Masurekar A, Goulden N, Green N, Révész T, Darbyshire P, Love S, Saha V (2010). "Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial". Lancet 376 (9757): 2009–2017. PMC 3010035. PMID 21131038. doi:10.1016/S0140-6736(10)62002-8. 
  2. ^ Katzung, Bertram G. (2006). "Cancer Chemotherapy". Basic and clinical pharmacology (10th ed.). New York: McGraw-Hill Medical Publishing Division. ISBN 0-07-145153-6. OCLC 157011367. 
  3. ^ Fox E (2006). "Management of worsening multiple sclerosis with mitoxantrone: a review". Clin Ther 28 (4): 461–74. PMID 16750460. doi:10.1016/j.clinthera.2006.04.013. 
  4. ^ "Mitoxantrone Hydrochloride (marketed as Novantrone and generics) - Healthcare Professional Sheet text version". U.S. Food and Drug Administration. Retrieved 19 September 2014. 
  5. ^ Wu, C. -C.; Li, Y. -C.; Wang, Y. -R.; Li, T. -K.; Chan, N. -L. (2013). "On the structural basis and design guidelines for type II topoisomerase-targeting anticancer drugs". Nucleic Acids Research 41 (22): 10630–10640. PMID 24038465. doi:10.1093/nar/gkt828.  edit
  6. ^ Mazerski J, Martelli S, Borowski E (1998). "The geometry of intercalation complex of antitumor mitoxantrone and ametantrone with DNA: molecular dynamics simulations". Acta Biochim. Pol. 45 (1): 1–11. PMID 9701490. 
  7. ^ Murdock, K. C.; Child, R. G.; Fabio, P. F.; Angier, Robert D.; Wallace, Roslyn E.; Durr, Frederick E.; Citarella, R. V. (1979). "Antitumor agents. 1. 1,4-Bis[(aminoalkyl)amino]-9,10-anthracenediones". Journal of Medicinal Chemistry 22 (9): 1024–30. PMID 490545. doi:10.1021/jm00195a002. 
  8. ^ Baron M, Giorgi-Renault S, Renault J et al. (1984). "Heterocycles with a quinone function.5.An abnormal reaction of butanedione with 1,2-diaminoanthraquinone - Crystalline structure obtained from naphto(2,3-f) quinoxaline-7,12 dione". Can. J. Chem. (in French) 62 (3): 526–530. doi:10.1139/v84-087.