Mitomycin


Mitomycin
Mitomycin
Identifiers
CAS number 50-07-7 YesY
PubChem 5746 YesY, 44286993 (7RYesY, 16757880 (7SYesY
ChemSpider 5544 YesY, 23136133 (7RYesY
UNII 50SG953SK6 YesY
DrugBank DB00305
KEGG C06681 YesY
ChEBI CHEBI:27504 YesY
ChEMBL CHEMBL105 YesY
ATC code L01DC03
Beilstein Reference 3570056
3DMet B02086
Jmol-3D images Image 1
Image 2
Properties
Molecular formula C15H18N4O5
Molar mass 334.33 g mol−1
Exact mass 334.127719706 g mol-1
Appearance White or colourless solid
Melting point

360 °C, 633 K, 680 °F (low of range)

Solubility in water 8.43 g L-1
log P -1.6
Isoelectric point 10.9
Pharmacology
Routes of
administration
Eye drops Intravenous
Metabolism Hepatic
Elimination
half-life
8–48 min
Legal status

POM(UK) -only(US)

Pregnancy
category
D(AU) D(US)
 YesY (verify) (what is: YesY/N?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

The mitomycins are a family of aziridine-containing natural products isolated from Streptomyces caespitosus or Streptomyces lavendulae.[1] One of these compounds, mitomycin C, finds use as a chemotherapeutic agent by virtue of its antitumour antibiotic activity. It is given intravenously to treat upper gastro-intestinal (e.g. esophageal carcinoma), anal cancers, and breast cancers, as well as by bladder instillation for superficial bladder tumours. It causes delayed bone marrow toxicity and therefore it is usually administered at 6-weekly intervals. Prolonged use may result in permanent bone-marrow damage. It may also cause lung fibrosis and renal damage.

Mitomycin C has also been used topically rather than intravenously in several areas. The first is cancers, particularly bladder cancers and intraperitoneal tumours. It is now well known that a single instillation of this agent within 6 hours of bladder tumor resection can prevent recurrence. The second is in eye surgery where mitomycin c 0.02% is applied topically for 20 seconds to prevent haze after PRK or superlasik. The third is in esophageal and tracheal stenosis where application of mitomycin C onto the mucosa immediately following dilatation will decrease re-stenosis by decreasing the production of fibroblasts and scar tissue.

Mechanism of Action

Mitomycin C is a potent DNA crosslinker. A single crosslink per genome has shown to be effective in killing bacteria. This is accomplished by reductive activation followed by two N-alkylations. Both alkylations are sequence specific for a guanine nucleoside in the sequence 5'-CpG-3'.[2] Potential bis-alkylating heterocylic quinones were synthetised in order to explore their antitumoral activities by bioreductive alkylation.[3] Mitomycin is also used as a chemetherapeutic agent in Glaucoma Surgery

Biosynthesis

In general, the biosynthesis of all mitomycins[4] proceeds via combination of 3-amino-5-hydroxybenzoic acid (AHBA), D-glucosamine, and carbamoyl phosphate, to form the mitosane core, followed by specific tailoring steps. The key intermediate, AHBA, is a common precursor to other anticancer drugs, such as rifamycin and ansamycin.

Specifically, the biosynthesis begins with the addition of phosphoenolpyruvate (PEP) to erythrose-4-phosphate (E4P) with a yet undiscovered enzyme, which is then ammoniated to give 4-amino-3-deoxy-D-arabino heptulosonic acid-7-phosphate (aminoDHAP). Next, DHQ synthase catalyzes a ring closure to give 4-amino3-dehydroquinate (aminoDHQ), which is then undergoes a double oxidation via aminoDHQ dehydratase to give 4-amino-dehydroshikimate (aminoDHS). The key intermediate, 3-amino-5-hydroxybenzoic acid (AHBA), is made via aromatization by AHBA synthase.

Mitomycin c AHBA.gif

Synthesis of the key intermediate, 3-amino-5-hydroxy-benzoic acid.

The mitosane core is synthesized as shown below via condensation of AHBA and D-glucosamine, although no specific enzyme has been characterized that mediates this transformation. Once this condensation has occurred, the mitosane core is tailored by a variety of enzymes. Unfortunately, both the sequence and the identity of these steps are yet to be determined.

  • Complete reduction of C-6 - Likely via F420-dependent tetrahydromethanopterin (H4MPT)) reductase and H4MPT:CoM methyltransferase
  • Hydroxylation of C-5, C-7 (followed by transamination), and C-9a. - Likely via cytochrome P450 monooxygenase or benzoate hydroxylase
  • O-Methylation at C-9a - Likely via SAM dependent methyltransferase
  • Oxidation at C-5 and C8 - Unknown
  • Intramolecular amination to form aziridine - Unknown
  • Carbamoylation at C-10 - Carbamoyl transferrase, with carbamoyl phosphate (C4P) being derived from L-citrulline or L-arginine

Mitomycin c tailoring.gif

References

  1. ^ Danshiitsoodol N, de Pinho CA, Matoba Y, Kumagai T, Sugiyama M (2006). "The mitomycin C (MMC)-binding protein from MMC-producing microorganisms protects from the lethal effect of bleomycin: crystallographic analysis to elucidate the binding mode of the antibiotic to the protein". J Molec Biol 360 (2): 398–408. doi:10.1016/j.jmb.2006.05.017. PMID 16756991. 
  2. ^ Tomasz, Maria (September 1995). "Mitomycin C: small, fast and deadly (but very selective).". Chemistry and Biology 2 (9): 575–579. doi:10.1016/1074-5521(95)90120-5. PMID 9383461. 
  3. ^ Renault, J.; Baron, M; Mailliet P. & al. Heterocyclic quinones.2.Quinoxaline-5,6-(and 5-8)-diones - Potential antitumoral agents. Eur. J. Med. Chem. 16, 6, 545–550, 1981.
  4. ^ Mao Y.; Varoglu M.; Sherman D.H. (April 1999). "Molecular characterization and analysis of the biosynthetic gene cluster for the antitumor antibiotic mitomycin C from Streptomyces Iavendulae NRRL 2564.". Chemistry and Biology 6 (4): 251–263. doi:10.1016/S1074-5521(99)80040-4. PMID 10099135. 

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Look at other dictionaries:

  • Mitomycin — Strukturformel Allgemeines Freiname Mitomycin Andere Namen …   Deutsch Wikipedia

  • mitomycin — Antibiotic produced by Streptomyces caespitosus, variants of which are designated m. A, m. B, etc.; m. C is an antineoplastic agent and a bacteriocide; inhibits DNA synthesis. * * * mi·to·my·cin .mīt ə mīs ən n 1) a complex of antibiotic… …   Medical dictionary

  • mitomycin C — Aziridine antibiotic isolated from Streptomyces caespitosus. Inhibits DNA synthesis by cross linking the strands and is used as an anti neoplastic agent. Most active in late G1 and early S phase. Mitomycin treated cells are sometimes used as… …   Dictionary of molecular biology

  • mitomycin — an anthracycline antibiotic that inhibits the growth of cancer cells. Administered by injection or bladder instillation, it causes severe marrow suppression but is of use in the treatment of stomach, breast, and bladder cancers. Trade names:… …   The new mediacal dictionary

  • mitomycin — noun Etymology: International Scientific Vocabulary mito (probably from New Latin mitosis) + mycin Date: 1956 a complex of antibiotic substances that is produced by a Japanese streptomyces (Streptomyces caespitosus); especially one form… …   New Collegiate Dictionary

  • mitomycin — mi·to·my·cin (mī tə mīʹsĭn) n. Any of a group of antibiotics produced by the soil actinomycete Streptomyces caespitosus that inhibit DNA synthesis and are used against bacteria and cancerous tumor cells.   [Probably mitosis + mycin.] * * * …   Universalium

  • mitomycin — noun Any of a family of aziridine containing natural products isolated from the filamentous bacterium Streptomyces lavendulae, one of which is used as a chemotherapeutic agent …   Wiktionary

  • Mitomycin — Mi|to|my|cin [... tsi:n] u. Mi|to|my|zin das; s, e Kurzw. aus ↑Mitoseu. ↑Streptomycin> (vor allem in der Krebstherapie angewendetes) ↑zytostatischwirksames ↑Antibiotikum …   Das große Fremdwörterbuch

  • mitomycin — mi·to·my·cin …   English syllables

  • mitomycin — An anticancer drug that belongs to the family of drugs called antitumor antibiotics …   English dictionary of cancer terms


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