Mitomycin

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Mitomycin
Stereo wireframe model of (4S,6S,7R,8S)-mitomycin
style="background: #F8EABA; text-align: center;" colspan="2" | Identifiers
CAS number 50-07-7 YesY
PubChem 351727 YesY, 44286993 (7RYesY, 16757880 (7SYesY
ChemSpider 312291 YesY, 23136133 (7RYesY
DrugBank DB00305
KEGG C06681
ChEBI 27504
ATC code L01DC03
SMILES Script error: No such module "collapsible list".
InChI Script error: No such module "collapsible list".
InChI key NWIBSHFKIJFRCO-UHFFFAOYS

A-N

Beilstein Reference 3570056
3DMet B02086
style="background: #F8EABA; text-align: center;" colspan="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
style="background: #F8EABA; text-align: center;" colspan="2" | 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 (what is this?)  (verify)
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]

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.

File: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

File:Mitomycin c tailoring.gif

References

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de:Mitomycin

fa:میتومایسین fr:Mitomycine C ko:미토마이신 he:מיטומיצין hu:Mitomicin ja:マイトマイシンC pl:Mitomycyna

zh:丝裂霉素C
  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. 
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  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.
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