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Mitomycin



Mitomycin
Systematic (IUPAC) name
6-Amino-1,1a,2,8,8a,8b-hexahydro-8- (hydroxymethyl)- 8a-methoxy-5-methyl-azirino[2', 3':3,4] pyrrolo[1,2-a]indole-4,7-dione carbamate (ester)
Identifiers
CAS number 50-07-7
ATC code L01DC03
PubChem 5746
DrugBank APRD00284
Chemical data
Formula C15H18N4O5 
Mol. mass 334.327 g/mol
Pharmacokinetic data
Bioavailability  ?
Metabolism Hepatic
Half life 8-48 min
Excretion  ?
Therapeutic considerations
Pregnancy cat.

D (Au, U.S.)

Legal status

℞-only (U.S.), POM (UK)

Routes [Intravenous therapy

The mitomycins are a family of aziridine-containing natural products isolated from Streptomyces lavendulae. 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) 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.

Additional recommended knowledge

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'.[1]

Biosynthesis

In general the biosynthesis of all mitomycins [2] proceed 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.


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


Formation of mitosane core followed by tailoring specific to Mitomycin C.

References

  1. ^ Tomasz, Maria (September 1995). "Mitomycin C: small, fast and deadly (but very selective).". Chemistry and Biology 2 (9): 575-579.
  2. ^ 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.
  • Hata, T.; Sano, Y.; Sugawara, R.; Matsumae, A.; Kanamori, K.; Shima, T.; Hoshi, T. J. Antibiot. Ser. A 1956, 9, 141-146.
  • Fukuyama, T.; Yang, L. "Total Synthesis of (±)-Mitomycins via Isomitomycin A." J. Am. Chem. Soc. 1987, 109, 7881-7882.
  • Mao, Y.; Varoglu, M.; Sherman, D.H. "Molecular characterization and analysis of the biosynthetic cluster for the antitumor antibiotic mitomycin C from Streptomyces lavendulae NRRL 2564." Chemistry & Biology 1999, 6, 251-263.
  • Varoglu, M.; Mao, Y.; Sherman, D.H. "Mapping the Biosynthetic Pathway by Functional Analysis of the MitM Aziridine N-Methyltransferase." J. Am. Chem. Soc. 2001, 123, 6712-6713 and references therein.
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Mitomycin". A list of authors is available in Wikipedia.
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