Mitomycin
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Mitomycin
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| 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 | |
| ATC code | L01 |
| PubChem | |
| DrugBank | |
| 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. | |
| Legal status | |
| 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.
Mitomycin C has also been used topically rather than intravenously in several areas. The first is cancers, particularly bladder cancers and intraperitoneal tumours. The second is in eye surgery and 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.
[edit] 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]
[edit] 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.
[edit] References
- ^ Tomasz, Maria (September 1995). "Mitomycin C: small, fast and deadly (but very selective).". Chemistry and Biology 2 (9): 575–579. doi:.
- ^ 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:.
- 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.
