Mitomycins

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Mitomycins
Stereo wireframe model of (4S,6S,7R,8S)-mitomycin
Mitomycin ball-and-stick.png
Names
IUPAC name
{11-Amino-7-methoxy-12-methyl-10,13-dioxo-2,5-diazatetracyclo[7.4.0.02,7.04,6]trideca-1(9),11-dien-8-yl}methyl carbamate
Preferred IUPAC name
[6-Amino-8a-methoxy-5-methyl-4,7-dioxo-1,1a,2,4,7,8,8a,8b-octahydroazireno[2',3':3,4]pyrrolo[1,2-a]indol-8-yl]methyl carbamate
Other names
Mitomycin C
Identifiers
50-07-7 YesY
3DMet B02086
3570056
ChEBI CHEBI:27504 YesY
ChEMBL ChEMBL105 YesY
ChemSpider 5544 YesY
23136133 (7R) N
DrugBank DB00305 YesY
7089
Jmol 3D model Interactive image
Interactive image
KEGG C06681 YesY
PubChem 5746
44286993 (7R)
16757880 (7S)
UNII 50SG953SK6 YesY
  • InChI=1S/C15H18N4O5/c1-5-9(16)12(21)8-6(4-24-14(17)22)15(23-2)13-7(18-13)3-19(15)10(8)11(5)20/h6-7,13,18H,3-4,16H2,1-2H3,(H2,17,22)/t6-,7+,13+,15-/m1/s1 YesY
    Key: NWIBSHFKIJFRCO-WUDYKRTCSA-N YesY
  • InChI=1S/C15H18N4O5/c1-5-9(16)12(21)8-6(4-24-14(17)22)15(23-2)13-7(18-13)3-19(15)10(8)11(5)20/h6-7,13,18H,3-4,16H2,1-2H3,(H2,17,22)/t6-,7+,13+,15-/m1/s1
  • Key: NWIBSHFKIJFRCO-WUDYKRTCSA-N
  • COC12C3NC3CN1C1=C(C2COC(N)=O)C(=O)C(N)=C(C)C1=O
  • CC1=C(C(=O)C2=C(C1=O)N3C[C@H]4[C@@H]([C@@]3([C@@H]2COC(=O)N)OC)N4)N
Properties
C15H18N4O5
Molar mass 334.33 g·mol−1
Appearance White or colourless solid
Melting point 360 °C (680 °F; 633 K) low of range
8.43 g L−1
log P -1.6
Isoelectric point 10.9
Pharmacology
ATC code L01DC03
Legal status
  • AU: D
  • US: D (Evidence of risk)
Eye drops Intravenous
Pharmacokinetics:
Hepatic
8–48 min
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
YesY verify (what is YesYN ?)
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 activity. It is given intravenously to treat upper gastro-intestinal cancers (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 to prevent scarring during glaucoma filtering surgery and to prevent haze after PRK or LASIK; mitomycin C has also been shown to reduce fibrosis in strabismus surgery.[2] 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'.[3] Potential bis-alkylating heterocylic quinones were synthetised in order to explore their antitumoral activities by bioreductive alkylation.[4] Mitomycin is also used as a chemotherapeutic agent in glaucoma surgery.

Biosynthesis

In general, the biosynthesis of all mitomycins[5] 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.svg

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.svg

Biological effects

In the bacterium Bacillus subtilis, mitomycin C induces competence for transformation.[6] Conjugation is a process of DNA transfer between cells, and is regarded as a form of bacterial sexual interaction. In the fruit fly Drosophila melanogaster, exposure to mitomycin C increases recombination during meiosis, a key stage of the sexual cycle.[7] In the plant Arabidopsis thaliana, mutant strains defective in genes necessary for recombination during meiosis and mitosis are hypersensitive to killing by mitomycin C.[8] It has been suggested that these, and other related findings, can be explained by the idea that during sexual processes in prokaryotes (transformation) and eukaryotes (meiosis) DNA crosslinks and other damages introduced by mitomycin C are removed by recombinational repair.[9]

Mitomycin C has recently been found to have very good activity against stationary phase [10] and against persisters [11] created by Borrelia burgdorferi, the causative agent of Lyme Disease.

References

  1. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Bernstein H, Bernstein C, Michod RE (2012). DNA repair as the primary adaptive function of sex in bacteria and eukaryotes. Chapter 1: pp.1-49 in: DNA Repair: New Research, Sakura Kimura and Sora Shimizu editors. Nova Sci. Publ., Hauppauge, N.Y. ISBN 978-1-62100-808-8 https://www.novapublishers.com/catalog/product_info.php?products_id=31918
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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  • Lua error in package.lua at line 80: module 'strict' not found. and references therein.
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