Calicheamicin

Calicheamicin γ1
Identifiers
CAS number 108212-75-5
Properties
Molecular formula C55H74IN3O21S4
Molar mass 1368.35 g mol−1
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Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

The calicheamicins are a class of enediyne antibiotics derived from the bacterium Micromonospora echinospora, with calicheamicin γ1 being the most notable.[1] It was isolated originally from a rock collected by a Scripps Research Institute chemist while hiking in Waco, Texas.[2] It is extremely toxic to all cells and its analogues have been used as targeted therapy against cancer. Calicheamicin γ1 and the related enediyne esperamicin are the two most potent antitumor agents known.[3]

Contents

Mechanism of toxicity

Calicheamicins are highly toxic to DNA, cleaving it readily. In vitro, calicheamicins bind with DNA in the minor groove, where they undergo a reaction analogous to the Bergman cyclization, generating a diradical species. Like all enediynes, this diradical, 1,4-dehydrobenzene, then abstracts hydrogen atoms from the sugar backbone of DNA, which results in strand scission.[4]

Biosynthesis

The core synthetic route like other characterized enediyne compounds is via a polyketide synthase pathway.[5] plus aryltetrasaccharide formed by nucleotide glycosyl transferases[6][7]

History

It has been proposed that Alexander the Great was poisoned by calicheamicin as the circumstances of his death are compatible with poisoning by water of the river Styx (Mavroneri) that was contaminated by this compound.[8][9]

See also

References

  1. ^ Lee, May D.; Manning, Joann K.; Williams, David R.; Kuck, Nydia A.; Testa, Raymond T.; Borders, Donald B. (July 1989). "Calichemicins, a novel family of antitumor antibiotics. 3. Isolation, purification and characterization of calichemicins β1Br, γ1Br, α2I, α3I, β1I, γ1I, and Δ1I". Journal of Antibiotics 42 (7): 1070–87. PMID 2753814. 
  2. ^ Total Synthesis and the Creative Process: An Interview with K.C. Nicolaou, Scripps Research Institute
  3. ^ Calicheamicin and Esperamicin are the two most potent antitumor agents known to man, Univ Of Georgia, Chem 4500
  4. ^ S. Walker; R. Landovitz; W.D. Ding; G.A. Ellestad; D. Kahne (1992). "Cleavage behavior of calicheamicin gamma 1 and calicheamicin T". Proc Natl Acad Sci U.S.A. 89 (10): 4608–12. doi:10.1073/pnas.89.10.4608. PMC 49132. PMID 1584797. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=49132. 
  5. ^ Horsman, GP; Chen, Y; Thorson, JS; Shen, B (2010 Jun 22). "Polyketide synthase chemistry does not direct biosynthetic divergence between 9- and 10-membered enediynes". Proc Natl Acad Sci U S A. 107 (25): 11331–5. doi:10.1073/pnas.1003442107. PMC 2895059. PMID 20534556. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2895059. 
  6. ^ Simkhada D, Oh TJ, Kim EM, Yoo JC, Sohng JK (2009 Jan). "Cloning and characterization of CalS7 from Micromonospora echinospora sp. calichensis as a glucose-1-phosphate nucleotidyltransferase". Biotechnol Lett. 31 (1): 147–53. doi:10.1007/s10529-008-9844-9. PMID 18807197. 
  7. ^ Zhang C, Bitto E, Goff RD, Singh S, Bingman CA, Griffith BR, Albermann C, Phillips GN Jr, Thorson JS (2008 Aug 25). "Biochemical and structural insights of the early glycosylation steps in calicheamicin biosynthesis". Chem Biol. 15 (8): 842–53. doi:10.1016/j.chembiol.2008.06.011. PMC 2965851. PMID 18721755. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2965851. 
  8. ^ Nick Squires (August 4, 2010). "Alexander the Great poisoned by the River Styx.html". Telegraph. http://www.telegraph.co.uk/news/worldnews/europe/greece/7924855/Alexander-the-Great-poisoned-by-the-River-Styx.html. 
  9. ^ Rossella Lorenzi (16-Jul-2010). "Alexander the Great killed by toxic bacteria". Discovery News. http://news.discovery.com/history/alexander-the-great-bacteria.html.