Calicheamicin

Calicheamicin

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Encyclopedia
The calicheamicins are a class of enediyne
Enediyne
Enediynes are a class of bacterial natural products characterized by either nine- and ten-membered rings containing two triple bonds separated by a double bond. Many of these compounds are capable of undergoing Bergman cyclization...

 antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...

s derived from the bacterium Micromonospora echinospora
Micromonospora echinospora
Micromonospora echinospora is a species of bacteria that is known for producing the enediyne antibiotic calicheamicins....

, with calicheamicin γ1 being the most notable. It was isolated originally from a rock collected by a Scripps Research Institute chemist while hiking in Waco, Texas
Waco, Texas
Waco is a city in and the county seat of McLennan County, Texas. Situated along the Brazos River and on the I-35 corridor, halfway between Dallas and Austin, it is the economic, cultural, and academic center of the 'Heart of Texas' region....

. It is extremely toxic to all cells and its analogues have been used as targeted therapy
Targeted therapy
Targeted therapy is a type of medication that blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with rapidly dividing cells...

 against cancer. Calicheamicin γ1 and the related enediyne esperamicin
Esperamicin
The esperamicins are a class of bacteria-derived chromoprotein enediyne antibiotics, of which esperamicin A1 is the most well studied. Esperamcin A1 and the related enediyne calicheamicin are the two most potent antitumor agents known. The esperamicins are extremely toxic DNA splicing...

 are the two most potent antitumor agents known.

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
Bergman cyclization
The Bergman cyclization or Bergman reaction or Bergman cycloaromatization is an organic reaction and more specifically a rearrangement reaction taking place when an enediyne is heated in presence of a suitable hydrogen donor . It is named for the American chemist Robert George Bergman...

, 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.

Biosynthesis


The core synthetic route like other characterized enediyne compounds is via a polyketide synthase
Polyketide synthase
Polyketide synthases are a family of multi-domain enzymes or enzyme complexes that produce polyketides, a large class of secondary metabolites, in bacteria, fungi, plants, and a few animal lineages...

 pathway. plus aryltetrasaccharide formed by nucleotide glycosyl transferases

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
Mavroneri
Mavronéri is a river identified with the River Styx of Greek mythology according to Hesiod’s description in Theogony. It is located near Nonakris in the Aroania Mountains of Arcadia on the Peloponnesian peninsula. Some scientists have speculated that the waters of the Mavronéri were used to poison...

) that was contaminated by this compound.

See also

  • Monoclonal antibodies
    Monoclonal antibodies
    Monoclonal antibodies are monospecific antibodies that are the same because they are made by identical immune cells that are all clones of a unique parent cell....

     using calicheamicins as cytotoxic agents:
    • Gemtuzumab ozogamicin
      Gemtuzumab ozogamicin
      Gemtuzumab ozogamicin is a drug-linked monoclonal antibody that was used to treat acute myelogenous leukemia from 2000-2010...

    • Inotuzumab ozogamicin
      Inotuzumab ozogamicin
      Inotuzumab ozogamicin is a humanized monoclonal antibody for the treatment of cancers. The monoclonal antibody is linked to a cytotoxic agent from the class of calicheamicins ....