Calicheamicin
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| Identifiers | |
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108212-75-5 
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| 3D model (Jmol) | Interactive image |
| ChemSpider |
27330302 
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| UNII |
99ZHU54I1K
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| Properties | |
| C55H74IN3O21S4 | |
| Molar mass | 1,368.34 g·mol−1 |
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Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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The calicheamicins are a class of enediyne antitumor antibiotics derived from the bacterium Micromonospora echinospora, with calicheamicin γ1 being the most notable. It was isolated originally in the mid-1980s from the chalky soil, or "calichi pits", located in Kerrville, Texas. The sample was collected by a scientist working for Lederle Labs. It is extremely toxic to all cells and, in 2000, a CD33 antigen-targeted immunoconjugate N-acetyl dimethyl hydrazide calicheamicin was developed and marketed as targeted therapy against the non-solid tumor cancer acute myeloid leukemia (AML). Calicheamicin γ1 and the related enediyne esperamicin are the two of the most potent antitumor agents known.
Calicheamicins target DNA and cause strand scission. Calicheamicins bind with DNA in the minor groove, wherein they then undergo a reaction analogous to the Bergman cyclization to generate a diradical species. This diradical, 1,4-didehydrobenzene, then abstracts hydrogen atoms from the deoxyribose (sugar) backbone of DNA, which ultimately leads to strand scission. The specificity of binding of calicheamicin to the minor groove of DNA was demonstrated by Crothers et al. (1999) to be due to the aryltetrasaccharide group of the molecule.
The core metabolic pathway for biosynthesis of this molecule resembles that of other characterized enediyne compounds and occurs via an iterative polyketide synthase (PKS) pathway. This type I PKS loads Acetyl-CoA and then repeatedly adds a total of seven Malonyl-CoAs. The growing polyketide is acted upon by the ketoreductase domain (KR) and dehydratase domain (DH) during each iteration to produce a 15-carbon polyene, which is then processed by accessory enzymes to yield the putative enediyne core of calicheamicin. Maturation of the polyketide core is anticipated to occur by the action of additional enzymes to provide a calicheamicinone-like intermediate as a substrate for subsequent glycosylation.
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