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• description

  Calicheamicins are a series of enediyne antitumor antibiotics originally isolated from the bacterium Micromonospora echinospora. They exert high cytotoxicity and have been applied in tumor therapies for over a decade-- a CD33 antigen-targeted immuno-conjugate: N-acetyl dimethyl hydrazide calicheamicin, was developed as a targeted therapy for non-solid tumor cancer acute myeloid leukemia (AML). Calicheamicin has several derivatives with different chemical modifications, among which γ1 is the most well-characterized. Calicheamicin γ1 contains an aglycon consisting of a bicycle tridec-9-ene-2,6-diyne system with a labile methyl trisulfide group and an aryltetrasaccharide chain. Calicheamicins also contain enediyne moieties that are structurally similar to other enediynes, such as esperamicins, neocarzinostatin, and kedarcidin, etc. After reduction by cellular thiols, the calicheamicin enediyne moieties rearrange to produce a 1, 4-benzenoid diradical.;

• Mode of Action

  Calicheamicins are highly toxic agents against DNA and they induce double-stranded DNA (dsDNA) breakages at sub-picomolar concentrations. For their mode of action, Calicheamicins bind to dsDNA minor groove, within which they undergo a cyclization reaction similar to Bergman cyclization and release a diradical species, namely 1,4-didehydrobenzene. 1,4-didehydrobenzene subsequently extracts hydrogen atoms from DNA deoxyribose (sugar) backbone, resulting in strand scission. The strong potency of the calicheamicins fits the concept of ADC payloads and they have been proven to be outstanding drug candidates for targeted cancer therapies. A hydrazide derived from Calicheamicin γ1 has been conjugated to the proteoglycan portion of the CT-M-01 (anti-polyepithelial mucin) antibody and the resulted ADC has shown promising effects to human breast carcinoma cells.
  
  Calicheamicins mode of action. Once inside the cells, Calicheamicin diffuses into the cell nucleus, where it binds to the DNA minor groove (modeled in the image) and induces double stranded DNA breakages. DNA breakages result in the elimination of the malignant cells by apoptosis.;

• Uses

  Calicheamicin, also known as Calicheamicin gamma(1,I) or Calichemicin gamma1, is an potent enediyne antitumor antibiotics derived from the bacterium Micromonospora echinospora. Calicheamicin targets DNA and cause strand scission. Calicheamicin binds with DNA in the minor groove, wherein it then undergos 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 is due to the aryltetrasaccharide group of the molecule.;

• Resistance

  Calicheamicin displays unbiased toxicity to bacteria, fungi, viruses, and eukaryotic cells and organisms, which raises questions as to how the calicheamicin-producing Micromonospora manages not to poison itself. An answer to this question was presented in 2003 when Thorson and coworkers presented the first known example of a "self-sacrifice" resistance mechanism encoded by the gene calC from the calicheamicin biosynthetic gene cluster. In this study, the scientists revealed calicheamicin to cleave the protein CalC site-specifically, destroying both the calicheamicin and the CalC protein, thereby preventing DNA damage. The same group went on to solve the structure of CalC and, more recently, in collaboration with scientists from the Center for Pharmaceutical Research and Innovation (CPRI), discover structural or functional homologs encoded by genes in the calicheamicin gene cluster previously listed as encoding unknown function. In this latter study, the authors suggest that CalC homologs may serve in a biosynthetic capacity as the long-sought-after polyketide cyclases required to fold or cyclize early intermediates en route to calicheamicin.;

• Structure

  Calicheamicin represents one of the most structurally complex natural products developed into an anticancer agent. The compound was isolated from the fermentation broth of a bacterium, Micromonospora echinospora ssp. calichensis. It contains four carbohydrate residues, a hexasubstituted benzene ring, an unusual N–O glycosidic linkage, a trisulfide moiety, and a bicycle[7.3.1]tridec-9-ene-2, 6-diyne system. The aglycon portion of calicheamicin and other 10-membered ring enediyne antitumor antibiotics contain dienonecarbamate and enediyne chromophores in a unique bicyclic ring structure in which these two subunits are essentially orthogonal to each other. After binding to the minor groove of DNA with some sequence specificity, calicheamicin is reduced by cellular thiols[1-2]. ;

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