Calicheamicins

Calicheamicins

Catalog Product Name CAS Number Molecular Formula Molecular Weight
BADC-00089 Calicheamicin 108212-75-5 C55H74IN3O21S4 1368.35
BADC-00723 N-Acetyl-Calicheamicin 108212-76-6 C57H76IN3O22S4 1410.38

As a class of novel antitumor antibiotics, enediyne antibiotics possess novel structure and unique action mechanism. The discovered enediyne antibiotics include Calicheamicins (CLMs), Kedarcidins, Dynemicins, Esperamicins, Neocarzinostatins (NCSs) and Lidamycins (LDMs) etc. The research indicated that enediyne antibiotics have good inhibitory activities against multiple tumors, especially blood tumors.

Chemical structure

Calicheamicins (CLMs) was isolated from the fermentation broth of a rare actinomycete micromonospora echinospora. It is a small molecule fat soluble compound, which has relatively high stability. The average molecular weight of CLMs is 1500 and has a rigid bicyclic with two hydroxyl side chains (R1 and R2), in which CLMs γ1is applied most clinically due to its strongest activities. The molecular structure of CLMs contains an enediyne core of 1,5-diyne-3-ene, a methyl trisulfide, a fully substituted benzene and four glycosides. As the recognizer and transmitter of CLMs, the auxiliary group (oligosaccharide fragment) in the molecule tightly binds the drug molecule to DNA. Enediyne core structure is an active section of antitumor activity, which is an efficient DNA cleaver.

Mechanism of action

Calicheamicins (CLMs) don’t directly cause DNA breakage. It requires an activation process to transform the structure into an active radical intermediate. The interaction pathway between CLMs with DNA can be divided into three steps: drug binding with DNA, drug activation and DNA strand breakage. CLMs first binds to DNA through the oligosaccharide group to embed drug molecules into the small groove of DNA double helix, thereby completing activation process by Bergman cyclization. Then, the hydrogen atoms on the DNA skeleton are rapidly captured by the diradical, causing DNA breakage and resulting in cytotoxicity. When DNA strand break, the enediyne core structure of CLMs plays a decisive role, and methyl trisulfide stimulates the activation of enediyne core.

Application

Calicheamicins (CLMs) have strong lethality ability against Gram-positive and Gram-negative bacteria, and its antibacterial activities is 4000 times higher than Adriamycin. The anticancer spectrum of CLMs includes P388 leukemia (ID50 =5.0 μg/kg) and B16 melanoma (ID50 =1.25 μg/kg), which is higher than that of Doxorubicin by 4000 times. Since the toxicity of CLMs is too strong (ED50/LD50 < 10) and the scope of effective dose is too narrow, it is difficult to apply the CLMs alone in clinical practice. Therefore, the clinical application of CLMs is mainly used for immune-linked antibody drugs to directly target tumor cells. Since the development of monoclonal antibody technology, a variety of monoclonal antibody conjugated drugs have been made by carrying CLMs with monoclonal antibody as carrier, many of which have been used in clinic.

References

  1. Lee, M.D.; et al. Calicheamicins-discovery, structure, chemistry, and interaction with DNA. Accounts of Chemical Research, 1991, 24: 235-243.
  2. Damle, N.K.; et al. Antibody-targeted chemotherapy with immunoconjugates of calicheamicin. Current Opinion in Pharmacology, 2003, 3: 386–390.
* Only for research. Not suitable for any diagnostic or therapeutic use.

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