Actinomycins structures

The NMR experiments 55 are obtained from actinomycin D in order to check the amino acid sequence, to assign proton-proton and some carbon-proton connectivities, and to deduce informations concerning proton distances and the spatial structure of both cyclopentapeptide lactone rings. Conditions CDCI3, 10 mg per 0.3 ml, 25 °C, 500 MHz H), 125 MHz ( C). (a) HH COSY plot ... 

FIGURE 12.16 The structures of ethidiutn bromide, acridine orange, and actinomycin D, three intercalating agents, and their effects on DNA structure. 

Chemical Name Complex actinomycin, see structural formula Common Name Meractinomycin Actinomycin D Actinomycin Aj Structural Formula ... 

Intercalating agents are hydrophobic, planar structures that can fit between the DNA base pairs in the center of the DNA double helix. These compounds (ethidium bromide and actinomycin D are often-used examples) take up space in the helix and cause the helix to unwind a little bit by increasing the pitch. The pitch is a measure of the distance between successive base pairs. 

There is a single prokaryotic RNA polymerase that synthesizes all types of RNA in the cell. The core polymerase responsible for making the RNA molecule has the subunit structure Ojpp. A protein factor called sigma (a) is required for the initiation of transcription at a promoter. Sigma factor is released immediately after initiation of transcription. Termination of transcription sometimes requires a protein called rho (p) faaor. This enzyme is inhibited by rifampin. Actinomycin D binds to the DNA preventing transcription. 

Perhaps a bit more subtle than those agents that react chemically with DNA are those that insert themselves between the stacked bases of the DNA double helix— intercalation. This alters the regular structure of the DNA molecule and may lead, for instance, to inhibition of mRNA synthesis. The structures of the intercalcating agents are generally quite complex and I will spare you the complexity. However, three names may be familiar—dactinomycin (Actinomycin D), daunorubicin (daunomycin), and doxorubicin (Adriamycin)— and intercalation is how they work. All three are natural products and were isolated from the fermentation broths of Streptomyces species. 

Three-Dimensional Structure of the Actinomycins H. Lackner, Angew. Chem., Int. Ed. Engl., 1975,14, 375-386. 

Lackner H, Bahner I, Shigematsu N, Pannell LK, Mauger AB (2000) Structures of Five Components of the Actinomycin Z Complex from Streptomyces fradiae, Two of Which Contain 4-Chlorothreonine. J Nat Prod 63 352... 

Actinomycin D is a commonly used inhibitor of both DNA and RNA synthesis. Its planar structure binds noncovalently between the stacked base pairs of duplex DNA this is called intercalation. In this situation the DNA functions as a poor template. Compounds that bind in a similar way include acridine and ethidium. These affect the fidelity of DNA replication. 

Yes. Actinomycin D blocks transcription by binding to the DNA template. In doing so, it recognizes a common structural feature of all duplex DNAs, binding by intercalation between stacked base pairs (Chap. 16). 

Actinomycin D has been clinically used for the treatment of many cancers and is known to be a DNA intercalator. The structure of actinomycin D is based on a phenoxazine ring bound to two cyclic pentapeptides [33]. The presence of the phenoxazine ring in the structure of actinomycin D suggests that phenoxazine derivatives may possess anticancer activity. Phenoxazine derivatives are known to be effective multidrug resistance (MDR) modulators in cancer cells [34], potent inhibitors of Akt signaling in cells [35], inhibitors of human plasma cholinesterase [36], and photo-chemotherapeutic agents in cancer cells [37]. Recent studies also show that the relatively water-soluble phenox-azines, such as 2-amino-4,4a-dihydro-4a,7-dimethyl-2H-phenoxazine-3-one and 2-aminophenoxazine-3-one, exert antitumor effects on various cancer cells in vitro and in vivo. [38]. We have investigated 24 phenoxazines [23,39] (Fig. 4). 

Microbial sources have been a very rich source for cancer chemotherapeutic agents. Of particular note is the Strep-tomyces spp., which has been responsible for the production of many approved anticancer agents that are in clinical practice. These agents are represented by highly diverse structural classes exemplified by the anthracycline family (e.g., doxom-bicin, 73) (72-74), actinomycin family (e.g., dactinomycin, 74), glycopeptides family (e.g., bleomycins A2 and B2, 75 and 76) (75), and mitomycin family (e.g., mitomycin C, 77) (72, 76). All these compounds specifically interact with DNA for then-mode of action. 

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