Actinomycin compound

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. 

The first antitumor antibiotic was actinomycin A which was isolated from a Streptomyces species. The actinomycins are chromopeptides containing a planar chromophore, responsible for the bright color of the compounds, with peptide side chains. The most important representative of this group which is in clinical use is actinomycin D, or dactinomycin. 

Actinomycin D is a complex chemical compound produced by the Streptomyces species of fungus and is used as an antibiotic. It is a well-established and potent teratogen and is also suspected of being carcinogenic. 

Intercalation has been demonstrated with a number of other compounds having a polycyclic aromatic system and groups capable of forming hydrogen bonds. Among such compounds are the antibacterial 9-aminoacridine, the antimalarials mepacrine and chloroquine, the veterinary trypanocide ethidium (246), the thioxanthone lucanthone (247 R = Me) and its more active metabolite hycanthone (247 R = CH20H), which are used in the treatment of schistosomiasis, and the antineoplastic alkaloid ellipticine (248). A number of antibiotics, including the actinomycins, echinomycin and bleomycin, also intercalate. 

Perhaps the best understood example of induction involves induction of the aromatic hydrocarbon receptor (AhR) by compounds such as TCDD and 3-methylcholanthrene. The use of suitable inhibitors of RNA and DNA polymerase activity has shown that inhibitors of RNA synthesis such as actinomycin D and mercapto(pyridethyl)benzimida-zole block aryl hydrocarbon hydroxylase induction, whereas hydroxyurea, at levels that completely block the incorporation of thymidine into DNA, has no effect. Thus it appears that the inductive effect is at the level of transcription and that DNA synthesis is not required. 

In the first category are such compounds as actinomycin, acridine, and ethidium that bind between the stacked bases of the DNA duplex, disrupting the normal... 

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. 

Fig. 3 Venn-diagram for selected compounds interacting with the key MDR-related ABC transporters. MDR-substrate anticancer agents. Abbreviations VCR vincristine, VP-16 etoposide, STER steroids, TAM tamoxiphen, TKI-INHIB tyrosin kinase inhibitors e.g. STI-571, DOX doxorubicine or adriamycin, DNR daunorubicin, EPIR epirubicin, MX mitoxantrone, TOPOT topotecan, iridotecan, BISANT bisanthrone, COLCH colchicin, ACT-D actinomycin D, MYTOM mytomycin, TX methotrexate, CPHAM cyclophosphamide, CHLB chlorambucil, CARM carmustine, LCV leucovorin, HUR hydroxy urea, CISPL cisplatin, TAXOL paclitaxel. (Reproduced from [4])...

Eighteen different actinomycins have been described, differing in the amino acid sequence in the peptide chains and the total synthesis of some have been reported.88 Much of our knowledge of this class is due to the work of Brockmann, who has published comprehensive reviews.47,89 Recently Weinstein et al.90 reported the synthesis of simple actinomycin analogs, which might yield effective antibacterial compounds or antitumor agents less toxic than the natural actinomycins. 

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. 

Most of the important antitumor compounds used for chemotherapy of tumors are microbially-produced antibiotics. These include actinomycin D, mitomycin, bleomycins and the anthracyclines, daunorubicin and doxorubicin. The recent successful molecule, taxol (=paclitaxel), was discovered in plants but also is a fungal metabolite. It is approved for breast and ovarian cancer and is the only antitumor drug known to act by blocking depolymerization of microtubules. In addition, taxol promotes tubulin polymerization and inhibits rapidly dividing mammalian cancer cells. It also inhibits fungi such as Pythium, Phytopthora and Aphanomyces spp. by the same mechanism. ... 

From Australian rutaceae, Melicope tereana, several alkaloids were isolated. From melicopine and melicopidine, after demethylation and nitric acid oxidation, two quinones, 248 and 249, were obtained (49MI1). Meli-copicine is similarly transformed into both quinones. Chemical degradation of actinomycin yielded a peptide-free quinone, actinomycinol (250). The mechanism of conversion of the phenoxazine skeleton in actinomycin into the acridonequinone has been outlined (58JCS469). The compound was synthesized and several derivatives were prepared (56CB1397 57CB44 58JCS496). 

Intercalating Agents are compounds with fused eiromatic ring systems that can wedge (intercalate) between the stacked base pairs of DNA. Tliis disrupts the structure of the DNA so that the replicative enzymes have difficulty in synthesizing DNA past the "intercalated" sites. Anthracycline glycosides and Actinomycin D are intercalators used to treat a variety of cancers. 

Phenoxazinone production was as well observed in incubation media of Secale cereale, but not in such of Vida faba and Triticum aestivum [180]. The compounds can be detected is well in incubation media of several dicotyledonous species [187]. Since surface sterilization of oat caryopses with NaOCl did not prevent phenoxazinone production, it is possible that the responsible microorganism(s) are located within the caryopses. Phenoxazinone itself has an inhibitory effect on oat radicle elongation, probably caused by intercalation of the phenoxazinone ring system to DNA, as it is known from the phenoxazinone ring system of the transcription inhibitor actinomycin D, an antibiotic produced by Strepto-myces species. 

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