Daunomycin - Daunorubicin

Antibiotics with antineoplastic activity continue to appear and rubidomycin (daunomycin, daunorubicin) [455] is currently receiving wide study. 

Rat liver canalicular membrane vesicles (CMV) have been used to examine the mechanisms of uptake of P-gp substrates such as daunomycin, daunorubicin, and vinblastine, whose biliary excretion is extensive (47,137, 408,409). Early work with plasma membrane vesicles, partially purified from MDR human KB carcinoma cells that accumulated [3H]vinblastine in an ATP-dependent manner, definitively showed how P-gp can act to efflux substrates from cancer cells (410). Additionally, these vesicles have been used to study microscopic aspects of P-gp-mediated efflux, such as the relationship of P-gp function to the membrane fluidity (137). 

Fluoroorotate 5-Fluorouridine (5-FUR) Bleomycin Cytosine arabinoside (Cytarabine) Daunomycin Daunorubicin Etoposide (VP-16)... 

Nevertheless, a few biosynthetic studies have shown that glycosyl transfer can occur much earlier, sometimes well before construction of the aglycon moiety is complete. In the perhaps best-known example, the biosynthesis of daunomycin (= daunorubicin, 29) and adriamycin (= doxorubicin, 30), glycosyl transfer of daunosamine is postulated to occur either at the aklavinone (38) stage [86], as in the biosynthesis of aclacinomycin A 37 (see above), or after 11-hydroxylation to -rhodomycinone [87], i. e., six to seven biosynthetic steps prior to completion of adriamycin formation (30, Scheme 17) [88]. 

A considerable amount of research has gone into elucidating the molecular mechanism of action of these antitumour quinones. While several mechanisms are possible, a single mechanism may not fully explain all of the observed cytotoxic effects. One of the objectives of the NCI and other studies elsewhere has been to determine if there were any structure-activity relationships within the major structural groups ranging from the simplest benzoquinones to the complex multiple heteroatom quinones. One of the main conclusions from these studies was that the most active compounds were mitomycin C, the 3,6-diaziridinylbenzoquinones with 2,5-alkylamino substituents, adriamycin (doxorubicin), daunomycin (daunorubicin) and AZQ (Figure 1). 

The most basic structural model for anthracyclines adriamycin (doxorubicin) and daunomycin (daunorubicin) was considered to be tiie strongly intramolecularly hydrogen-bonded naphthazarin (5,8-dihydroxy-1,4-naphthoquinone) (Section 3.2). It is usually customary to study the way in which such simple quinones form radicals in order to gain insight into the way more complex quinones might produce toxic and other effects. This is more so as the radical centres in the complex molecules are usually located in these simpler model structures. Treatment of naphthazarin will also demonstrate how various data may be compiled and compared. 

Several quinones are used clinically in the chemotherapy of cancer [61,62]. Some examples are adriamycin (doxorubicin), daunomycin (daunorubicin), mitomycin C and more recent diaziridinyl benzoquinones and diamino anthraquinones [5]. Physiological enzyme based reduction of these quinones caused by xanthine oxidase, cytochrome P450 reductase etc.[63], leads to the formation of semiquinone and hydroquinone forms. Pulse radiolysis can generate and characterise these intermediates and products [10]. 

Daunorubicin (daunomycin, Dauno, Creubidine)c Liposomal daunorubicin (DaunoXome)... 

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. 

The medically useful products demethyltetracycline and doxorubicin (adriamycin) were discovered by simple mutation of the cultures producing tetracycline and daunorubicin (daunomycin), respectively. The tectmique of mutational biosynthesis (mutasynthesis) has been used for the discovery of many new aminoglycoside, macrolide, and anthracycline antibiotics. In this tectmique, a non-producing mutant ( idiotroph ) is isolated and then fed various analogs of the missing moiety. When such a procedure leads to a return of antibiotic activity, it usually is due to the... 

Daunorubicin (Daunomycin and Cerubidine) and doxorubicin (Adriamycin) bind to and cause the intercalation of the DNA molecule, thereby inhibiting DNA template function. They also provoke DNA chain scission and chromosomal damage. Daunorubicin is useful in treating patients with acute lymphocytic or acute granulocytic leukemia. Adriamycin is useful in cases of solid tumors such as sarcoma, metastatic breast cancer, and thyroid cancer. These agents cause stomatitis, alopecia, myelosuppression, and cardiac abnormalities ranging from arrhythmias to cardiomyopathy. 

Daunorubicin (Daunomycin and Cerubidine) and doxorubicin (Adriamycin) bind to and cause the intercalation of the DNA molecule, thereby inhibiting DNA template function. They also provoke DNA chain scission and chromosomal damage. 

Daunorubicin (daunomycin) 30-60 mg/m2 daily IV for 3 days, or 30-60 mg/m2 IV weekly Nausea, fever, red urine (not hematuria) Cardiotoxicity (see text), alopecia, bone marrow depression... 

Scheme 13. The antitumor antibiotics daunomycin (29 = daunorubicin) and adiiamycin (30 = doxorubicin) are polyketides with an attached deox ugar moiety. Polyketide oligodeoxy-saccharides characterized by one or more deoxysaccharide chains include the anthracyclines arugomycin (31) [73a] and viriplanin (32), the angucyclines landomycin A (see 12 in Scheme 6) and vineomycin A, (33 = P1894B [74]), and the aureolic acid antibiotics mithramycin (34) and UCH9 (35).Also,orthosomydn antibiotics, such as avUamycin A (36) can be considered as polyketide oligodeoxysaccharides...

The dehydratase gene drtrM from S. peucetius is located in the daunorubicin biosynthetic cluster. Although the gene was believed to be required for the synthesis of daunosamine, a frameshift in the DNA sequence was detected which causes premature termination of translation. Inactivation of dnrM did not prevent daunorubicin production. The data indicate that the product of a second dehydratase gene detected outside of the biosynthetic gene cluster is involved in the biosynthesis of daunomycin (29) [144]. 

Daunorubicin daunomycin FK5O6 tacrolismus, fujimycin HSR-903 olamufloxacin vincristine leurocristine. Controversial data, whether this substance is really a P-gp substrate. 

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