Daunorubicin synthesis

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. 

In Fig. 1 various targets of some important cytostatic agents are depicted. Their main mechanisms of action can be briefly summarized as follows. Pentostatin blocks purine nucleotides by inhibiting adenosine deaminase. 6-Mercaptopurine and 6-thioguanine inhibit purine ring biosynthesis and they inhibit nucleotide interconversions. Methotrexate by inhibiting dihydrofolate reduction blocks thymidine monophosphate and purine synthesis. 5-Fluorouracil also blocks thymidine monophosphate synthesis. Dactinomycin, daunorubicin, doxorubicin and mitoxantrone intercalate with DNA and inhibit RNA synthesis. L-asparaginase deaminates... 

The anthracycline antibiotics, which include doxorubicin, daunorubicin, bleomycin, and mitomycin C, inhibit DNA and RNA synthesis. Doxorubicin also interfers with topoisomerase II (a DNA gyrase), the activity of which is markedly increased in proliferating cells. Structurally related to doxorubicin are epirubicin and mitozantrone. The cytotoxic antibiotics are used to treat leukaemias and lymphomas and also for solid tumours in the breast, lung, thyroid and ovary. Cardiotoxicity is the major dose-limiting factor, with arrhythmias and myocardial depression (Bacon and Nuzzo 1993). The chronic phase of cardiotoxicity is a dose-dependent cardiomyopathy that leads to congestive heart failure in 2-10% of patients. Myocardial injury is the result of oxygen free radical formation. Children are particularly sensitive to these cardiotoxic reactions and may require a heart transplant in their later years. Epirubicin is less cardiotoxic than doxorubicin. 

A.J. Versluis, E.T. Rump, P.C. Rensen, T.J. Van Berkel and M.K. Bijsterbosch, Synthesis of a lipophilic daunorubicin derivative and its incorporation into lipidic carriers developed for LDL receptor-mediated tumor therapy, Pharm Res. 15 (1998) 531-537. 

F. Animati, F. Arcamone, M. Berettoni, A. Cipollone, M. Franciotti, and P. Lombardi, New anthracycline disaccharide. Synthesis of L-daunosaminyl-a(l->4)-2-deoxy-L-rhamnosyl and of L-daunosamyl-a(l->4)-2-deoxy-L-fucosyl daunorubicin analogues, J. Chem. Soc. Perkin Trans. 

Fan E, Shi W, Lowary TL (2007) Synthesis of daunorubicin analogues containing truncated aromatic cores and unnatural monosaccharide residues. J Org Chem 72 2917-2928... 

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]. 

Anthracydines have several modes of action leading to anticancer activity. They intercalate between base pairs in DNA, interfering with nucleic acid synthesis. Anthracydines also inhibit DNA topoisomerases I and II, which leads to DNA double-strand breaks. In addition, doxorubicin and daunorubicin may form complexes with metals such as iron. Although these metal-anthracycline complexes result in oxygen free radical formation, which may contribute to antitumor activity, membrane damage incurred from the free radicals is thought to be the mechanism responsible for... 

Masquelier M, Baurain R, Trouet A. Amino acid and dipeptide derivatives of daunorubicin. 1. Synthesis, physicochemical properties, and lysosomal digestion. J Med Chem 1980 23 1166-1170. 

Idarubicin is an anthracycUne, which is a DNA-intercalating analog of daunorubicin, which has an inhibitory effect nucleic acid synthesis and interacts with the enzyme topo-isomerase II. 

Kar AK, Braun PD, Wandless TJ (2000) Synthesis and Evalution of Daunorubicin-Paclitaxel Dimers. Bioorg Med Chem Lett 10 261... 

Enzymatic catalysis is also used in the synthesis of l-"C-labeled D-fructose and o-glucose firom mannitol and glucitol, respectively (Ogren and Langstrom 1998). The preparation of S-adenosyl-L-[ C]methionine (Guegen et al. 1982), [ C]epinephrine (Soussain et al. 1984), and [ C]daunorubicin (Eriks-Fluks et al. 1998) are other examples of enzyme catalysis. The nucleosides [ C]thymidine and [ C]-2 -arabino-2 -fluoro-P-5-methyl-uridine have been prepared by enzymes immobilized on hollow fiber membranes using [ C]formaldehyde as the labeled precursor (Hughes and Jay 1995). 

Cicrcq E. Synthesis and cytostatic properties of daunorubicin derivatives, containing N-phenylthiouiea or N-ethylthiourea moieties in the 3 -position. J Antibiot i 991 44 192-199. 

Tsuchiya T, Takagi Y. Synthesis and biological activities of fluorinated daunorubicin and doxonibicin analogues. Pricbe W, ed. Anthracycline Antibiotics New Analt ues. Methods of Delivery, and Mechanisms of Action. Washington D.C. American Oiemical Society Press, 1995 100-114. 

In the A Word About... Polycyclic Aromatic Hydrocarbons and Cancer on page 136, it was noted that some polycyclic aromatic hydrocarbons are used to treat cancer. Indeed, daunorubicin (below) is a member of the an-thracycline family, and these compounds are some of the most effective chemotherapy tools used in anticancer treatment. A compound like m-hydroxybenzaldehyde could be considered as an intermediate in the synthesis of daunorubicin. Using benzaldehyde as a starting reagent, suggest a synthesis of m-hydroxybenzaldehyde. 

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