Daunomycin synthesis

Thomas G. J. Synthesis of AnthracycUnes Related to Daunomycin in Recent Prog. Chem. Synth. Antihiot. 1990 467, Eds. Lukacs G. and Ohno M., Pb. Springer Berlin... 

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. 

An improved total synthesis of the aglycone (180) of 11-deoxyadriamycin-type antibiotics, which show stronger antineoplastic activity and/or less car-diotoxicity than daunomycin and adriamycin, was accomplished by applying the method to dihydroxyacetone (180) from ethynylcarbinol (182), prepared by strong base-induced cycloaddition of the substituted tetrahydrohomophthalic anhydride (181) [137], using PIFA [78] (Scheme 46). 

Daunomycin and its analog adriamycin are in clinical use as potent antitumor agents in combination chemotherapy against acute lymphocytic leukemia. It has been suggested that the antitumor properties are associated with intercalation of the anthracycline ring of the antibiotic into the DNA of rapidly proliferating neoplastic cells and subsequent blocking of RNA synthesis (72-75). [5]... 

Direct reactions with DNA serve as the molecular basis for the action of several anti-tumor drugs. Cancer is primarily a disease of uncontrolled cell growth, and cell growth depends on DNA synthesis. Cancer cells are often more sensitive than normal cells to compounds that damage DNA. For example, the anti-tumor drug cisplatin reacts with guanine bases in DNA and the daunomycin antibiotics act by inserting into the DNA chain between base pairs. In either case, these biochemical events can lead to the death of a tumor cell. 

This regioselective synthesis of benzannelated rings, which, unlike its Friedel Crafts equivalent, is not perturbed by the nature of other directing groups carried by the ring, has been used in several syntheses. Indanone 76 from cyclisation of 75 is an intermediate in a synthesis of nanaomycin A,44 and tetralone 77 is an intermediate in a synthetic study towards daunomycin 45... 

The anthracyciinone class of anticancer compounds (which includes daunomycin and adriamycin) can be made using a mercury (I I )-promoted alkyne hydration. You saw the synthesis of alkynes in this class on Chapter 9 where we discussed additions of metallated alkynes to ketones. Here is the final step in a synthesis of the anticancer compound deoxydaunomycinone the alkyne is hydrated using Hg2+ in dilute sulfuric acid the sulfuric acid also catalyses the hydrolysis of the phenolic acetate to give the final product. 

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]. 

Thiophene analogs of daunomycin (172, 173) were prepared in multistep reactions. The synthesis is based on a strong base-induced cycloaddition of homophthalic anhydrides. In the final step, glycosidation yielded a mixture of CL- and )S-glycosides from which the a-isomer was separated (87TL3971). 

The inhibitory activity of daunomycin and its structural analogues on viral oncogenesis by FLV and RSV, and on in vitro transformation by MSV (M) suggests that it is the activity of the virus-associated enzymes which is sensitive to these antibiotics. The RNA-dependent DNA polymerase of the virions is responsible for the synthesis of viral DNA. Table 16 shows how the reverse-transcriptase activity of MSV (M), FLV and RSV is inhibited by various daunomycin derivatives. 

Anthracycline antibiotics represented by daunomycin and adriamycin are weU known as anticancer agents and their reaction mechanisms with DNA have been extensively studied. However, an approach to understand the mechanism of drug action based on organic synthesis is still open. 

Antibiotics with Antineoplastic Activity - A number of tumor -inhibitory antibiotics form stable complexes with DNA thereby interfering with synthesis of RNA. Three of these antibiotics, actinomycin, mithramycin and daunomycin (which is probably identical to rubidomycin) possess... 

The utility of oxaziridines in asymmetric a-hydroxylation also extends to reactions with achiral enolates. This has been made possible by the discovery that certain chiral A -sulfonyl oxaziridines can react with enolates to afford a-hydroxy carbon compounds in excellent yield and enantioselectivity. An application of a highly selective sulfonyloxaziridine derived from camphor to the synthesis of daunomycin is shown in Scheme 8.23. Attack of the oxaziridine presumably occurs such that the enolate ester avoids nonbonded interactions with the exo methoxy group on the bicyclic ring system (cf. Schemes 8.23c and d). This is a very useful reaction of wide scope, and can be carried out on both stabilized enolates derived from keto esters (shown) and simple ketone enolates [99]. 

Scheme 8.23. (a) Application of enolate oxidation reactions of a chiral oxaziridine to the synthesis of an AB ring synthon of daunomycin [100]. ffc) Structure of the oxaziridine used. Proposed (c) favored and (d) disfavored transition structures (see also ref. [101]). 

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