Anthracycline antibiotics synthesis

As exemplified in the present procedure, the reaction has been optimized and extended in scope it affords functionalized benzocyclobutenes as well as substituted isoquinolines in high yields. Benzocyclobutenes have been used as intermediates in the synthesis of many naturally occurring alkaloids, - steroids,polycyclic terpenoids,and anthracycline antibiotics. The traditional routes leading to the preparation of benzocyclobutenes have been... 

Similar results are obtained with the /htetralone derivatives 12, which are useful building blocks in the synthesis of anthracycline antibiotics. Furthermore, the usefulness of the diastereoselec-tive addition to ot-oxo acetals was impressively demonstrated in the synthesis of (-)-7-deoxy-daunomycinone, which uses the completely stereoselective addition of (trimethylsi-lylethynyl)magnesium chloride to the /i-tetraione acetal 12 (R =OMOM R2 = Br) as the key reaction31. 

Tomioka et al.74 reported an interesting example of applying chiral diamine (—)-102 in the synthesis of the chromophore part of anthracycline antibiotics (Scheme 4-34). 

Fritzsche H, Wahnert U, Chaires JB, Dattagupta N, Schlessinger IT5, Crothers DM (1987) Anthracycline antibiotics. Interaction with DNA and nucleosomes and inhibition of DNA synthesis. Biochemistry 26(7) 1996-2000... 

In the total synthesis of an anthracycline antibiotic, the key step was an asymmetric halolactonization reaction. The corresponding bromolactones were formed with high stereoselectivity (d.s. > 90%). (S)-Proline was used as chiral auxiliary. 

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. 

This reaction was used for an asymmetric synthesis of aklavinone (8), an aglycone of the anthracycline antibiotics. The key step was the reaction of the acetal 6 with 2,... 

Thus, the development of new anthracycline antibiotics is of interest in which the therapeutical width is enhanced by decreasing toxicity and increasing specificity. Several screening methods are presently available in clinical tests. One is carried out by measurement of the survival rate of mice, induced with P 388 leukemia carcinoma [30, 32], Other methods are based on in-vitro tests either the 50% inhibitory concentration (IC50) of nucleosomal RNA synthesis is measured or the growth of tumor cell cultures like He La is observed [34],... 

A new asymmetric synthesis of anthracycline antibiotics such as ( + )-4-demeth-oxydaunomycinone (5) is based on dihydroxylation of 1 with Os04 in the presence of the diamine (-)-2, which provides the diol 3 in 82% ee.5 The product is converted into (+)-5 by four known reactions. 

Lown and Sondhi were interested in the synthesis of chromophores of the anthracycline antibiotics in which the quinone ring c was replaced by a y-pyrone. The y-pyrone ring was prepared by an oxidative cyclization mediated by DDQ, presumably proceeding via the quinone (Scheme 27). 

A good application of this strategy was reported by Ragharan and Kahne [224] in the synthesis of the trisaccharide of the anthracycline antibiotic, cicla-mycin 0 111 (Scheme 39 a) [225]. The structure of this highly deoxygenated car-... 

Another approach to the anthracycline antibiotics is exemplified by the synthesis of a-citromycinone (244) see Scheme 20 [57,58]. In this instance the electrochemically generated brominated quinone monoketal 240 was converted to the lithiated species 241. Its reaction with ketal 242, a rather remarkable synthon for the 1,4-dipole 243 [60,61], proceeded smoothly to afford, after sequential treatment with aqueous acid and boron tribromide, a 60% yield of a-citromycinone (244). 

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. 

The total synthesis of the methyl ester of the anthracycline antibiotic vineomycinone B2 is summarized in Scheme 44. The key step of this synthesis is introduction of the pyranose side chain by means of a... 

More recently, research indicates that the anthracycline compounds have an inhibitory effect on the intracellular enzyme topoisomerase II (also see Chapter 7). This has been taken as evidence that this enzyme may be the primary target for these drugs. A more balanced view at this time may be that the carcinolytic mechanism of action of the anthracycline antibiotics is related to the binding affinity to DNA (intercalation), inhibition of nucleic acid synthesis, and topoisomerase II interactions. 

Doxorubicin is an antineoplastic/anthracycline antibiotic. It binds DNA and inhibits nucleic acid synthesis. Cell structure studies have demonstrated rapid cell penetration and perinuclear chromatin binding, rapid inhibition of mitotic activity and nucleic acid synthesis, and induction of mutagenesis and chromosomal aberrations. It is indicated in treatment of ovarian cancer in patients whose disease has progressed or recurred after platinum-based chemotherapy and in treatment of AIDS-related Kaposi s sarcoma in patients whose disease has progressed on prior combination chemotherapy or who are intolerant to such therapy. 

THP-Protected lactamide 459 has been used to synthesize (2R, 3 S)-2,3-(cyclohex-ylidenedioxy)butanal (462), a key intermediate for the synthesis of L-daunosamine, the amino sugar component of natural anthracycline antibiotics [85] (Scheme 66). The crucial reaction in the sequence is the yw-selective hydrosilane/fluoride reduction of ketone 460, which... 

Intramolecular Marschalk cyclization. This reaction is a key step in a total synthesis of daunomycinone (3), the aglycone of an anthracycline antibiotic. Thus treatment of 1 with Na2S204 and NaOH in dioxane at 25°-90° results in... 

Elbs oxidation (1, 952), The Elbs oxidation is a key step in a recent regio-specific synthesis of islandicin monomethyl ether (3), a possible precursor to anthracycline antibiotics (equation I). ... 

Keywords Anthracyclinones - Anthracycline antibiotics Diastereoselective synthesis Enantioselective catalysis... 

Keywords Anthracyclines Antibiotics Daunosamine Glycosylation Synthesis... 

This protocol for the synthesis of anthracycline antibiotics was very efficient and useful, and was used for various kinds of anthracycline antibiotics, such as 11-deoxydaunomycin [26-28] and heteroanthracyclines [29- 36]. D-... 

CyelizatioH with rearrangement. In connection with studies directed toward a synthesis of anthracycline antibiotics, Sih and co-workers treated the tetra-hydronaphthyl ester of 3-methoxyphthalic acid (1), prepared as shown, with BF3 etherate at 90°. The product (2) is formed by a Fries rearrangement followed by cyclodehydration. 

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