Antibiotic anthracycline

The structures of several new anthracycline antibiotics have been elucidated including rudolphomycin, which possesses the trisaccharide unit (17) containing a novel unsaturated amino-glycosulose. Disaccharide fragments obtained from carminomycin II and III by catalytic hydrogenation were found to contain daunosamine and an acyclic hemiacetal of 2,4-dideoxy-tetrose. Fermentation broths have yielded a number of daunorubicin analogues (modified in the tetracycline unit).  

Synthetic approaches to anthracycline antibiotics have been reviewed. Several papers report syntheses of daunorubicin analogues by the glycosidation of daunomycinone derivatives with amino-sugars glycosides of daunomycinone have been prepared from 3-epf-L-daunosamine, D-acosamine, D-daunosamine, D-ristosamine, and 3-ep(-D-daunosamine, and 4-demethoxy-9-deoxy-9-methyl 

Falkowski, J. Golik, A. Jarzebski, B. Stefanska, and E. Borowski, Symp. Pap. — lUPAC Int. Symp. Chem. Nat. Prod., 11th, 1978, 2, 258 Chem. Abstr., 1980, 92, 59147). 

The structures of cosmomycins A,B,C, and D, new differentiation inducers produced by S. cosmosus. have been elucidated. They contain one or two trisaccharide chains attached to (8- or iT-rhodo- 

A new -rhodomycin derivative has been obtained from a Strepto- 

Analogues of daunorubicin have been prepared from modified sugars. 3 -Epi, 3 -hydroxy-3, 5 -diepi, and 3, 6 -dihydroxy-3, 5 -diepi 2 -halo,and 3 -C-methyl analogues were prepared using appropriate glycals or glycosyl halides with daunomycinone  

Two new compounds, roseorubicin A and B, have been isolated from the culture broth of Actinomyces rossoviolaceus. Roseorubicin A (16) contains a pentasaccharide chain, L-rhodinose L-rhodinose 2-deoxy-L-fucose - L-rhososamine 

L-rhodosamine, which on mild acid hydrolysis gave roseorubicin B, the corresponding tetracycline disaccharide, which in turn could be selectively hydrolysed to 7-rhodomycin 1, the simple rhodosaminyl glycoside. 

Nogalamycin has been converted to a series of aglycone analogues, and the stereochemistry of the anthracycline ring investigated.  

The gross structure of nogalamycin (527) has been reported. It contains nogalose (6-deoxy-3-C-methyl-2,3,4-tri-0-methyl-L-mannose) and a 3,6-dideoxy-3-di-methylaminohexose that is linked both glycosidically and through C-5 to ring A of the tetracycline system. 

Nineteen anthracycline-related antibiotics have been found in fermentation broths of Streptomyces galilaeus strain MA144-M1. They contain rhodosamine or N-methyldaunosamine attached to ring d of the tetracycline system, as in 

A series of e-rhodomycinone glycopyranosides, including those derived from L-fucose, L-rhamnose, and D-ribose and their 2-deoxy analogues, has been synthesized the 3,4-di-0-acetyl-2-deoxy-D-eryt/jro-pentopyranosyl derivative showed 

Several reports have described the glycosylation of suitably protected dauno-mycinones and related compounds. Methyl A-trifluoroacetyl-a-daunosaminide 

Arcamone, S. Penco, and A. Vigevani, Cancer Chemother, Report, Part 3, 1975, 6, 123 Chem. Abs., 1976, 84, 44 593j). 

The structure of rimocidin (from S. rimosus), which contains mycosamine attached to a polyene macrolide ring, has been reported. 3-0-(2,6-Dideoxy-a-L-ribo- and -flm6mo-hexopyranosyl)erythronolide B, aberrant metabolites in the biosynthesis of erythromycin, have been isolated from the fermentation broth of S. erythreus, an erythromycin-producing organism. A new lankamycin antibiotic, isolated from the fermentation broth of S. violaceoniger, has been shown to contain the unsaturated derivative 4-0-acetyl-2,3,6-trideoxy-3-C-methyl-L-tAreo-hex-2-enopyranose (379) in place of 4-O-acetylarcanose (4-0-acetyl-2,6-dideoxy-3-C,0-dimethyl-L-xry/o-hexo3e).  

Methanolysis of the turimycin complex from a Streptomyces species yielded methyl a- and 8-mycarosides and the corresponding 4-O-acetyl, 4-O-propionyl, and 4-0-butyryl derivatives.  

The use of m.s. in elucidation of the structures of polyene macrolide antibiotics is referred to in Chapter 24. 

4-0-Demethyl-ll-deoxydoxorubicin and some analogues have been 

Several papers report synthesis of 3 -N-alkylated derivatives 

7-0-C3-Amino-2,3,6-trideoxy-4-0-(2,6-dideoxy- -L-lyxo-hexo-pyranosyl)- -L-lyxo-hexopyranosyl] daunomycinone has been synthesized by standard SnCl -catalysed glycosylation of 

A review (in Russian) has appeared on actinomycin A. (See Vol, 13, p.l62). The isolation and characterization of new anthracyline antibiotics, auromycins and sulphurmycins, obtained from culture of streptomyces galileus strain OBB-111, has been reported. They contain new aglycones auromycinone and 

The monoacetyl trisaccharide which can be obtained from tri-O-acetyl aclacinomycin A by hydrogenolysis has been used to form o -glycosides from various aglycones (aklavinone. 

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Dihydioxytetiahydionapthacenedione derivatives, used as intermediates for the anthracycline antibiotics have been prepared by Friedel-Crafts reaction of tetralin derivatives with orthophthaloyl chlotide [88-95-9J in high yields (93). 

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. 

Heparin has been reported to complex with a variety of basic species, including biogenic amines and drugs for reviews, see Refs. 10 and 391. For its possible relevance to the pharmacological properties of heparin and complexed species, mention is made here of complexes with histamine392,393 and anthracycline antibiotics.394 C.d. studies on the interaction of basic homopolypeptides with heparin and other glycosaminogly-cans have shown that heparin is able to induce an ordered, helical conformation in the polypeptide.395 397 Similar, and even more dramatic, effects were observed with mixed basic polypeptides, presumed to represent better models for the biologically relevant interactions with plasma proteins.368... 

The discovery of monoclonal antibodies and combining them with polymeric prodrugs is the newest approach to overcome the lack of selectivity for disposition in target tissue (23). Recently the selectivity of antibody-targeted polymeric anthracycline antibiotics to T lymphocytes was accomplished (25). In addition decreased immunogenicity of proteinaceous conjugates with IgG and human transferrin has been reported (26). 

There are various pathways for free radical-mediated processes in microsomes. Microsomes can stimulate free radical oxidation of various substrates through the formation of superoxide and hydroxyl radicals (the latter in the presence of iron) or by the direct interaction of chain electron carriers with these compounds. One-electron reduction of numerous electron acceptors has been extensively studied in connection with the conversion of quinone drugs and xenobiotics in microsomes into reactive semiquinones, capable of inducing damaging effects in humans. (In 1980s, the microsomal reduction of anticancer anthracycline antibiotics and related compounds were studied in detail due to possible mechanism of their cardiotoxic activity and was discussed by us earlier [37], It has been shown that semiquinones of... 

The second mechanism is realized when organic or inorganic compounds are reduced by endogenous reductants (for example, by NADH or NADPH and the other components of mitochondrial or microsomal respiratory chains). The typical compounds are anthracycline antibiotics and carbon tetrachloride. CC14 is easily reduced by microsomes to the free radical CC13 , which is able to abstract a hydrogen atom from unsaturated lipids and initiate lipid peroxidation. Because of this, the CCl4-initiated lipid peroxidation is a reliable and frequently applied model system for the study of in vitro iron-independent lipid peroxidation and the effects of antioxidants (see for example Ref. [54]). 

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). 

Figure 2.7 Purification of a mixture of anthracycline antibiotics using heart cut recycle liquid chromatography to yield the most active fraction. Conditions column, JAIGEL-310 eluent, chloroform-methanol-25% NH4OH (200 5 1) flow rate, 4 ml min-1 detection refractivity index.

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... 

Daunorubicin is an anthracycline antibiotic used in chemotherapy. It is diluted with infusion fluid to a concentration of 1 mg/mL and given over 20 minutes to reduce the occurrence of irritation. A liposomal formulation is also available. 

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... 

Cystostatic antibiotics insert themselves into the DNA double strand this may lead to strand breakage (e.g., with bleomycin). The anthracycline antibiotics daunorubkin and adriamycin (doxorubicin) may induce cardiomyopathy. Bleomycin can also cause pulmonary fibrosis. 

El Khadem, H.S. (Ed.) Anthracycline Antibiotics, Academic Press, New York 1982. 

Batrakova EV, Dorodnych TY, Klinskh EY, Kliushnenkova EN, Shemchukova OB, Goncharova ON, Arjakov SA, Alakhov VY, Kabanov AV. Anthracycline antibiotics non-covalently incorporated into block copolymer micelles in vivo evaluation of anti-cancer activity. Br J Cancer 1996 74 1545-1552. 

The anthracycline antibiotics are fermentation products of Streptomyces peucetius. Daunorubicin (Cerubidine) is used to treat acute leukemias, while its structural analogue, doxorubicin (Adriamycin) is extensively employed against a broad spectrum of cancers. Although... 

It is a cytotoxic anthracycline antibiotic isolated from Streptomyces pneuceticus. It is... 

Reactive derivatives of anthracycline antibiotics were synthesized and attached to polymeric carriers. To bind adriamycin to poly(glutamic acid) and poly(aspartic acid) via ester bonds, Zunino et al. [147] used the reaction of alkylbromides (14-bromodaunorubicin) with the carboxylic group of the carrier. 

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. 

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