Anthracycline glycosides

J. Thiem and D. Springer, Synthesis and hydrogenation studies of 3-azidohex-2-enopyranosides, precursors of the sugar constituents of anthracycline glycosides, Carbohydr. Res., 136 (1985) 325-334. 

Y. Takagi, K. Nakai, T. Tsuchiya, T. Takeuchi, A 5 -(Trifluoromethyl)anthracycline glycoside Synthesis of antitumor-active 7-0-(2,6-dideoxy-6,6,6-trifluoro-a-L-/yxo-hexopyranosyl)adriamycinone, J. Med. Chem. 39 (1996) 1582-1588. 

Anticancer idarubicin/anthracycline glycoside Zavedos/Farmitalia drugs Idamycin/Adria... 

Idarubicin is a semisynthetic anthracycline glycoside analog of daunorubicin and is approved for use in combination with cytarabine for induction therapy of acute myeloid leukemia. When combined with cytarabine, idarubicin appears to be more active than daunorubicin in producing complete remissions and in improving survival in patients with acute myelogenous leukemia. 

Benzylic hydroxylation.3 Direct introduction of the Cl0-hydroxyI group into anthracycline glycosides can be effected with (CH3)3NO. Thus 1 is converted into oxaunomycin (2) in 82% yield from reactions in DMF. The yield is only 53% when acetone is the solvent, and is also lower (34%) in the absence of the Cn-hydroxyl group. 

Intercalating Agents are compounds with fused eiromatic ring systems that can wedge (intercalate) between the stacked base pairs of DNA. Tliis disrupts the structure of the DNA so that the replicative enzymes have difficulty in synthesizing DNA past the "intercalated" sites. Anthracycline glycosides and Actinomycin D are intercalators used to treat a variety of cancers. 

Daunomycin (310) and doxorubicin (311) are anthracycline glycosides, isolated from Streptomyces peucetius [18]. These compounds are used in cancer chemotherapy due to their ability to bind DNA. Both compounds inhibit RT and production of murine leukemia virus [18]. 

Oki T, Yoshimoto A, Kouno K, Inui T, Takeuchi T, Umezawa H (1981) Anthracycline glycosides. EP Patent 26 849 (Chem Abstr 95 40852)... 

Fujiwara A, Hoshino T (1983) Optically active anthracycline glycosides, 4-deoxy-aclacinomycins A and B and pharmaceutical preparations. EP Patent 83019 (Chem Abstr 99 120690)... 

Therefore, it is not surprising that the fascination of fluorine entered the field of anthracycline glycoside synthesis. Remarkable chemical interest consequently arose on the introduction of fluorine into the anthracycline molecule with the aim of altering the biorelevance of functional groups, thus providing new compounds whose DNA-drug interaction and antitumor properties could be compared with those exhibited by the clinically used an-thracyclines (1-4) (Fig. 1). 

S Kaneko, M Kishikawa, T Sato, K Maeda. Manufacture of freeze-dried anthracycline glycoside preparations with improved solubility. Japanese Patent 07076515, June 30, 1993. 

McCarvillc M, Marshall V. Paitiai purification and characterization of a bacterial enzyme catalyzing reductive cleavage of anthracycline glycosides. Biochem Biophys Res Ccunmun... 

Antibiotics. - Reversed-phase h.p.l.c. analyses have been reported for the following dialkylamino-sugar-containing antibiotics the anthracycline glycoside 3 -deamino-3 -[2(S)-methoxy-4-morpholinyl]doxorubicin and its possible 13-dehydro-metabolite, the macrolide antibiotics rokitamycin and josamycin as their dansylhydrazone derivatives. In addition, erythromycin ethyl succinate and its process impurities erythromycin A, the ethyl succinate esters of erythromycin B and C and A-(ethyl succinyl)-iV-demethyletythromycin A were analyzed by ion-pair reversed-phase h.p.l.c. ... 

All of Hamao U mezawa s work was closely connected with carbohydrates. The principal compounds that he developed, namely, kanamycin, dibekacin (with the elucidation of the resistance mechanism), kasugamycin, formycin, bleomycin, and anthracyclines, are all glycosides. The l.m.w. enzyme-inhibitors, exemplified by bestatin, are mostly oligopeptides, and are the only exceptions. 

The present contribution centers on stereoselective syntheses of mono- and in particular oligo-saccharides of the 2-deoxy- and the 2,6-dideoxy series as well as some branched-chain species. These are the principal sugar portions in a large number of important natural glycosides, such as the cardiac glycosides (3), the orthosomy-cins (D, the tetronic acids (5), the aureolic acids (6, see below), and the anthracyclines (2, see below), to name just a few. 

Both procedures for selective syntheses of 2,6-dideoxy-a- and B-glycosides will be outlined in the aure-olic acid and also the anthracycline oligosaccharide series. 

Complex glycosylated compounds like macrolides, anthracyclines, aureolic acids, cardiac glycosides, orthosomycines and tetronic acids are of considerable scientific as well as pharmaceutical interest. Obviously, each of them is responsible for certain therapeutic effects with respect to different diseases. Anthracyclines and aureolic acids are applied in cancer chemotherapy, orthosomycines are active as antibiotics against Gram-positive bacteria, and the cardiac glycosides are used in the treatment of cardiac insufficiency. 

Anthracyclines isolated from stieptomyces show a 2,3,6-trideoxy-3-amino-L-/yxo-configurated sugar oc-attached to the aglycon. Therefore, the first interest centered on the synthesis of aminodeoxy sugars in the l-lyxo series, e.g., daunosamine [46-50]. Several new glycosides were prepared [51] in order to evaluate structure-activity relationships. 

L-Oliose (2,6-dideoxy-L-/v. o-hexose, 54L) is the internal unit in the trisaccharide chain glycosidically linked to the anthracycline Aclacinomycin... 

Kimura, Y, Suzuki, M, Matsumoto, T, Ahe, R, Terashima, S, Trimethylsilyl trifluoromethanesulfonate (trimethylsilyl triflate) as an excellent glycosidation reagent for anthracycline synthesis. Simple and efficient synthesis of optically pure 4-demethoxydaunoruhicin, Chem. Lett, 501 -504, 1984. 

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