Daunosamine analogues

Deoxy-3 -homo-daunosamine analogues of anthracyclines containit 3-aminomethyl-2,3,4,6-tetradeoxy-a-L-hexosyl compounds have been synthesized, giving products with potent cytotoxic activity. ... 

Similarly, 1,4-addition of azide to L-e yt/iro-hex-2-enopyranose provided a stereoselective route to the methyl and benzyl glycosides of L-acosamine (3-amino-2,3,6-trideoxy-L-am6ino-hexose). Inversion at C-4 yielded the L-daunosamine analogues, in the same manner as detailed above (ref. 23). Sugar aldehydes have been chain extended to unsaturated N-methylthiazolium salts such as (39) and (41), which were converted through Michael addition of benzylamine, to the 3-amino-2,3-dideoxy-0(-D-t/irco-pentopyranoside (40) and the 7-deoxy-6-e/7i-lincosamine derivative (42) as shown in Schemes 8 and 9, respectively. 3-epi-... 

Dondoni, A, Fantin, G, Fogagnolo, M, Merino, P, Regio- and stereoselective conjugate addition of nitrogen nucleophiles to 2-alkenyl iV-methylthiazolium iodides. Synthesis of 3-epi-daunosamine and some lincosamine analogues. Tetrahedron, 46, 6167-6184, 1990 see also Ref. [97b]. 

Idarubicin (Fig. 42.17) is the 4-desmethoxy analogue of daunorubicin. The loss of the C4-ether flattens the D ring, facilitating intercalation between DNA base pairs. In turn, this orients the daunosamine sugar in the minor groove in a way that better stabilizes the ternary complex between drug, DNA, and topoisomerase (42). 

The syntheses of glycosides and esters of daunosamine (3-amino-2,3,6-trideoxy-L-/yxo-hexose) suitable for use in the synthesis of analogues of dauno-mycin and daunosamine-containing oligosaccharides have been reported. Methyl (methyl 3-acetamido-2,3-dideoxy-a-D- fe< -hexopyranosid)uronate (6) has been described in which the carboxylate grouping was established from the corresponding 6-azide by sequential photolysis, mild hydrolysis, and oxidation of the 6-aldehydo group. 

From Chiral Non-carbohydrates. - The 3-amino-3,6-dideoxy-hexose derivative 50 was the major product obtained from aldol condensation of the tricarbonyliron-diene complex 47 with the (R)-lactaldehyde derivative 48 (Scheme 14). Adduct 49 was the major (45%) of four isomers formed. If decom-plexation (step iv) preceded reduction (step ii), then the 2-epimer of 50 predominated. IV-Acetyl-L-daunosamine and its 5-C-isobutyl analogue (52) were synthesized from the corresponding cyanohydrin derivatives 51 by chain extension (Scheme 15). Aziridination of chiral traws-a,p-unsaturated esters such as 53 gave mainly two isomeric 2,3-epimines, e.g. 54 and 55 in the ratio 67 33 (Scheme... 

Furanoside analogues of daunorubicin or adriamycin have been prepared, derived from D-ribofuranose and daunosamine the latter sugar coupled to daunomycinone gave compounds which were less active than the pyranosyl analogue, but were much. less toxic and... 

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... 

The 7-0-j3-D-glucosamine derivative of daunomycinone was the first compound prepared in which the daunosamine residue is replaced [70]. The compound is however inactive in vivo [223] due to its inability to bind to DNA [213]. Esterification of the 7-OH group of daunomycin has also been attempted, for example compounds (89-93) show some activity in vivo [86,224]. It is interesting to compare the related compounds (94) and (95). The latter appears to have the greater degree of cellular penetration since it is about three times more active as an inhibitor of cellular nucleic acid synthesis, yet it shows no in vivo activity whereas compound (94) shows low activity [72]. The simpler analogue (95) therefore has an unfavourable distribution or is more rapidly hydrolysed. 

Curtius reaction. - The C-3-branched 3-amino-2,3,6-trideoxy-sugar analogue 40 of daunosamine has been synthesized from the di-C-branched derivative 39, and converted to the bicyclic derivative 41 (Scheme 11). Preparation of an analogous derivative 42 from a known... 

Synthesis of daunosamine and Its analogues, and coupling to an aglycone Comments... 

The retention of activity is expected since a substituent here would not fundamentally interfere with DNA binding according to the models proposed for the intercalation complex. Rubidazone, the benzhydrazone (A -benzoylhydrazone) of daunomycin [229], has been shown to be at least equivalent to daunomycin in the treatment of acute myeloblastic leukaemia [230] and in animal tests is claimed to be less cardiotoxic than adriamycin yet equivalent in potency [231]. Recently Gabbay has reported studies on a group of compounds (98-102) which have an amino substituent at C-13 [86]. All compounds bind to DNA in a similar manner to daunomycin but activity in vivo is much reduced as would be expected. It is significant that the water-soluble a ycones (101) and (102) retain activity in in vitro tests, although activity is lower than for the ycosidic analogues. This emphasises that the daunosamine unit can be replaced. 

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