Synthesis and antitumor activity of sugar-ring hydroxyl analogues of daunorubicin.
Daunorubicin analogues in which the natural amino sugar, daunosamine, is replaced by neutral 2,6-dideoxy-hexopyranosyl residues have been prepared in high yields. Glycosidation of 3,4-di-O-acetyl-2,6-dideoxy-alpha-L-lyxo-hexopyranosyl chloride (13) with daunomycinone under Koenigs-Knorr conditions yielded exclusively the protected alpha-anomeric product 4, which was converted into the free glycoside 5. In contrast, the 1-chloro-D-ribo isomer 19, bearing p-nitrobenzoyl groups for hydroxyl-group protection, furnished a 5:3 mixture of the alpha (6) and beta (7) glycosides. Separation and individual deprotection afforded the target compounds 8 (from 6) and 9 (from 7). Whereas all of the D-ribo analogues (6--9) are inactive as antitumor agents in vivo against P388 lymphocytic leukemia in mice, the protected L-lyxo glycoside 4 (T/C 186) and also the free glycoside 5 (T/C 183) are highly effective in this test system; 5 is also active (T/C 146) in vivo against murine B16 melanocarcinoma.
D000818:Animals; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D066298:In Vitro Techniques; D007942:Leukemia, Experimental / Q000188:drug therapy; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D013329:Structure-Activity Relationship
D003630:Daunorubicin