Synthesis of daunorubicin analogues with novel 9-acyl substituents.
Synthetic approaches to anthracyclines bearing novel 9-acyl substituents were investigated. Reaction of the lithium enolate of N-(trifluoroacetyl)daunorubicin (9) with methyl iodide in tetrahydrofuran afforded only the 9-propionyl derivative 10 in high yield. Reaction of 10 under identical conditions cleanly afforded the 9-isobutyryl derivative 11. Extension of this procedure to other alkylating agents (ethyl iodide, benzyl bromide, and heptyl iodide) required hexamethylphosphoramide as cosolvent and afforded mixtures of mono- and dialkylated products as well as recovered 9. The amino group was deblocked with NaOH in aqueous tetrahydrofuran, except in the case of the dibenzyl derivative 13 which was inert under these conditions. The 9-formyl analogue 23 was prepared via NaIO4 cleavage of 13-dihydroadriamycin (21). Antitumor evaluation against P388 leukemia in mice showed 23 to have activity comparable to the parent compounds, while the C-alkylated analogues were less active.
D000818:Animals; D004247:DNA / Q000378:metabolism; D004273:DNA, Neoplasm / Q000096:biosynthesis; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D007939:Leukemia L1210 / Q000378:metabolism; D007942:Leukemia, Experimental / Q000188:drug therapy; D051379:Mice; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013329:Structure-Activity Relationship
D004273:DNA, Neoplasm; D012334:RNA, Neoplasm; D004247:DNA; D003630:Daunorubicin