title: Synthesis and antitumor activity of novel 4-demethoxyanthracyclines.
abstract: A versatile and efficient synthetic route to 4-demethoxyanthracyclinones has been utilized in the preparation of a number of aglycons having 9-alkyl, 9-(hydroxylalkyl), or 9-carbamoyl substituents. Silver trifluoromethanesulfonate catalyzed coupling of these aglycons with various daunosamine derivatives has yielded a series of novel anthracyclines which have been evaluated as antitumor agents. 9-Alkylanthracyclines 22, 23, 33, and 34 have higher efficacy vs L-1210 leukemia than the parent 4-demethoxydaunorubicin (21), or the natural anthracyclines daunorubicin (1) and doxorubicin (2). 9-(Hydroxyalkyl) derivatives have in most cases high efficacy but are slightly less potent than 21. 9-Methyl analogue 22 has higher efficacy vs P388 leukemia than other anthracyclines tested, while 9-(hydroxymethyl) derivative 37 retains similar efficacy to anthracyclines 1, 2, and 21 but is considerably more potent. The N-substituted 9-carbamoylanthracyclines are devoid of antitumor activity.
authors.affiliation: Roche Products Limited, Welwyn Garden City, Hertfordshire, England.
authors.forename: N
authors.initials: N
authors.lastname: Adams
authors.forename: C
authors.initials: C
authors.lastname: Blake
authors.forename: M J
authors.initials: MJ
authors.lastname: Broadhurst
authors.forename: D J
authors.initials: DJ
authors.lastname: Bushnell
authors.forename: C H
authors.initials: CH
authors.lastname: Hassall
authors.forename: H R
authors.initials: HR
authors.lastname: Hartmann
authors.forename: E
authors.initials: E
authors.lastname: Keech
authors.forename: A R
authors.initials: AR
authors.lastname: Stratton
authors.forename: G J
authors.initials: GJ
authors.lastname: Thomas
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000627:therapeutic use; D055598:Chemical Phenomena; D002621:Chemistry; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D005260:Female; D015255:Idarubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D013329:Structure-Activity Relationship
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D015255:Idarubicin