title: Prodrugs of anthracyclines for chemotherapy via enzyme-monoclonal antibody conjugates.
abstract: New prodrugs of daunorubicin, 1c, 1e and 2c, including a galactopyranosyl residue linked to the N-3' of the daunosaminyl moiety through substituted o- or p-benzyloxycarbonyl groups were synthesized. Their low cytotoxicity and high stability in plasma fulfil the conditions for antibody-directed enzyme prodrug therapy (ADEPT). Enzymatic hydrolysis using alpha-D-galactosidase gives rise to daunorubicin by subsequent self-elimination of the spacers. However, elimination clearly depends on the aromatic substitution pattern, as demonstrated especially by comparison with non-substituted analogues.
authors.affiliation: Laboratoire de Chimie XII, Poitiers, France.
authors.forename: J P
authors.initials: JP
authors.lastname: Gesson
authors.forename: J C
authors.initials: JC
authors.lastname: Jacquesy
authors.forename: M
authors.initials: M
authors.lastname: Mondon
authors.forename: P
authors.initials: P
authors.lastname: Petit
authors.forename: B
authors.initials: B
authors.lastname: Renoux
authors.forename: S
authors.initials: S
authors.lastname: Andrianomenjanahary
authors.forename: H
authors.initials: H
authors.lastname: Dufat-Trinh Van
authors.forename: M
authors.initials: M
authors.lastname: Koch
authors.forename: S
authors.initials: S
authors.lastname: Michel
authors.forename: F
authors.initials: F
authors.lastname: Tillequin
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D003630:Daunorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D004355:Drug Stability; D057487:Enzyme Therapy; D006801:Humans; D000922:Immunotoxins / Q000097:blood / Q000737:chemistry* / Q000633:toxicity; D051379:Mice; D010636:Phenols / Q000097:blood / Q000138:chemical synthesis / Q000633:toxicity; D011355:Prodrugs / Q000138:chemical synthesis / Q000627:therapeutic use*; D013329:Structure-Activity Relationship; D000519:alpha-Galactosidase / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D010636:Phenols; D011355:Prodrugs; D000519:alpha-Galactosidase; D003630:Daunorubicin