title: Synthesis and biological evaluation of novel prodrugs of anthracyclines for selective activation by the tumor-associated protease plasmin.
abstract: New prodrugs of daunorubicin and doxorubicin designed for selective activation by the serine protease plasmin are described. The low toxic prodrugs 3, 4, and 5 are converted to the corresponding cytotoxic drugs upon proteolysis by the tumor-associated protease plasmin. Application of a self-eliminating spacer was essential for enzyme activation. A prodrug containing a chloro-substituted spacer was synthesized with the aim of enhancing the rate of conversion by plasmin. All prodrugs were highly stable in buffer solution and in serum and on the average 15-fold less cytotoxic than the parent drugs in seven human tumor cell lines. A marked in vitro selectivity was demonstrated by incubation of the doxorubicin prodrugs with a plasmin generating MCF-7 breast cancer cell line transfected with urokinase-type plasminogen activator (u-PA) in comparison with the nontransfected nonplasmin generating cell line. Prodrugs 4 and 5 showed the same cytotoxic effect as the free parent drug doxorubicin in the u-PA transfected cells, indicating complete conversion of the prodrug by plasmin. Addition of the plasmin inhibitor Trasylol drastically increased the ID(50) values in the u-PA transfected MCF-7 cells for both prodrugs 4 and 5.
authors.affiliation: Department of Organic Chemistry, NSR-Center for Molecular Structure, Design and Synthesis, University of Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands.
authors.forename: F M
authors.initials: FM
authors.lastname: de Groot
authors.forename: A C
authors.initials: AC
authors.lastname: de Bart
authors.forename: J H
authors.initials: JH
authors.lastname: Verheijen
authors.forename: H W
authors.initials: HW
authors.lastname: Scheeren
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001711:Biotransformation; D004354:Drug Screening Assays, Antitumor; D005341:Fibrinolysin / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D009682:Magnetic Resonance Spectroscopy; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D011355:Prodrugs; D005341:Fibrinolysin