title: Synthesis and biological evaluation of prodrugs based on the natural antibiotic duocarmycin for use in ADEPT and PMT.
abstract: Chemotherapy of malign tumors is usually associated with serious side effects as common anticancer drugs lack selectivity. An approach to deal with this problem is the antibody-directed enzyme prodrug therapy (ADEPT) and the prodrug monotherapy (PMT). Herein, the synthesis and biological evaluation of new glycosidic prodrugs suitable for both concepts are described. All prodrugs but one are stable in human serum and show QIC(50) values (IC(50) of prodrug/IC(50) of prodrug in the presence of the appropriate glycohydrolase) of up to 6500. This is the best value found so far for compounds interacting with DNA.
authors.affiliation: Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstraße 2, 37077 Göttingen, Germany. ltietze@gwdg.de
authors.forename: Lutz F
authors.initials: LF
authors.lastname: Tietze
authors.forename: Kianga
authors.initials: K
authors.lastname: Schmuck
authors.forename: Heiko J
authors.initials: HJ
authors.lastname: Schuster
authors.forename: Michael
authors.initials: M
authors.lastname: Müller
authors.forename: Ingrid
authors.initials: I
authors.lastname: Schuberth
mesh_terms: D000906:Antibodies / Q000627:therapeutic use; D004247:DNA / Q000378:metabolism*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D000080890:Duocarmycins; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D000906:Antibodies; D000080890:Duocarmycins; D007211:Indoles; D011355:Prodrugs; D011758:Pyrroles; C066098:duocarmycin SA; D004247:DNA; D005966:Glucuronidase