title: Asymmetric synthesis and biological evaluation of glycosidic prodrugs for a selective cancer therapy.
abstract: A severe limitation in cancer therapy is the often insufficient differentiation between malign and benign tissue using known chemotherapeutics. One approach to decrease side effects is antibody-directed enzyme prodrug therapy (ADEPT). We have developed new glycosidic prodrugs such as (-)-(1S)-26 b based on the antibiotic (+)-duocarmycin SA ((+)-1) with a QIC(50) value of 3500 (QIC(50)=IC(50) of prodrug/IC(50) of prodrug+enzyme) and an IC(50) value for the corresponding drug (prodrug+enzyme) of 16 pM. The asymmetric synthesis of the precursor (-)-(1S)-19 was performed by arylation of the enantiomerically pure epoxide (+)-(S)-29 (> or = 98 % ee).
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: J Marian
authors.initials: JM
authors.lastname: von Hof
authors.forename: Birgit
authors.initials: B
authors.lastname: Krewer
authors.forename: Michael
authors.initials: M
authors.lastname: Müller
authors.forename: Felix
authors.initials: F
authors.lastname: Major
authors.forename: Heiko J
authors.initials: HJ
authors.lastname: Schuster
authors.forename: Ingrid
authors.initials: I
authors.lastname: Schuberth
authors.forename: Frauke
authors.initials: F
authors.lastname: Alves
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000080890:Duocarmycins; D006027:Glycosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D009369:Neoplasms / Q000188:drug therapy; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000080890:Duocarmycins; D006027:Glycosides; D007211:Indoles; D011355:Prodrugs; D011758:Pyrroles; C066098:duocarmycin SA; D001616:beta-Galactosidase