Asymmetric synthesis and biological evaluation of glycosidic prodrugs for a selective cancer therapy.
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).
Tietze
Lutz F
LF
Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany. ltietze@gwdg.de
von Hof
J Marian
JM
Krewer
Birgit
B
Müller
Michael
M
Major
Felix
F
Schuster
Heiko J
HJ
Schuberth
Ingrid
I
Alves
Frauke
F
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
D000970:Antineoplastic Agents; D000080890:Duocarmycins; D006027:Glycosides; D007211:Indoles; D011355:Prodrugs; D011758:Pyrroles; C066098:duocarmycin SA; D001616:beta-Galactosidase