Synthesis and Biological Studies of Different Duocarmycin Based Glycosidic Prodrugs for Their Use in the Antibody-Directed Enzyme Prodrug Therapy

The synthesis and biological evaluation of novel prodrugs for use in the antibody directed enzyme prodrug therapy (ADEPT) of cancer based on the cytotoxic antibiotic duocarmycin SA (1) are described. In this approach, we investigated the influence of the sugar moiety of the glycosidic prodrug on the...

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Veröffentlicht in:	Journal of medicinal chemistry 2009-01, Vol.52 (2), p.537-543
Hauptverfasser:	Tietze, Lutz F, Schuster, Heiko J, Krewer, Birgit, Schuberth, Ingrid
Format:	Artikel
Sprache:	eng
Schlagworte:	Antibodies - therapeutic use Antineoplastic agents beta-Galactosidase - therapeutic use Biological and medical sciences Chromatography, High Pressure Liquid General aspects Glycosides - chemistry Indoles - chemical synthesis Indoles - chemistry Indoles - pharmacology Magnetic Resonance Spectroscopy Medical sciences Neoplasms - drug therapy Neoplasms - therapy Pharmacology. Drug treatments Prodrugs - chemical synthesis Prodrugs - chemistry Prodrugs - pharmacology Pyrroles - chemical synthesis Pyrroles - chemistry Pyrroles - pharmacology Spectrometry, Mass, Electrospray Ionization
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Zusammenfassung:	The synthesis and biological evaluation of novel prodrugs for use in the antibody directed enzyme prodrug therapy (ADEPT) of cancer based on the cytotoxic antibiotic duocarmycin SA (1) are described. In this approach, we investigated the influence of the sugar moiety of the glycosidic prodrug on the QIC50 values as well as on the stability and the water solubility. The best result was found for prodrug 22 containing an α-mannoside moiety with a QIC50 value of 4500.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm8009102