Synthesis and biological evaluation of a novel pentagastrin-toxin conjugate designed for a targeted prodrug mono-therapy of cancer.
A novel carbamate prodrug 2 containing a pentagastrin moiety was synthesized. 2 was designed as a detoxified analogue of the highly cytotoxic natural antibiotic duocarmycin SA (1) for the use in a targeted prodrug monotherapy of cancers expressing cholecystokinin (CCK-B)/gastrin receptors. The synthesis of prodrug 2 was performed using a palladium-catalyzed carbonylation of bromide 6, followed by a radical cyclisation to give the pharmacophoric unit 10, coupling of 10 to the DNA-binding subunit 15 and transformation of the resulting seco-drug 3b into the carbamate 2 via addition of a pentagastrin moiety.
Tietze
Lutz F
LF
Institute of Organic and Biomolecular Chemistry, Georg-August-University Göttingen, Tammannstraße 2, D-37077 Göttingen, Germany.
Panknin
Olaf
O
Institute of Organic and Biomolecular Chemistry, Georg-August-University Göttingen, Tammannstraße 2, D-37077 Göttingen, Germany.
Krewer
Birgit
B
Institute of Organic and Biomolecular Chemistry, Georg-August-University Göttingen, Tammannstraße 2, D-37077 Göttingen, Germany.
Major
Felix
F
Institute of Organic and Biomolecular Chemistry, Georg-August-University Göttingen, Tammannstraße 2, D-37077 Göttingen, Germany.
Schuberth
Ingrid
I
Institute of Organic and Biomolecular Chemistry, Georg-August-University Göttingen, Tammannstraße 2, D-37077 Göttingen, Germany.