Enantio- and diastereoselective synthesis of duocarmycine-based prodrugs for a selective treatment of cancer by epoxide opening.

Abstract

For the enantio- und diastereoselective synthesis of the prodrug 2, the N-tert-butyloxycarbonyl-protected amine 7 was alkylated with the enantiopure epoxide 14 to give the amide 10. A regio- and facial-selective metal-mediated cyclisation by using a cuprate led to 17 with an inversion of configuration at C10. Subsequent transformation of the hydroxy group in 17 by using the Appel procedure afforded (1S,10R)-9 with an unusual double inversion owing to neighbouring-group participation of the N-tert-butoxycarbonyl group. (1S,10R)-9 is the key intermediate in the synthesis of the prodrug 2, which has been developed for a selective treatment of cancer based on the antibody-directed enzyme prodrug therapy as an analogue of the natural antibiotic duocarmycine SA (1).

• Authors: Lutz F Tietze, Heiko J Schuster, Sonja M Hampel, Stephan Rühl, Roland Pfoh
• Journal: Chemistry (Weinheim an der Bergstrasse, Germany) (Chemistry) Vol. 14 Issue 3 Pg. 895-901 ( 2008) ISSN: 0947-6539 [Print] Germany
• PMID: 18033701 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Duocarmycins
• Epoxy Compounds
• Indoles
• Prodrugs
• Pyrrolidinones
• duocarmycin A

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, therapeutic use)
• Crystallography, X-Ray
• Cyclization
• Duocarmycins
• Epoxy Compounds (chemical synthesis, chemistry)
• Indoles (chemical synthesis, chemistry)
• Models, Molecular
• Molecular Conformation
• Neoplasms (drug therapy)
• Prodrugs (chemical synthesis, chemistry, therapeutic use)
• Pyrrolidinones (chemical synthesis, chemistry)
• Stereoisomerism