Solid-phase synthesis of duocarmycin analogues and the effect of C-terminal substitution on biological activity

Stephenson, Michael J., Howell, Lesley A., O’connell, Maria A., Fox, Keith R., Adcock, Claire, Kingston, Jenny, Sheldrake, Helen, Pors, Klaus, Collingwood, Stephen P. and Searcey, Mark (2015) Solid-phase synthesis of duocarmycin analogues and the effect of C-terminal substitution on biological activity. The Journal of Organic Chemistry, 80 (19), 9454-9467. (doi:10.1021/acs.joc.5b01373).

Abstract

The duocarmycins are potent antitumor agents with potential for use in the development of antibody–drug conjugates (ADCs) as well as being clinical candidates in their own right. In this article, we describe the synthesis of a duocarmycin monomer (DSA) that is suitably protected for utilization in solid-phase synthesis. The synthesis was performed on a large scale, and the resulting racemic protected Fmoc-DSA subunit was separated by supercritical fluid chromatography (SFC) into the single enantiomers; its application to solid-phase synthesis methodology gave a series of monomeric and extended duocarmycin analogues with amino acid substituents. The DNA sequence selectivity was similar to that in previous reports for both the monomeric and extended compounds. Substitution at the C-terminus of duocarmycin caused a decrease in antiproliferative activity for all of the compounds studied. An extended compound containing an alanine at the C-terminus was converted to the primary amide or to an extended structure containing a terminal tertiary amine, but this had no beneficial effects on biological activity.

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Contributors

Author: Keith R. Fox

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