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

Michael Stephenson, Lesley Howell, Maria O'Connell, Keith R. Fox, Claire Adcock, Jenny Kingston, Helen Sheldrake, Klaus Pors, Stephen P. Collingwood, Mark Searcey

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Abstract

The duocarmycins are potent antitumour agents with potential in the development of antibody drug conjugates (ADCs) as well as being clinical candidates in their own right. In this paper, we describe the synthesis of a duocarmycin monomer (DSA) that is suitably protected for utilisation 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. 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 previous reports for both the monomeric and extended compounds. The substitution at the C-terminus of the 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.
Original languageEnglish
Pages (from-to)9454–9467
Number of pages14
JournalThe Journal of Organic Chemistry
Volume80
Issue number19
Early online date10 Sep 2015
DOIs
Publication statusPublished - 2 Oct 2015

Keywords

  • Duocarmycin SA
  • Natural product
  • SOLID-PHASE SYNTHESIS

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