Collingwood, Stephen, Stephenson, Michael, Howell, Lesley, O'Connell, Maria, Kingston, Jenny, Sheldrake, Helen, Pors, Claus, Searcy, Mark and Adcock, Claire (2015) The effect of substitutions on the C-terminus of duocarmycin analogues derived from solid phase synthesis. Journal of the American Chemical Society.

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 super-critical 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 sequence selectivity on DNA matched reported data 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. With an extended compound containing an alanine at the C-terminus, converting it to the primary amide or to an extended structure containing a terminal tertiary amine had no beneficial effects on biological activity

Item Type:	Article
Date Deposited:	26 Apr 2016 23:45
Last Modified:	26 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/23958