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Solid-phase synthesis of duocarmycin analogues and the effect of C-terminal substitution on biological activity
Stephenson, M.J. Howell, L.A. O'Connell, M.A. Fox, K.R. Adcock, C. Kingston, J. Sheldrake, Helen M. Collingwood, S.P. Searcey, M.
Stephenson, M.J.
Howell, L.A.
O'Connell, M.A.
Fox, K.R.
Adcock, C.
Kingston, J.
Sheldrake, Helen M.
Collingwood, S.P.
Searcey, M.
Publication Date
2015-10
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This document is the Accepted Manuscript version of a Published Work
that appeared in final form in Journal of Organic Chemistry, copyright © American Chemical
Society after peer review and technical editing by the publisher. To access the final edited and
published work see http://dx.doi.org/10.1021/acs.joc.5b01373
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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.
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Accepted manuscript
Citation
Stephenson MJ, Howell LA, O’Connell MA et al (2015) Solid-phase synthesis of
duocarmycin analogues and the effect of C-terminal substitution on biological activity. Journal of
Organic Chemistry. 80(19): 9454-9467.
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Article