Stephenson, M.J.Howell, L.A.O'Connell, M.A.Fox, K.R.Adcock, C.Kingston, J.Sheldrake, Helen M.Pors, KlausCollingwood, S.P.Searcey, M.2025-05-012016-11-012025-05-012015-10Stephenson 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.https://bradscholars.brad.ac.uk/handle/10454/10171.2YesThe 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.enThis 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.5b01373DuocarmycinsAntitumour agentsAntibody drug conjugates (ADCs)Solid phase synthesisC-terminal substitutionArticlehttps://doi.org/10.1021/acs.joc.5b01373Unspecified