title: Solid-Phase Synthesis of Duocarmycin Analogues and the Effect of C-Terminal Substitution on Biological Activity.
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.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Stephenson
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Howell
authors.forename: Maria A
authors.initials: MA
authors.lastname: O'Connell
authors.affiliation: Centre for Biological Sciences, University of Southampton , Life Sciences Building 85, Southampton SO17 1BJ, United Kingdom.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Fox
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals UK Limited , Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Adcock
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals UK Limited , Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors.forename: Jenny
authors.initials: J
authors.lastname: Kingston
authors.affiliation: Institute for Cancer Therapeutics, University of Bradford , Bradford, West Yorkshire BD7 1DP, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Sheldrake
authors.affiliation: Institute for Cancer Therapeutics, University of Bradford , Bradford, West Yorkshire BD7 1DP, United Kingdom.
authors.forename: Klaus
authors.initials: K
authors.lastname: Pors
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharmaceuticals UK Limited , Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Collingwood
authors.forename: Mark
authors.initials: M
authors.lastname: Searcey
mesh_terms: D000478:Alkylation; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry; D001483:Base Sequence; D000080890:Duocarmycins; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D060327:Solid-Phase Synthesis Techniques; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000903:Antibiotics, Antineoplastic; D000080890:Duocarmycins; D007211:Indoles; D011760:Pyrrolidinones; C058289:duocarmycin A