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

Stephenson, Michael ORCID: https://orcid.org/0000-0002-2594-1806, Howell, Lesley, O'Connell, Maria ORCID: https://orcid.org/0000-0002-0267-0951, Fox, Keith R., Adcock, Claire, Kingston, Jenny, Sheldrake, Helen, Pors, Klaus, Collingwood, Stephen P. and Searcey, Mark ORCID: https://orcid.org/0000-0003-2273-8949 (2015) Solid-phase synthesis of duocarmycin analogues and the effect of C-terminal substitution on biological activity. The Journal of Organic Chemistry, 80 (19). 9454–9467. ISSN 0022-3263

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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.

Item Type:	Article
Uncontrolled Keywords:	duocarmycin sa,natural product,solid-phase synthesis
Faculty \ School:	Faculty of Science > School of Pharmacy (former - to 2024) Faculty of Science > School of Chemistry (former - to 2024)
UEA Research Groups:	Faculty of Science > Research Groups > Medicinal Chemistry (former - to 2017) Faculty of Science > Research Groups > Pharmaceutical Cell Biology (former - to 2017) Faculty of Science > Research Groups > Chemical Biology and Medicinal Chemistry (former - to 2021) Faculty of Science > Research Groups > Molecular and Tissue Pharmacology Faculty of Science > Research Groups > Chemistry of Life Processes
Depositing User:	Pure Connector
Date Deposited:	25 Sep 2015 13:24
Last Modified:	24 Sep 2024 11:24
URI:	https://ueaeprints.uea.ac.uk/id/eprint/54517
DOI:	10.1021/acs.joc.5b01373

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