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.
Original language | English |
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Pages (from-to) | 9454–9467 |
Number of pages | 14 |
Journal | The Journal of Organic Chemistry |
Volume | 80 |
Issue number | 19 |
Early online date | 10 Sept 2015 |
DOIs | |
Publication status | Published - 2 Oct 2015 |
Keywords
- Duocarmycin SA
- Natural product
- SOLID-PHASE SYNTHESIS
Profiles
-
Maria O'Connell
- Faculty of Science - Associate Dean for Research
- School of Chemistry, Pharmacy and Pharmacology - Professor of Cell Biology
- Molecular and Tissue Pharmacology - Group Lead
- HealthUEA - Steering Committee Member
Person: Research Group Member, Academic, Teaching & Research
-
Mark Searcey
- School of Chemistry, Pharmacy and Pharmacology - Professor
Person: Research Centre Member, Academic, Teaching & Research