Synthesis and biological evaluation of a novel C8-pyrrolobenzodiazepine (PBD) adenosine conjugate. A study on the role of the PBD ring in the biological activity of PBD-conjugates

Lindsay Ferguson, Sanjib Bhakta, Keith R. Fox, Geoff Wells, Federico Brucoli*

*Corresponding author for this work

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Abstract

Here we sought to evaluate the contribution of the PBD unit to the biological activity of PBD-conjugates and, to this end, an adenosine nucleoside was attached to the PBD A-ring C8 position. A convergent approach was successfully adopted for the synthesis of a novel C8-linked pyrrolo(2,1-c)(1,4)benzodiazepine(PBD)-adenosine(ADN) hybrid. The PBD and adenosine (ADN) moieties were synthesized separately and then linked through a pentynyl linker. To our knowledge, this is the first report of a PBD connected to a nucleoside. Surprisingly, the compound showed no cytotoxicity against murine cells and was inactive against Mycobacterium aurum and M. bovis strains and did not bind to guanine-containing DNA sequences, as shown by DNase I footprinting experiments. Molecular dynamics simulations revealed that the PBD-ADN conjugate was poorly accommodated in the DNA minor groove of two DNA sequences containing the AGA-PBD binding motif, with the adenosine moiety of the ligand preventing the covalent binding of the PBD unit to the guanine amino group of the DNA duplex. These interesting findings shed further light on the ability of the substituents attached at the C8 position of PBDs to affect and modulate the biological and biophysical properties of PBD hybrids.

Original languageEnglish
Article number1243
Number of pages14
JournalMolecules
Volume25
Issue number5
DOIs
Publication statusPublished - 10 Mar 2020

Keywords

  • Adenosine nucleoside
  • Anti-mycobacterial compounds
  • C8-linked pyrrolobenzodiazepine (PBD) conjugates
  • DNA minor groove binding agents
  • DNase I footprinting
  • Heterodimeric hybrids
  • High-throughput spot-culture growth inhibition assay

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