Synthesis of novel pyrrolobenzodiazepine (PBD) C1-substituted monomers and dimers with DNA-binding activity and cytotoxicity

  • Bioorg Med Chem Lett. 2025 Apr 15:119:130095. doi: 10.1016/j.bmcl.2025.130095.
George Procopiou  1 ,  Paul J M Jackson  1 ,  Paolo Andriollo  1 ,  Md Mahbub Hasan  1 ,  Nicolas Veillard  1 ,  Khondaker Miraz Rahman  1 ,  David E Thurston  2
Affiliations
  • 1. School of Cancer & Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
  • 2. School of Cancer & Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK. Electronic address: [email protected].
PMID: 39778751 DOI: 10.1016/j.bmcl.2025.130095
Abstract

The Pyrrolobenzodiazepines (PBDs) represent a major class of sequence-selective DNA-alkylating molecules, one example of which, in its dimeric DNA-cross-linking form, is employed as the payload in the Anticancer Antibody Drug Conjugate (ADC) loncastuximab tesirine-lpyl. To date, PBD analogues have been produced with substituents at every position of the tricyclic skeleton except the C1-position. We report here the first synthesis of a C1-subsitituted PBD monomer and dimer, both of which possess DNA-binding activity and cytotoxicity in a Cancer cell line.

Keywords
ADC; Antitumour; C1-substituted; DNA cross-linking; DNA-binding; PBD; Pyrrolobenzodiazepine.
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