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

George Procopiou; Paul J.M. Jackson; Paolo Andriollo; Md Mahbub Hasan; Nicolas Veillard; Khondaker Miraz Rahman; David E. Thurston

doi:10.1016/j.bmcl.2025.130095

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

George Procopiou, Paul J.M. Jackson, Paolo Andriollo, Md Mahbub Hasan, Nicolas Veillard, Khondaker Miraz Rahman, David E. Thurston^*

^*Corresponding author for this work

Institute of Pharmaceutical Science

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	130095
Journal	BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS
Volume	119
Early online date	6 Jan 2025
DOIs	https://doi.org/10.1016/j.bmcl.2025.130095
Publication status	Published - 15 Apr 2025

Keywords

ADC
Antitumour
C1-substituted
DNA cross-linking
DNA-binding
PBD
Pyrrolobenzodiazepine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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

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.",

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T1 - Synthesis of novel pyrrolobenzodiazepine (PBD) C1-substituted monomers and dimers with DNA-binding activity and cytotoxicity

AU - Procopiou, George

AU - Jackson, Paul J.M.

AU - Andriollo, Paolo

AU - Hasan, Md Mahbub

AU - Veillard, Nicolas

AU - Rahman, Khondaker Miraz

AU - Thurston, David E.

PY - 2025/4/15

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AB - 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.

KW - ADC

KW - Antitumour

KW - C1-substituted

KW - DNA cross-linking

KW - DNA-binding

KW - PBD

KW - Pyrrolobenzodiazepine

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JF - BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS

M1 - 130095

ER -

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

Abstract

Keywords

UN SDGs

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