An asymmetric C8/C8'-tripyrrole-linked sequence-selective pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimer DNA interstrand cross-linking agent spanning 11 DNA base pairs

Arnaud C Tiberghien; David A Evans; Konstantinos Kiakos; Christopher R H Martin; John A Hartley; David E Thurston; Philip W Howard

doi:10.1016/j.bmcl.2008.01.096

An asymmetric C8/C8'-tripyrrole-linked sequence-selective pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimer DNA interstrand cross-linking agent spanning 11 DNA base pairs

Bioorg Med Chem Lett. 2008 Mar 15;18(6):2073-7. doi: 10.1016/j.bmcl.2008.01.096. Epub 2008 Jan 30.

Authors

Arnaud C Tiberghien¹, David A Evans, Konstantinos Kiakos, Christopher R H Martin, John A Hartley, David E Thurston, Philip W Howard

Affiliation

¹ Spirogen Ltd, 29/39 Brunswick Square, London WC1N 1AX, UK.

PMID: 18272367
DOI: 10.1016/j.bmcl.2008.01.096

Abstract

A novel sequence-selective extended PBD dimer 4 has been synthesized that binds with high affinity to an interstrand cross-linking site spanning 11 DNA base pairs. Despite its molecular weight (984.07) and length, the molecule has significant DNA interstrand cross-linking potency (approximately 100-fold greater than the clinically used agent melphalan) and sub-micromolar cytotoxicity in a number of tumour cell lines, suggesting that it readily penetrates cellular and nuclear membranes to reach its DNA target.

MeSH terms

Base Sequence
Benzodiazepines / chemical synthesis*
Benzodiazepines / chemistry
Benzodiazepines / pharmacology*
Cross-Linking Reagents / chemical synthesis*
Cross-Linking Reagents / chemistry
Cross-Linking Reagents / pharmacology*
DNA / metabolism*
DNA Footprinting
Dimerization
Humans
K562 Cells
Molecular Sequence Data
Molecular Structure
Pyrroles / chemical synthesis*
Pyrroles / chemistry
Pyrroles / pharmacology*
Sequence Homology, Nucleic Acid
Structure-Activity Relationship

Substances

Cross-Linking Reagents
Pyrroles
pyrrolo(2,1-c)(1,4)benzodiazepine
Benzodiazepines
DNA