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.
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.
Tiberghien
Arnaud C
AC
Spirogen Ltd, 29/39 Brunswick Square, London WC1N 1AX, UK.
Evans
David A
DA
Kiakos
Konstantinos
K
Martin
Christopher R H
CR
Hartley
John A
JA
Thurston
David E
DE
Howard
Philip W
PW
D001483:Base Sequence; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism*; D018983:DNA Footprinting; D019281:Dimerization; D006801:Humans; D020014:K562 Cells; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012689:Sequence Homology, Nucleic Acid; D013329:Structure-Activity Relationship
D003432:Cross-Linking Reagents; D011758:Pyrroles; C438462:pyrrolo(2,1-c)(1,4)benzodiazepine; D001569:Benzodiazepines; D004247:DNA