Design, synthesis, and biophysical and biological evaluation of a series of pyrrolobenzodiazepine-poly(N-methylpyrrole) conjugates.
A novel series of methyl ester-terminated C8-linked pyrrolobenzodiazepine (PBD)-poly(N-methylpyrrole) conjugates (50a-f) has been synthesized and their DNA interaction evaluated by thermal denaturation, DNA footprinting, and in vitro transcription stop assays. The synergistic effect of attaching a PBD unit to a polypyrrole fragment is illustrated by the large increase in DNA binding affinity (up to 50-fold) compared to the individual PBD and pyrrole components. 50a-f were found to bind mainly to identical DNA sequences but with apparent binding site widths increasing with molecular length and the majority of sites conforming to the consensus motif 5'-XGXWz (z = 3 +/- 1; W = A or T; X = any base but preferably a purine). They also provided robust sequence-selective blockade of transcription at sites corresponding approximately to their DNA footprints. 50a-f were shown to have good cellular/nuclear penetration properties, and a degree of correlation between cytotoxicity and DNA-binding affinity was observed.
Wells
Geoff
G
Cancer Research UK Gene Targeted Drug Design Research Group, The School of Pharmacy, University of London, 29/39 Brunswick Square, London WC1N 1AX, UK.
Martin
Christopher R H
CR
Howard
Philip W
PW
Sands
Zara A
ZA
Laughton
Charles A
CA
Tiberghien
Arnaud
A
Woo
Chi Kit
CK
Masterson
Luke A
LA
Stephenson
Marissa J
MJ
Hartley
John A
JA
Jenkins
Terence C
TC
Shnyder
Steven D
SD
Loadman
Paul M
PM
Waring
Michael J
MJ
Thurston
David E
DE
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D018983:DNA Footprinting; D004354:Drug Screening Assays, Antitumor; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D009691:Nucleic Acid Denaturation; D010539:Permeability; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic
D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; D011758:Pyrroles; D001569:Benzodiazepines; D004247:DNA