Design, Synthesis, and Biophysical and Biological Evaluation of a Series of Pyrrolobenzodiazepine−Poly(N-methylpyrrole) Conjugates

• Published in: Journal of medicinal chemistry Vol. 49; no. 18; pp. 5442 - 5461
• Main Authors: Wells, Geoff, Martin, Christopher R. H, Howard, Philip W, Sands, Zara A, Laughton, Charles A, Tiberghien, Arnaud, Woo, Chi Kit, Masterson, Luke A, Stephenson, Marissa J, Hartley, John A, Jenkins, Terence C, Shnyder, Steven D, Loadman, Paul M, Waring, Michael J, Thurston, David E
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 07.09.2006; Amer Chemical Soc
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Benzodiazepines - chemical synthesis; Benzodiazepines - chemistry; Benzodiazepines - pharmacology; Biological and medical sciences; Cell Line, Tumor; Cell Membrane Permeability; Cell Nucleus - metabolism; Chemistry, Medicinal; DNA - chemistry; DNA Footprinting; Drug Screening Assays, Antitumor; Heterocyclic Compounds, 3-Ring - chemical synthesis; Heterocyclic Compounds, 3-Ring - chemistry; Heterocyclic Compounds, 3-Ring - pharmacology; Humans; Life Sciences & Biomedicine; Medical sciences; Miscellaneous; Models, Molecular; Nucleic Acid Denaturation; Permeability; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Transcription, Genetic; (PBD)-DISTAMYCIN HYBRID; DNA-BINDING AFFINITY; LINKER LENGTH; HYBRID MOLECULES; IN-VITRO CYTOTOXICITY; OLIGOPYRROLE CARRIERS; INTERSTRAND CROSS-LINKING; MINOR-GROOVE; NUCLEIC-ACIDS; DUPLEX DNA; Human; Leukemia; Footprinting technique; Pyrrole derivative polymer; Cytotoxicity; Thermal denaturation; Molecular interaction; In vitro; Modeling; Biological activity; Biological fixation; Cell line; DNA; Molecular model; Conjugated compound; Chemical synthesis; Tumor cell
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm051199z

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.