title: Synthesis of a novel C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione library: effect of C2-aryl substitution on cytotoxicity and non-covalent DNA binding.
abstract: A 23-member C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione (PBD dilactam) library has been synthesized using Suzuki coupling, and the effect of base upon racemisation at the C11a-position during the cross-coupling reaction studied. Three library members (21, 30 and 33) were sufficiently cytotoxic in the NCI's preliminary screen to warrant further evaluation, and one (30, R=p-Br) was found to be cytotoxic at the sub-micromolar level in the A498 renal cancer cell line. DNA thermal denaturation studies suggested that this activity may be associated with non-covalent DNA interaction, and also demonstrated that introduction of C2-C3 unsaturation and addition of C2-aryl functionalities to the PBD dilactam skeleton significantly enhanced helix stabilisation compared to the unsubstituted PBD dilactam (6).
authors.affiliation: Cancer Research UK Gene Targeted Drug Design Research Group, The School of Pharmacy, University of London, 29/39 Brunswick Square, London WC1N 1AX, UK.
authors.forename: Dyeison
authors.initials: D
authors.lastname: Antonow
authors.forename: Terence C
authors.initials: TC
authors.lastname: Jenkins
authors.forename: Philip W
authors.initials: PW
authors.lastname: Howard
authors.forename: David E
authors.initials: DE
authors.lastname: Thurston
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D019540:Area Under Curve; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000494:pharmacology*; D002384:Catalysis; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004273:DNA, Neoplasm / Q000378:metabolism*; D006358:Hot Temperature; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009691:Nucleic Acid Denaturation; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D001569:Benzodiazepines