title: Design, synthesis and in vitro cytotoxicity studies of novel pyrrolo[2,1-c][1,4]benzodiazepine (PBD)--polymade conjugates and 2,2'-PBD dimers.
abstract: A series of novel pyrrolo[2,1-c][l,4]benzodiazepine (PBD)-polyamide conjugates (1 and 2) and 2,2'-PBD dimers (3, 4 and 5) were synthesized and evaluated for cytotoxicity in >60 human tumor cell lines. In general PBD-polyamide conjugates (1 and 2) exhibit higher cytotoxic potency compared with 2,2'-PBD dimers (3, 4 and 5). Compound 2 exhibits a wide spectrum of anticancer activities against 17 cell lines in six cancer panels with LC50 values of <9 microM, and is especially effective against colon cancer, melanoma, renal cancer and breast cancer. Compound 1 selectively affects cell growth against renal cancer A 498 cell line and compound 4 affects cell growth against breast cancer MDA-MB-231/ATCC cell line with an LC50 value 0.06 microM. Increases in the chain length of the linker in 2,2'-PBD dimers significantly increase the cytotoxic potency and increases in the number of pyrrole groups in the PBD-polyamide conjugates similarly increase the cytotoxic potency.
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, Canada.
authors.forename: B S
authors.initials: BS
authors.lastname: Reddy
authors.forename: Y
authors.initials: Y
authors.lastname: Damayanthi
authors.forename: B S
authors.initials: BS
authors.lastname: Reddy
authors.forename: J W
authors.initials: JW
authors.lastname: Lown
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000633:toxicity*; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000633:toxicity*; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000633:toxicity; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D019281:Dimerization; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009757:Nylons / Q000138:chemical synthesis / Q000633:toxicity; D011758:Pyrroles / Q000138:chemical synthesis / Q000633:toxicity; D014407:Tumor Cells, Cultured / Q000187:drug effects*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; D009757:Nylons; D011758:Pyrroles; D001569:Benzodiazepines