title: Redesigning the DNA-targeted chromophore in platinum-acridine anticancer agents: a structure-activity relationship study.
abstract: Platinum-acridine hybrid agents show low-nanomolar potency in chemoresistant non-small cell lung cancer (NSCLC), but high systemic toxicity in vivo. To reduce the promiscuous genotoxicity of these agents and improve their pharmacological properties, a modular build-click-screen approach was used to evaluate a small library of twenty hybrid agents containing truncated and extended chromophores of varying basicities. Selected derivatives were resynthesized and tested in five NSCLC cell lines representing large cell, squamous cell, and adenocarcinomas. 7-Aminobenz[c]acridine was identified as a promising scaffold in a hybrid agent (P1-B1) that maintained submicromolar activity in several of the DNA-repair proficient and p53-mutant cancer models, while showing improved tolerability in mice by 32-fold compared to the parent platinum-acridine (P1-A1). The distribution and DNA/RNA adduct levels produced by the acridine- and benz[c]acridine-based analogues in NCI-H460 cells (confocal microscopy, ICP-MS), and their ability to bind G-quadruplex forming DNA sequences (CD spectroscopy, HR-ESMS) were studied. P1-B1 emerges as a less genotoxic, more tolerable, and potentially more target-selective hybrid agent than P1-A1.
authors.affiliation: Department of Chemistry, Wake Forest University, Winston-Salem, NC 27109 (USA).
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Pickard
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Bartenstein
authors.forename: Laura G
authors.initials: LG
authors.lastname: Haines
authors.forename: Keith E
authors.initials: KE
authors.lastname: Levine
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Kucera
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bierbach
mesh_terms: D000166:Acridines / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D018736:DNA Adducts / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D054856:G-Quadruplexes / Q000187:drug effects; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry* / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics; D051379:Mice; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents; D018736:DNA Adducts; D007364:Intercalating Agents; D009944:Organoplatinum Compounds
keywords: DNA adducts; anticancer drugs; cellular target; cytotoxicity; intercalation