title: Synthesis, aqueous reactivity, and biological evaluation of carboxylic acid ester-functionalized platinum-acridine hybrid anticancer agents.
abstract: The synthesis of platinum-acridine hybrid agents containing carboxylic acid ester groups is described. The most active derivatives and the unmodified parent compounds showed up to 6-fold higher activity in ovarian cancer (OVCAR-3) and breast cancer (MCF-7, MDA-MB-231) cell lines than cisplatin. Inhibition of cell proliferation at nanomolar concentrations was observed in pancreatic (PANC-1) and nonsmall cell lung cancer cells (NSCLC, NCI-H460) of 80- and 150-fold, respectively. Introduction of the ester groups did not affect the cytotoxic properties of the hybrids, which form the same monofunctional-intercalative DNA adducts as the parent compounds, as demonstrated in a plasmid unwinding assay. In-line high-performance liquid chromatography and electrospray mass spectrometry (LC-ESMS) shows that the ester moieties undergo platinum-mediated hydrolysis in a chloride concentration-dependent manner to form carboxylate chelates. Potential applications of the chloride-sensitive ester hydrolysis as a self-immolative release mechanism for tumor-selective delivery of platinum-acridines are discussed.
authors.affiliation: Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina 27109, USA.
authors.forename: Leigh A
authors.initials: LA
authors.lastname: Graham
authors.forename: Jimmy
authors.initials: J
authors.lastname: Suryadi
authors.forename: Tiffany K
authors.initials: TK
authors.lastname: West
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Kucera
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bierbach
mesh_terms: D002264:Carboxylic Acids / Q000737:chemistry*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004952:Esters; D006801:Humans; D010984:Platinum / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D014867:Water
chemical_list: D002264:Carboxylic Acids; D004952:Esters; D014867:Water; D010984:Platinum