title: Dinuclear platinum complexes with N, N'-bis(aminoalkyl)-1,4-diaminoanthraquinones as linking ligands. Part I. Synthesis, cytotoxicity, and cellular studies in A2780 human ovarian carcinoma cells.
abstract: A series of N, N'-bis(aminoalkyl)-1,4-diaminoanthraquinones (aminoalkyl=2-aminoethyl, 3-aminoprop-1-yl and 4-aminobut-1-yl) was functionalized with trans-platinum DNA-binding moieties. Cytotoxicity testing in A2780 human ovarian carcinoma cells revealed high anticancer activity of the formed cationic dinuclear platinum complexes. The cationic dinuclear platinum complexes with the shortest aminoalkyl chain were shown to be the most active, which agrees with the structure-activity relationship found for the corresponding free ligands without platinum. The N, N'-bis(aminoalkyl)-1,4-diaminoanthraquinones partly circumvent cisplatin resistance, whereas their dinuclear platinum complexes were found susceptible to the resistance mechanisms in A2780cisR. The platinum complexes have resistance factors comparable to the control dinuclear complex BBR3005 [(trans-PtCl(NH3)2)2)(micro-(NH2(CH2)6NH2))](NO3)2. The 1,4-diaminoanthraquinone moiety is fluorescent, and thus the cellular processing of the compounds could be monitored by time-lapse digital fluorescence microscopy. The intercalators without platinum were shown to enter the cells within minutes. The platinum complexes enter the cells more slowly. Most likely, the positive charges of the platinum complexes hamper the diffusion through the membrane. Interestingly, the platinum complexes are processed differently than the platinum-free compounds by the cells. After 24 hours the fluorescent platinum complexes are encapsulated in large vesicles in the cytosol. Co-localization of the anthraquinone fluorescence with Lysotracker Green DND-26 shows that these vesicles are acidic compartments, probably lysosomes.
authors.affiliation: Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands.
authors.forename: Bart A J
authors.initials: BA
authors.lastname: Jansen
authors.forename: Peter
authors.initials: P
authors.lastname: Wielaard
authors.forename: Ganna V
authors.initials: GV
authors.lastname: Kalayda
authors.forename: Maura
authors.initials: M
authors.lastname: Ferrari
authors.forename: Chris
authors.initials: C
authors.lastname: Molenaar
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Tanke
authors.forename: Jaap
authors.initials: J
authors.lastname: Brouwer
authors.forename: Jan
authors.initials: J
authors.lastname: Reedijk
mesh_terms: D000880:Anthraquinones; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001692:Biological Transport; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005456:Fluorescent Dyes; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008247:Lysosomes / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013329:Structure-Activity Relationship
chemical_list: D000880:Anthraquinones; D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D008024:Ligands; D009944:Organoplatinum Compounds; D004247:DNA