title: Development of ruthenium antitumor drugs that overcome multidrug resistance mechanisms.
abstract: Organometallic ruthenium(II) complexes of the general formula [Ru(eta6-p-cymene)Cl2(L)] and [Ru(eta6-p-cymene)Cl(L)2][BPh4] with modified phenoxazine- and anthracene-based multidrug resistance (MDR) modulator ligands (L) have been synthesized, spectroscopically characterized, and evaluated in vitro for their cytotoxic and MDR reverting properties in comparison with the free ligands. For an anthracene-based ligand, coordination to a ruthenium(II) arene fragment led to significant improvement of cytotoxicity as well as Pgp inhibition activity. A similar, but weaker effect was also observed when using a benzimidazole-phenoxazine derivative as Pgp inhibitor. The most active compound in terms of both Pgp inhibition and cytotoxicity is [Ru(eta6-p-cymene)Cl2(L)], where L is an anthracene-based ligand. Studies show that it induces cell death via inhibition of DNA synthesis. Moreover, because the complex is fluorescent, its uptake in cells was studied, and relative to the free anthracene-based ligand, uptake of the complex is accelerated and accumulation of the complex in the cell nucleus is observed.
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Vock
authors.forename: Wee Han
authors.initials: WH
authors.lastname: Ang
authors.forename: Claudine
authors.initials: C
authors.lastname: Scolaro
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Phillips
authors.forename: Lucienne
authors.initials: L
authors.lastname: Lagopoulos
authors.forename: Lucienne
authors.initials: L
authors.lastname: Juillerat-Jeanneret
authors.forename: Gianni
authors.initials: G
authors.lastname: Sava
authors.forename: Rosario
authors.initials: R
authors.lastname: Scopelliti
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dyson
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D000081007:Cymenes; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D039821:Monoterpenes / Q000737:chemistry; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010078:Oxazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012428:Ruthenium
chemical_list: D000873:Anthracenes; D000970:Antineoplastic Agents; D002614:Chelating Agents; D000081007:Cymenes; D008024:Ligands; D039821:Monoterpenes; D009942:Organometallic Compounds; D010078:Oxazines; C007210:4-cymene; D012428:Ruthenium