Structure−Activity Relationships for Cytotoxic Ruthenium(II) Arene Complexes Containing N,N-, N,O-, and O,O-Chelating Ligands

• Published in: Journal of medicinal chemistry Vol. 49; no. 23; pp. 6858 - 6868
• Main Authors: Habtemariam, Abraha, Melchart, Michael, Fernández, Rafael, Parsons, Simon, Oswald, Iain D. H, Parkin, Andrew, Fabbiani, Francesca P. A, Davidson, James E, Dawson, Alice, Aird, Rhona E, Jodrell, Duncan I, Sadler, Peter J
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 16.11.2006
• Subjects: 2,2'-Dipyridyl - chemistry; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Benzene Derivatives - chemistry; Carboplatin - pharmacology; Cell Line, Tumor; Chelating Agents - chemistry; Cisplatin - pharmacology; Crystallography, X-Ray; Diamines - chemistry; Doxorubicin - pharmacology; Drug Screening Assays, Antitumor; Humans; Ligands; Molecular Structure; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Polycyclic Compounds - chemistry; Ruthenium; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm060596m

We report structure−activity relationships for organometallic RuII complexes of the type [(η6-arene)Ru(XY)Cl]Z, where XY is an N,N- (diamine), N,O- (e.g., amino acidate), or O,O- (e.g., β-diketonate) chelating ligand, the arene ranges from benzene derivatives to fused polycyclic hydrocarbons, and Z is usually PF6. The X-ray structures of 13 complexes are reported. All have the characteristic “piano-stool” geometry. The complexes most active toward A2780 human ovarian cancer cells contained XY = ethylenediamine (en) and extended polycyclic arenes. Complexes with polar substituents on the arene or XY = bipyridyl derivatives exhibited reduced activity. The activity of the O,O-chelated complexes depended strongly on the substituents and on the arene. For arene = p-cymene, XY = amino acidate complexes were inactive. Complexes were not cross-resistant with cisplatin, and cross-resistance to Adriamycin was circumvented by replacing XY = en with 1,2-phenylenediamine. Some complexes were also active against colon, pancreatic, and lung cancer cells.