Ruthenium(II) arene anticancer complexes with redox-active diamine ligands.
The synthesis and characterization of ruthenium(II) arene complexes of the general formula [(eta(6)-arene)Ru(XY)Z](+), where arene = p-cymene (p-cym), hexamethylbenzene (hmb), or biphenyl (bip), XY = o-phenylenediamine (o-pda), o-benzoquinonediimine (o-bqdi), or 4,5-dimethyl-o-phenylenediamine (dmpda), and Z = Cl, Br, or I, are reported (complexes 1-6). In addition, the X-ray crystal structures of [(eta(6)-p-cym)Ru(o-pda)Cl]PF(6) (1) and [(eta(6)-hmb)Ru(o-bqdi)Cl]PF(6) (3PF(6)) are described. The Ru-N distances in 3PF(6) are significantly shorter [2.033(4) and 2.025(4) A] compared to those in 1 [2.141(2) and 2.156(2) A]. All of the imine complexes (3-5) exhibit a characteristic broad (1)H NMR NH resonance at ca. delta 14-15. Complex 1 undergoes concomitant ligand-based oxidation and hydrolysis (38% after 24 h) in water. The oxidation also occurs in methanol. The iodido complex [(eta(6)-p-cym)Ru(o-bqdi)I]I (4) did not undergo hydrolysis, whereas the chlorido complex 3 showed relatively fast hydrolysis (t(1/2) = 7.5 min). Density functional theory calculations showed that the total bonding energy of 9-EtG in [(eta(6)-p-cym)Ru(o-pda)(9-EtG-N7)](2+) (1EtG) is 23.8 kJ/mol lower than that in [(eta(6)-p-cym)Ru(o-bqdi)(9-EtG-N7)](2+) (3EtG). The greater bonding energy is related to the contribution from strong hydrogen bonding between the NH proton of the chelating ligand and O6 of 9-EtG (1.69 A). A loss of cytotoxic activity was observed upon oxidation of the amine ligand to an imine (e.g., IC(50) = 11 microM for 1 and IC(50) > 100 microM for 3, against A2780 ovarian cancer cells). The relationship between the cytotoxic activity and the solution and solid state structures of the imine and amine complexes is discussed.
School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, UK.
Tijana
T
Bugarcic
Abraha
A
Habtemariam
Robert J
RJ
Deeth
Francesca P A
FP
Fabbiani
Simon
S
Parsons
Peter J
PJ
Sadler
D045744:Cell Line, Tumor; D003959:Diamines / Q000138:chemical synthesis; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D005260:Female; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008956:Models, Chemical; D015394:Molecular Structure; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010084:Oxidation-Reduction; D010655:Phenylenediamines / Q000737:chemistry* / Q000494:pharmacology*; D012428:Ruthenium / Q000494:pharmacology / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
D003959:Diamines; D008024:Ligands; D010655:Phenylenediamines; C011793:4,5-dimethyl-1,2-phenylenediamine; D012428:Ruthenium; C034193:1,2-diaminobenzene