Amide linkage isomerism as an activity switch for organometallic osmium and ruthenium anticancer complexes.
We show that the binding mode adopted by picolinamide derivatives in organometallic Os(II) and Ru(II) half-sandwich complexes can lead to contrasting cancer cell cytotoxicity. N-Phenyl picolinamide derivatives (XY) in Os(II) (1, 3-5, 7, 9) and Ru(II) (2, 6, 8, 10) complexes [(eta(6)-arene)(Os/Ru)(XY)Cl](n+), where arene = p-cymene (1-8, 10) or biphenyl (9), can act as N,N- or N,O-donors. Electron-withdrawing substituents on the phenyl ring resulted in N,N-coordination and electron-donating substituents in N,O-coordination. Dynamic interconversion between N,O and N,N configurations can occur in solution and is time- and temperature- (irreversible) as well as pH-dependent (reversible). The neutral N,N-coordinated compounds (1-5 and 9) hydrolyzed rapidly (t(1/2) <or= min), exhibited significant (32-70%) and rapid binding to guanine, but no binding to adenine. The N,N-coordinated compounds 1, 3, 4, and 9 exhibited significant activity against colon, ovarian, and cisplatin-resistant ovarian human cancer cell lines (3 >> 4 > 1 > 9). In contrast, N,O-coordinated complexes 7 and 8 hydrolyzed slowly, did not bind to guanine or adenine, and were nontoxic.
Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.
Sabine H
SH
van Rijt
Andrew J
AJ
Hebden
Thakshila
T
Amaresekera
Robert J
RJ
Deeth
Guy J
GJ
Clarkson
Simon
S
Parsons
Patrick C
PC
McGowan
Peter J
PJ
Sadler
D000225:Adenine / Q000031:analogs & derivatives / Q000737:chemistry; D000577:Amides / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007536:Isomerism; D007700:Kinetics; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D009942:Organometallic Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D009992:Osmium / Q000737:chemistry*; D010848:Picolinic Acids / Q000737:chemistry; D011789:Quantum Theory; D012428:Ruthenium / Q000737:chemistry*; D013816:Thermodynamics
D000577:Amides; D000970:Antineoplastic Agents; D008024:Ligands; D009942:Organometallic Compounds; D010848:Picolinic Acids; C001172:9-ethyladenine; D009992:Osmium; D006147:Guanine; D012428:Ruthenium; C014542:9-ethylguanine; D004247:DNA; C003142:picolinamide; D000225:Adenine