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 OsII and RuII half-sandwich complexes can lead to contrasting cancer cell cytotoxicity. N-Phenyl picolinamide derivatives (XY) in OsII (1, 3-5, 7, 9) and RuII (2, 6, 8, 10) complexes [(η6-arene)(Os/Ru)(XY)Cl]n+, where arene=p-cymene (1-8, 10) or biphenyl (9), can act asN,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 (t1/2 ≤ 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. © 2009 American Chemical Society.