| Abstract
| - Relatively little is known about the kinetics or the pharmacological potential of organometallic complexes of osmiumcompared to its lighter congeners, iron and ruthenium. We report the synthesis of seven new complexes, [(η6-arene)Os(NN)Cl]+, containing different bidentate nitrogen (N,N) chelators, and a dichlorido complex, [(η6-arene)Os(N)Cl2]. The X-ray crystal structures of seven complexes are reported: [(η6-bip)Os(en)Cl]PF6 (1PF6),[(η6-THA)Os(en)Cl]BF4 (2BF4), [(η6-p-cym)Os(phen)Cl]PF6 (5PF6), [(η6-bip)Os(dppz)Cl]PF6 (6PF6), [(η6-bip)Os(azpy-NMe2)Cl]PF6 (7PF6), [(η6-p-cym)Os(azpy-NMe2)Cl]PF6 (8PF6), and [(η6-bip)Os(NCCH3-N)Cl2] (9), where THA =tetrahydroanthracene, en = ethylenediamine, p-cym = p-cymene, phen = phenanthroline, bip = biphenyl, dppz= [3,2-a: 2‘,3‘-c]phenazine and azpy-NMe2 = 4-(2-pyridylazo)-N,N-dimethylaniline. The chelating ligand was foundto play a crucial role in enhancing aqueous stability. The rates of hydrolysis at acidic pH* decreased when theprimary amine N-donors (NN = en, t1/2 = 0.6 h at 318 K) are replaced with π-accepting pyridine groups (e.g., NN= phen, t1/2 = 9.5 h at 318 K). The OsII complexes hydrolyze up to 100 times more slowly than their RuII analogues.The pK*a of the aqua adducts decreased with a similar trend (pK*a = 6.3 and 5.8 for en and phen adducts,respectively). [(η6-bip)Os(en)Cl]PF6/BF4 (1PF6/BF4) and [(η6-THA)Os(en)Cl]BF4 (2BF4) were cytotoxic toward boththe human A549 lung and A2780 ovarian cancer cell lines, with IC50 values of 6−10 μM, comparable to theanticancer drug carboplatin. 1BF4 binds to both the N7 and phosphate of 5‘-GMP (ratio of 2:1). The formationconstant for the 9-ethylguanine (9EtG) adduct [(η6-bip)M(en)(9EtG)]2+ was lower for OsII (log K = 3.13) than RuII(log K = 4.78), although the OsII adduct showed some kinetic stability. DNA intercalation of the dppz ligand in6PF6 may play a role in its cytotoxicity. This work demonstrates that the nature of the chelating ligand can play acrucial role in tuning the chemical and biological properties of [(η6-arene)Os(NN)Cl]+ complexes.
- Nine half-sandwich osmium(II) arene complexes containing N-donor ligands have been synthesized and characterized. Seven X-ray crystal structures are reported. The aqueous stability was enhanced by the presence of an N,N-chelating ligand, and the hydrolysis of complexes containing chelated primary amine N-donors was ∼8 times more rapid than for complexes containing π-acceptors such as pyridine. Complexes containing ethylenediamine as a chelator exhibited high activity against cancer cells, comparable to that of carboplatin.
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