Chloro Half-Sandwich Osmium(II) Complexes: Influence of Chelated N,N-Ligands on Hydrolysis, Guanine Binding, and Cytotoxicity

Relatively little is known about the kinetics or the pharmacological potential of organometallic complexes of osmium
compared 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 found
to play a crucial role in enhancing aqueous stability. The rates of hydrolysis at acidic pH* decreased when the
primary 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 both
the human A549 lung and A2780 ovarian cancer cell lines, with IC50 values of 6−10 μM, comparable to the
anticancer drug carboplatin. 1BF4 binds to both the N7 and phosphate of 5‘-GMP (ratio of 2:1). The formation
constant 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 in
6PF6 may play a role in its cytotoxicity. This work demonstrates that the nature of the chelating ligand can play a
crucial role in tuning the chemical and biological properties of [(η6-arene)Os(NN)Cl]+ complexes.