NMR studies of group 8 metallodrugs: 187Os-enriched organo-osmium half-sandwich anticancer complex

Abstract

We report the synthesis of the organo-osmium anticancer complex [Os(η⁶-p-cym)(N,N-azpy-NMe₂)Br]PF₆ (1) containing natural abundance ¹⁸⁷Os (1.96%), and isotopically-enriched (98%) [¹⁸⁷Os]-1. Complex 1 and [¹⁸⁷Os]-1 contain a π-bonded para-cymene (p-cym), a chelated 4-(2-pyridylazo)-N,N-dimethylaniline (azpy-NMe₂), and a monodentate bromide as ligands. The X-ray crystal structure of 1 confirmed its half-sandwich ‘piano-stool’ configuration. Complex 1 is a member of a family of potent anticancer complexes, and exhibits sub-micromolar activity against A2780 human ovarian cancer cells (IC₅₀ = 0.40 μM). Complex [¹⁸⁷Os]-1 was analysed by high-resolution ESI-MS, 1D ¹H and ¹³C NMR, and 2D ¹H COSY, ¹³C–¹H HMQC, and ¹H–¹⁸⁷Os HMBC NMR spectroscopy. Couplings of ¹H and ¹³C nuclei from the azpy/p-cym ligands to ¹⁸⁷Os were observed with J-couplings (¹J to ⁴J) ranging between 0.6–8.0 Hz. The ¹⁸⁷Os chemical shift of [¹⁸⁷Os]-1 (−4671.3 ppm, determined by 2D ¹H–¹⁸⁷Os HMBC NMR) is discussed in relation to the range of values reported for related Os(II) arene and cyclopentadienyl complexes (−2000 to −5200 ppm).