Nmr Studies Of Group 8 Metallodrugs: Os-187-Enriched Organo-Osmium Half-Sandwich Anticancer Complex

We report the synthesis of the organo-osmium anticancer complex [Os(eta(6)-p-cym)(N,N-azpy-NMe2)Br]PF6 (1) containing natural abundance Os-187 (1.96%), and isotopically-enriched (98%) [Os-187]-1. Complex 1 and [Os-187]-1 contain a pi-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 mu M). Complex [Os-187]-1 was analysed by high-resolution ESI-MS, 1D H-1 and C-13 NMR, and 2D H-1 COSY, C-13-H-1 HMQC, and H-1-Os-187 HMBC NMR spectroscopy. Couplings of H-1 and C-13 nuclei from the azpy/p-cym ligands to Os-187 were observed with J-couplings ((1)J to (4)J) ranging between 0.6-8.0 Hz. The Os-187 chemical shift of [Os-187]-1 (-4671.3 ppm, determined by 2D H-1-Os-187 HMBC NMR) is discussed in relation to the range of values reported for related Os(ii) arene and cyclopentadienyl complexes (-2000 to -5200 ppm).