Novel rhodium, iridium, and ruthenium half-sandwich complexes containing (N,N)-bound picolinamide ligands have been prepared for use as anticancer agents. The complexes show promising cytotoxicities, with the presence, position, and number of halides having a significant effect on the corresponding IC50 values. One ruthenium complex was found to be more cytotoxic than cisplatin on HT-29 and MCF-7 cells after 5 days and 1 h, respectively, and it remains active with MCF-7 cells even under hypoxic conditions, making it a promising candidate for in vivo studies.

We report the synthesis and characterisation of 32 half sandwich phenylazopyridine Os II arene complexes [Os(h 6 -arene)(phenylazopyridine)X] + in which X is chloride or iodide, the arene is p-cymene or biphenyl and the pyridine and phenyl rings contain a variety of substituents (F, Cl, Br, I, CF 3 , OH or NO 2 ). Ten X-ray crystal structures have been determined. Cytotoxicity towards A2780 human ovarian cancer cells ranges from high potency at nanomolar concentrations to inactivity. In general the introduction of an electron-withdrawing group (e.g. F, Cl, Br or I) at specific positions on the pyridine ring significantly increases cytotoxic activity and aqueous solubility. Changing the arene from p-cymene to biphenyl and the monodentate ligand X from chloride to iodide also increases the activity significantly. Activation by hydrolysis and DNA binding appears not to be the major mechanism of action since both the highly active complex [Os(h 6 -bip)(2-F-azpy)I]PF 6 (9) and the moderately active complex [Os(h 6 -bip)(3-Cl-azpy)I]PF 6 ( 23) are very stable and inert towards aquation. Studies of octanol-water partition coefficients (log P) and subcellular distributions of osmium in A2780 human ovarian cancer cells suggested that cell uptake and targeting to cellular organelles play important roles in determining activity. Although complex 9 induced the production of reactive oxygen species (ROS) in A2780 cells, the ROS level did not appear to play a role in the mechanism of anticancer activity. This class of organometallic osmium complexes has new and unusual features worthy of further exploration for the design of novel anticancer drugs.

Reporting potent anticancer activity of new functionalised Group 9 dimers.

A library of new bis-picolinamide ruthenium(III) dihalide complexes of the type RuX2L2 (X = Cl or I and L = picolinamide) have been synthesised and characterised. They exhibit different picolinamide ligand binding modes, whereby one ligand is bound (N,N) and the other bound (N,O). Structural studies reveal a mixture of cis and trans isomers for the RuCl2L2 complexes but upon a halide exchange reaction to RuI2L2, only single trans isomers are present. High cytotoxic activity against human cancer cell lines was observed, with potencies for some complexes similar to or better than cisplatin. Conversion to RuI2L2 substantially increased activity towards cancer cell lines by >12-fold. The RuI2L2 complexes displayed potent activity against the A2780cis (cisplatin-resistant human ovarian cancer) cell line, with >4-fold higher potency than cisplatin. Equitoxic activity was observed against normoxic and hypoxic cancer cells, indicating the potential to eradicate both the hypoxic and aerobic fractions of solid tumours with similar efficiency. Selected complexes were also tested against non-cancer ARPE-19 cells. The RuI2L2 complexes are more potent than the RuCl2L2 analogues, and also more selective towards cancer cells with a selectivity factor >7-fold.

This work presents the synthesis of eight new rhodium­(III) dihalido complexes, [RhX2(L)­(LH)] (where X = Cl or I), which incorporate two bidentate N-(3-halidophenyl)picolinamide ligands. The ligands have different binding modes in the complexes, whereby one is neutral and bound via N,N (LH) coordination, while the other is anionic and bound via N,O (L) coordination. The solid state and solution studies confirm multiple isomers are present when X = Cl; however, after a halide exchange with potassium iodide (X = I) the complexes exist exclusively as single stable trans isomers. NMR studies reveal the Rh­(III) trans diiodido complexes remain stable in aqueous solution with no ligand exchange reported over 96 h. Chemosensitivity data against a range of cancer cell lines show two cytotoxic complexes, where L = N-(3-bromophenyl)­picolinamide ligand. The results have been compared to the analogous Ru­(III) complexes and overall highlight the Rh­(III) trans diiodido complex to be ∼78× more cytotoxic than the analogous Rh­(III) dichlorido complex, unlike the Ru­(III) complexes which are equitoxic against all cell lines. Additionally, the Rh­(III) trans diiodido complex is more selective toward cancerous cells, with selectivity index (SI) values >25-fold higher than cisplatin against colorectal carcinoma.