In Vivo Selectivity and Localization of Reactive Oxygen Species (ROS) Induction by Osmium Anticancer Complexes That Circumvent Platinum Resistance.

Platinum drugs are widely used for cancer treatment. Other precious metals are promising, but their clinical progress depends on achieving different mechanisms of action to overcome Pt-resistance. Here, we evaluate 13 organo-Os complexes: 16-electron sulfonyl-diamine catalysts [(η6-arene)Os( N, N')], and 18-electron phenylazopyridine complexes [(η6-arene)Os( N, N')Cl/I]+ (arene = p-cymene, biphenyl, or terphenyl). Their antiproliferative activity does not depend on p21 or p53 status, unlike cisplatin, and their selective potency toward cancer cells involves the generation of reactive oxygen species. Evidence of such a mechanism of action has been found both in vitro and in vivo. This work appears to provide the first study of osmium complexes in the zebrafish model, which has been shown to closely model toxicity in humans. A fluorescent osmium complex, derived from a lead compound, was employed to confirm internalization of the complex, visualize in vivo distribution, and confirm colocalization with reactive oxygen species generated in zebrafish.

Combatting AMR: photoactivatable ruthenium(ii)-isoniazid complex exhibits rapid selective antimycobacterial activity.

The novel photoactive ruthenium(ii) complex cis-[Ru(bpy)2(INH)2][PF6]2 (1·2PF6, INH = isoniazid) was designed to incorporate the anti-tuberculosis drug, isoniazid, that could be released from the Ru(ii) cage by photoactivation with visible light. In aqueous solution, 1 rapidly released two equivalents of isoniazid and formed the photoproduct cis-[Ru(bpy)2(H2O)2]2+ upon irradiation with 465 nm blue light. We screened for activity against bacteria containing the three major classes of cell envelope: Gram-positive Bacillus subtilis, Gram-negative Escherichia coli, and Mycobacterium smegmatis in vitro using blue and multi-colored LED multi-well arrays. Complex 1 is inactive in the dark, but when photoactivated is 5.5× more potent towards M. smegmatis compared to the clinical drug isoniazid alone. Complementary pump-probe spectroscopy measurements along with density functional theory calculations reveal that the mono-aqua product is formed in <500 ps, likely facilitated by a 3MC state. Importantly, complex 1 is highly selective in killing mycobacteria versus normal human cells, towards which it is relatively non-toxic. This work suggests that photoactivatable prodrugs such as 1 are potentially powerful new agents in combatting the global problem of antibiotic resistance.

Excited-State Dynamics of a Two-Photon-Activatable Ruthenium Prodrug.

We present a new approach to investigate how the photodynamics of an octahedral ruthenium(II) complex activated through two-photon absorption (TPA) differ from the equivalent complex activated through one-photon absorption (OPA). We photoactivated a Ru(II) polypyridyl complex containing bioactive monodentate ligands in the photodynamic therapy window (620-1000 nm) by using TPA and used transient UV/Vis absorption spectroscopy to elucidate its reaction pathways. Density functional calculations allowed us to identify the nature of the initially populated states and kinetic analysis recovers a photoactivation lifetime of approximately 100 ps. The dynamics displayed following TPA or OPA are identical, showing that TPA prodrug design may use knowledge gathered from the more numerous and easily conducted OPA studies.

Ultrafast photo-induced ligand solvolysis of cis-[Ru(bipyridine)2(nicotinamide)2](2+): experimental and theoretical insight into its photoactivation mechanism.

Mechanistic insight into the photo-induced solvent substitution reaction of cis-[Ru(bipyridine)2(nicotinamide)2](2+) (1) is presented. Complex 1 is a photoactive species, designed to display high cytotoxicity following irradiation, for potential use in photodynamic therapy (photochemotherapy). In Ru(II) complexes of this type, efficient population of a dissociative triplet metal-centred ((3)MC) state is key to generating high quantum yields of a penta-coordinate intermediate (PCI) species, which in turn may form the target species: a mono-aqua photoproduct [Ru(bipyridine)2(nicotinamide)(H2O)](2+) (2). Following irradiation of 1, a thorough kinetic picture is derived from ultrafast UV/Vis transient absorption spectroscopy measurements, using a 'target analysis' approach, and provides both timescales and quantum yields for the key processes involved. We show that photoactivation of 1 to 2 occurs with a quantum yield ≥0.36, all within a timeframe of ~400 ps. Characterization of the excited states involved, particularly the nature of the PCI and how it undergoes a geometry relaxation to accommodate the water ligand, which is a keystone in the efficiency of the photoactivation of 1, is accomplished through state-of-the-art computation including complete active space self-consistent field methods and time-dependent density functional theory. Importantly, the conclusions here provide a detailed understanding of the initial stages involved in this photoactivation and the foundation required for designing more efficacious photochemotherapy drugs of this type.

Photoactivatable metal complexes: from theory to applications in biotechnology and medicine.

This short review highlights some of the exciting new experimental and theoretical developments in the field of photoactivatable metal complexes and their applications in biotechnology and medicine. The examples chosen are based on some of the presentations at the Royal Society Discussion Meeting in June 2012, many of which are featured in more detail in other articles in this issue. This is a young field. Even the photochemistry of well-known systems such as metal-carbonyl complexes is still being elucidated. Striking are the recent developments in theory and computation (e.g. time-dependent density functional theory) and in ultrafast-pulsed radiation techniques which allow photochemical reactions to be followed and their mechanisms to be revealed on picosecond/nanosecond time scales. Not only do some metal complexes (e.g. those of Ru and Ir) possess favourable emission properties which allow functional imaging of cells and tissues (e.g. DNA interactions), but metal complexes can also provide spatially controlled photorelease of bioactive small molecules (e.g. CO and NO)--a novel strategy for site-directed therapy. This extends to cancer therapy, where metal-based precursors offer the prospect of generating excited-state drugs with new mechanisms of action that complement and augment those of current organic photosensitizers.