Jonathan R. Dilworth

The biomedical chemistry of technetium and rhenium

This review describes recent developments in the chemistry of both first and second generation 99m-technetium-based imaging agents. The material is presented according to the biological target for the agent, and where possible actual images are presented to indicate the type of information available to the clinician. Beta emitting isotopes of rhenium offer a possible method for the in situ treatment of cancerous tissue using analogous targeting strategies to those for technetium. Recent developments in the relevant coordination chemistry of rhenium and their extension to in vitro and in vivo studies are presented.

Thiolato-complexes of the transition metals

A. Introduction B. Complexes with terminal thiolato-ligands (i) Mononuclear homoleptic complexes with monoand bi-dentate thiolates _ (ii) Mononuclear complexes with heteroligands (a) Oxo-complexes (b) Complexes with metal-nitrogen multiple bonds (c) Miscellaneous monomeric thiolato complexes with other heteroligands . (iii) Complexes with sterically hindered thiolato-ligands (a) Chromium, molybdenum and tungsten (b) Manganese, technetium and rhenium (c) Iron, ruthenium and osmium. (d) Cobalt, rhodium and iridium. (e) Copper, silver and gold C. Complexes with CL’-bridging thiolato-ligands (i) Introduction (ii) Dinuclear and linear polynuclear complexes with two p2-thiolato-ligands . . (a) Molybdenum ..... (b) Manganese, technetium and rhenium (c) Iron (d) Cobalt (e) Nickel, palladium and platinum (f) Copper, silver and gold. (g) Zinc, cadmium and mercury (iii) Complexes with three Ir_2-thiolato-ligands (iv) Complexes with quadruple r2-thiolato-ligands (v) Three-dimensional clusters (a) Clusters with tetrahedral metal centres (b) Copper and silver (c) Nickel, palladium and platinum (d) Other cluster types D. Complexes with p’-bridging thiolato-ligands E. Synthesis of thiolato-complexes . .

THE COORDINATION CHEMISTRY OF SUBSTITUTED HYDRAZINES

A. Introduction . _ . _ _ _ _ _ . . _ . . . . . . . . . * . . 29 B. Nomenclature . _ . _ . . . , . . . _ . . . . . . . . . . . 31 C. Simple co-ordinative behaviour _ _ _ _ _ _ _ . _ _ _ . . . . * . 31 1. As monodentate figands _ . . . . . . . . . . . . . . * * . 31 Ii. As bidentate figands . . . _ _ . _ _ . . _ . _ _ . _ _ _ * * 36 01 Bonding via nitrogens . . . . . . . . . . _ . . . . . 36 (ii) Bonding via nitrogen and oxygen . . . . . . . . . . . . . 41 (iii) Bonding via nitrogen and sulphur . . . . . . . . . . . 43 (iv) Hydrazines with phosphorusand arsenic-containing substituents . _ 46 D. Reactions invoIving elimination of dinitrogen _ . _ _ _ _ _ . . . . 47 E. Formation of diazene. diazenidoand hydrazido-complexes . _ _ _ . . * . 48 F. Formation of dithiolene-like complexes _ . . . . _ _ _ _ . . . * . 54 G. Reactions with co-ordinated ligands . . . . . . . . . . . . 57 References . . _ . . . . . . _ . . . . . . . . . . . . . . 58

The preparation and coordination chemistry of phosphorussulfur donor ligands

Abstract This article describes the synthesis and coordination chemistry of five broad types of ligands containing both phosphorus and sulfur donor centres, reviewing the literature up to the end of 1997. Phosphinothiolate ligands combine a phosphine centre with a thiol functionality (usually deprotonated on coordination); phosphinothioether ligands are similar in overall appearance, but contain a thioether group in place of the thiol functionality. Phosphinothioformamides (of general formula R 2 PC(S)NHR′) and phosphinodithioformates (of general formula R 2 PCS 2 − ) belong to the larger class of hetero-allylic ligands, being the phosphorus equivalents of thioureas and dithiocarbamates respectively. Finally, diphosphine monosulfides are related to the well-known diphosphine ligands (e.g. dppe) by the oxidation of one of the two phosphorus(III) centres to a phosphine sulfide. The review contains 340 references and 18 endnotes.

Towards new transition metal-based hypoxic selective agents for therapy and imaging.

The greater lability of Co(II) relative to Co(III) can potentially be used to achieve selective delivery of nitrogen mustard type molecules to hypoxic cells. Attempts to improve the stability of the Co(II) state by utilising tripodal tetradentate ligands are described, together with the results of DF calculations. Rhenium has two beta-emitting isotopes (186)Re and (188)Re that have potential for use to treat cancer if the complexes can be targeted with sufficient specificity. We describe some new rapid low temperature routes using hydrazines to labile Re(V) and Re(III) species which provide potential convenient access to a wide range of oxo- and diazenido-complexes. The synthesis of new Re(V) and Re(III) thiosemicarbazone complexes is presented in the context of obtaining hypoxic selective species. Copper(II) bis(thiosemicarbazone) complexes are known to be hypoxic selective and spectroscopic, cyclic voltammetric and computational studies of the mechanism are presented, together with the synthesis of new Cu(II) complexes directed towards the hypoxic selective delivery of nitrogen mustard type molecules.

Probing the mechanism of hypoxia selectivity of copper bis(thiosemicarbazonato) complexes: DFT calculation of redox potentials and absolute acidities in solution

Density functional theory (DFT) calculations have been performed using the uB3LYP/6-31++G(d,p) model to calculate the solution phase one-electron reduction potentials (E(calc)) and absolute pKa values of a series of copper bis(thiosemicarbazonato) complexes. The effects of solvation in water and dimethylsulfoxide (DMSO) are incorporated as a self-consistent reaction field (SCRF) using the integral equation formalism polarisable continuum model (IEFPCM) and are found to be essential for quantitative agreement with an average error in E(calc) of -0.02 V compared to experiment. The bonding and spin densities are examined through the use of Natural Bond Order analysis and the results used to rationalise the calculated and observed reduction potentials. Calculated estimates of pKa values of several copper(II) species are presented and their implications for the mechanisms of transport and trapping within hypoxic cells are considered. Reduction is found to be a prerequisite for protonation of the complexes which suggests their transport in the blood stream as neutral species, and the mechanistic sequence is identified as a sequential electrochemical-chemical (EC) process. The complex equilibria of protonation, reoxidation and dissociation are discussed and the copper(I) diprotonated, cationic complex of diacetyl bis(4-methyl-3-thiosemicarbazonato)copper(II), Cu(I)ATSMH2(+), is identified as a possible candidate for the initial species trapped in hypoxic cells.

Structural trends in copper(II) bis(thiosemicarbazone) radiopharmaceuticals

Redox-related changes in biological properties of copper bis(thiosemicarbazone) radiopharmaceuticals are induced by backbone alkylation. To determine whether these changes are mediated by changes in core structural parameters, eight X-ray structures of variously alkylated complexes were determined. The complexes include the hypoxia tracer diacetylbis(4-methyl-3-thiosemicarbazonato)copper(II) (CuATSM). The structures of the nickel analogue NiATSM and the corresponding free ligand ATSMH2 were also included. Distortions from planarity were slight and only present when there were significant intermolecular interactions (mainly pairs of N–H–N and N–H–S hydrogen bonds). These give rise to cross-linked flat or helical ribbons of complexes. Alkylation at the terminal nitrogen atoms interrupts hydrogen bonding, allowing complexes to become planar, but does not otherwise affect the coordination sphere. Alkylation at the backbone carbon atoms increases the backbone C–C bond length, allowing the metal to fit better into the ligand cavity with shorter Cu–S bonds.

Structural information from orientationally selective DEER spectroscopy

Double electron-electron resonance (DEER) spectroscopy can determine, from measurement of the dipolar interaction, the distance and orientation between two paramagnetic centres in systems lacking long-range order such as powders or frozen solution samples. In spin systems with considerable anisotropy, the microwave pulses excite only a fraction of the electron paramagnetic resonance (EPR) spectrum and the resulting orientation selection needs to be explicitly taken into account if a meaningful distance and orientation is to be determined. Here, a general method is presented to analyze the dipolar interaction between two paramagnetic spin centres from a series of DEER traces recorded so that different orientations of the spin-spin vector are sampled. Delocalised spin density distributions and spin projection factors (as for example in iron-sulfur clusters), are explicitly included. Application of the analysis to a spin-labelled flavoprotein reductase/reduced iron-sulfur ferredoxin protein complex and a bi-radical with two Cu(ii) ions provides distance and orientation information between the radical centres. In the protein complex this enables the protein-protein binding geometry to be defined. Experimentally, orientationally selective DEER measurements are possible on paramagnetic systems where the resonator bandwidth allows the frequencies of pump and detection pulses to be separated sufficiently to excite enough orientations to define adequately the spin-spin vector.

In Vitro and In Vivo Evaluation of Bifunctional Bisthiosemicarbazone 64Cu-Complexes for the Positron Emission Tomography Imaging of Hypoxia

The copper(II) bisthiosemicarbazonato complex, copper-diacetyl-bis(N4-methylthiosemicarbazonate) (Cu-ATSM), has been used clinically as a positron emission tomography (PET) tracer for the delineation of hypoxia. Six novel, asymmetric bis(thiosemicarbazones) derived from diacetyl-2-(4-N-methyl-3-thiosemicarbazone)-3-(4-N-amino-3-thiosemicarbazone) (H2ATSM/A), one of which contained a nitroimidazole functionality, were radiolabeled with 64Cu (t1/2=12.7 h, beta+=19.3%). In vitro studies were performed on three of the compounds using EMT6 mammary carcinoma cells under hypoxic and normoxic conditions. All compounds displayed rapid cellular association and appreciable hypoxic selectivity with increased uptake under normoxic and hypoxic conditions when compared to 64Cu-ATSM. Biodistribution and small animal PET imaging studies were then carried out in vivo using two compounds in EMT6 tumor-bearing mice. The compounds showed high tumor uptake, but also substantial accumulation in the liver. These complexes demonstrate that H 2ATSM/A represents a novel and versatile synthetic platform that can be utilized to provide hypoxic cell selectivity through functionalization of the bisthiosemicarbazonate group.

Cellular confocal fluorescence studies and cytotoxic activity of new Zn(II) bis(thiosemicarbazonato) complexes

We report the synthesis and characterisation of new, highly fluorescent, zinc complexes of bis(thiosemicarbazone) ligands incorporating extended aromatic backbones which are cytotoxic at levels comparable to cisplatin; cellular fluorescence imaging studies suggest these cause cell death by disruption of mitochondria.