Advances in copper complexes as anticancer agents.

Thiosemicarbazone complexes of copper(II): structural and biological studies

Metal-based antitumor drugs play a relevant role in antiblastic chemotherapy. Cisplatin is regarded as one of the most effective drugs, even if severe toxicities and drug resistance phenomena limit its clinical use. Therefore, in recent years there has been a rapid expansion in research and development of novel metal-based anticancer drugs to improve clinical effectiveness, to reduce general toxicity and to broaden the spectrum of activity. The variety of metal ion functions in biology has stimulated the development of new metallodrugs other than Pt drugs with the aim to obtain compounds acting via alternative mechanisms of action. Among non-Pt compounds, copper complexes are potentially attractive as anticancer agents. Actually, since many years a lot of researches have actively investigated copper compounds based on the assumption proposal that endogenous metals may be less toxic. It has been established that the properties of copper-coordinated compounds are largely determined by the nature of ligands and donor atoms bound to the metal ion. In this review, the most remarkable achievements in the design and development of copper(I, II) complexes as antitumor agents are discussed. Special emphasis has been focused on the identification of structure-activity relationships for the different classes of copper(I,II) complexes. This work was motivated by the observation that no comprehensive surveys of copper complexes as anticancer agents were available in the literature. Moreover, up to now, despite the enormous efforts in synthesizing different classes of copper complexes, very few data concerning the molecular basis of the mechanisms underlying their antitumor activity are available. This overview, collecting the most significant strategies adopted in the last ten years to design promising anticancer copper(I,II) compounds, would be a help to the researchers working in this field.

Copper complexes as anticancer agents

Main group metal complexes of semicarbazones and thiosemicarbazones. A structural review

Copper is found in all living organisms and is a crucial trace element in redox chemistry, growth and development. It is important for the function of several enzymes and proteins involved in energy metabolism, respiration, and DNA synthesis, notably cytochrome oxidase, superoxide dismutase, ascorbate oxidase, and tyrosinase. The major functions of copper-biological molecules involve oxidation-reduction reactions in which they react directly with molecular oxygen to produce free radicals. Therefore, copper requires tightly regulated homeostatic mechanisms to ensure adequate supplies without any toxic effects. Overload or deficiency of copper is associated, respectively, with Wilson disease (WD) and Menkes disease (MD), which are of genetic origin. Researches on Menkes and Wilson disorders have provided useful insights in the field of copper homeostasis and in particular into the understanding of intracellular trafficking and distribution of copper at molecular levels. Therapies based on metal supplementation with copper histidine or removal of copper excess by means of specific copper chelators are currently effective in treating MD and WD, respectively. Copper chelation therapy is now attracting much attention for the investigation and treatment of various neurodegenerative disorders such as Alzheimer, Parkinson and CreutzfeldtJakob. An excess of copper appears to be an essential co-factor for angiogenesis. Moreover, elevated levels of copper have been found in many types of human cancers, including prostate, breast, colon, lung, and brain. On these basis, the employment of copper chelators has been reported to be of therapeutic value in the treatment of several types of cancers as anti-angiogenic molecules. More recently, mixtures of copper chelators with copper salts have been found to act as efficient proteasome inhibitors and apoptosis inducers, specifically in cancer cells. Moreover, following the worldwide success of platinum(II) compounds in cancer chemotherapy, several families of individual copper complexes have been studied as potential antitumor agents. These investigations, revealing the occurrence of mechanisms of action quite different from platinum drugs, head toward the development of new anticancer metallodrugs with improved specificity and decreased toxic side effects.

Copper in diseases and treatments, and copper-based anticancer strategies.

The nature of metal complexes of heterocyclic thiosemicarbazones reported in the literature through 1989 have been reviewed with an emphasis on variations in stoichiometry and stereochemistry. A brief introduction is followed by a survey of the biological activity of the uncomplexed thiosemicarbazones. Next is a section on the chemical nature of thiosemicarbazones including a discussion of preparative methods, modes of coordination and isomerism. This is followed by a discussion of structural information and biological activity of the iron(III), iron(II), copper(II), cobalt(III), cobalt(II) and nickel(II) complexes of heterocyclic thiosemicarbazones. Short sections on the biological activity of other chelating thiosemicarbazones and metal complexes are also included.

Structural and physical correlations in the biological properties of transition metal heterocyclic thiosemicarbazone and S -alkyldithiocarbazate complexes

A. Introduction (i) Biological importance of copper(H) complexes (ii) Historical interest in copper thiosemicarbazone complexes (iii) Synthesis (iv) Bonding types B. Crystal structures of copper thiosemicarbazones C. Magnetic studies (i) Magnetic moments (ii) Electron spin resonance spectra (a) Bis(thiosemicarbazones), Cu(SNNS) (b) Tridentate thiosemicarbazones, Cu(ONS) (c) Tridentate thiosemicarbazones, Cu(NNS) (d) Pentadentate thiosemicarbazones, Cu(SNNNS) D.Spectralstudies.. (i) Infrared spectra (ii) Electronic spectra E. Thermal studies F. Electrochemical studies G. Recent biological studies of thiosemicarbazones H. Conclusion References 50 50 51 52 52 53 56 56 57 57 58 59 60 60 60 61 63 64 65 66 67

Thiosemicarbazone Complexes of Copper(II): Structural and Biological Studies

https://escholarship.org/content/qt5wk2v4f4/qt5wk2v4f4.pdf

Inequivalent coordination of thiosemicarbazone ligands in cobalt (III) and chromium (III) complexes

Phenyl pyruvate thiosemicarbazone (H2PPVATSC) coordinates in its binegative thiolate form to cobalt(III) in the complex isolated from basic medium. An X-ray structure determination of the resulting meridional isomer was found to contain mutually cis sulphur, trans nitrogen, and trans oxygen donor atoms, respectively. The two five-membered rings formed by each ligand are puckered towards each other, resulting in a distortion from regular octahedral geometry about the cobalt atom. The complex was found to exhibit only a metal-based one electron reversible reduction at -0.97 V, while the parent ligand yields a c.v. profile consisting of two irreversible reduction peaks at -0.75 and -1.05V respectively, the latter corresponding to the reduction of the azomethine group.

Synthesis, spectroscopic and structural characterization of the mer isomer of ammonium bis(phenylpyruvic acid thiosemicarbazone)-cobalt(III) hemihydrate

Pramila Sonawane

Papers

Thiosemicarbazone complexes of copper(II): structural and biological studies

Structural and physical correlations in the biological properties of transition metal heterocyclic thiosemicarbazone and S -alkyldithiocarbazate complexes

Thiosemicarbazone Complexes of Copper(II): Structural and Biological Studies

Inequivalent coordination of thiosemicarbazone ligands in cobalt (III) and chromium (III) complexes

Synthesis, spectroscopic and structural characterization of the mer isomer of ammonium bis(phenylpyruvic acid thiosemicarbazone)-cobalt(III) hemihydrate