Four Cu(I) complexes were synthesized with a family of pyridylmethylamide ligands, HLR [HLR = N-(2-pyridylmethyl)acetamide, R = null; 2,2-dimethyl-N-(2-pyridylmethyl)propionamide, R = Me3; 2,2,2-triphenyl-N-(2-pyridylmethyl)acetamide, R = Ph3)]. Complexes 1–3 were synthesized from the respective ligand and [Cu(CH3CN)4]PF6 in a 2 : 1 molar ratio: [Cu(HL)2]PF6 (1), [Cu2(HLMe3)4](PF6)2 (2), [Cu(HLPh3)2]PF6 (3). Complex 4, [Cu(HL)(CH3CN)(PPh3)]PF6, was synthesized from the reaction of HL with [Cu(CH3CN)4]PF6 and PPh3 in a 1 : 1 : 1 molar ratio. X-Ray crystal structures reveal that complexes 1, 3 and 4 are mononuclear Cu(I) species, while complex 2 is a Cu(I) dimer. The copper ions are four-coordinate with geometries ranging from distorted tetrahedral to seesaw in 1, 2, and 4. Complexes 1 and 2 are very air sensitive and they display similar electrochemical properties. The coordination geometry of complex 3 is nearly linear, two-coordinate. Complex 3 is exceptionally stable with respect to oxidation in the air, and its cyclic voltammetry shows no oxidation wave in the range of 0–1.5 V. The unusual inertness of complex 3 towards oxidation is attributed to the protection from bulky triphenyl substituent of the HLPh3 ligand. A new geometric parameter for four-coordinate compounds, τ4, is proposed as an improved, simple metric for quantitatively evaluating the geometry of four-coordinate complexes and compounds.

Structural variation in copper(I) complexes with pyridylmethylamide ligands: structural analysis with a new four-coordinate geometry index, tau4.

Advances in copper complexes as anticancer agents.

http://www.sciencemadness.org/talk/files.php?pid=302583&aid=26587

Azole-based energetic salts.

2.3.5. Multi-NHCs Linked by Spacers 3568 2.4. The Ag2O Route 3570 2.4.1. Feasibility 3570 2.4.2. Complications 3571 2.4.3. Theoretical Consideration 3572 2.5. Applications 3572 2.5.1. Ag(I)-NHCs in NHC Transfer 3572 2.5.2. Ag(I)-NHCs in Catalysis 3572 2.5.3. Ag(I)-NHCs in Medicine 3572 2.5.4. Ag(I)-NHCs in Nanomaterials 3573 3. Au(I)and Au(III)-NHCs 3573 3.1. Historical Background 3573 3.2. General Synthetic Methods 3573 3.3. Formation of Au(I)and Au(III)-NHCs 3574 3.3.1. Neutral [Au(NHC)L] 3574 3.3.2. Ionic [Au(NHC)L][Anion] 3576 3.3.3. Multinuclear Au(I)-NHCs 3578 3.3.4. Other Classes of Au(I)-NHCs 3578 3.3.5. Au(III)-NHC Complexes 3579 3.4. Applications 3579 3.4.1. Au(I)and Au(III)-NHCs in Catalysis 3579 3.4.2. Au(I)-NHCs in Medicine 3580 4. Cu(I)and Cu(II)-NHCs 3581 4.1. Historical Background 3581 4.2. General Synthetic Methods 3582 4.3. Formation of Cu(I)and Cu(II)-NHCs 3583 4.3.1. Complexes Containing the Cu(NHC)2 Core 3583 4.3.2. [Cu(NHC)(Halide)] 3583 4.3.3. [Cu(NHC)(Ligand)] 3584 4.3.4. Multinuclear Cu(I)and Cu(II)-NHCs 3589 4.4. Catalysis 3591 4.4.1. Past Events 3591 4.4.2. Recent Advancements 3591 5. Photoluminescence 3592 6. Conclusions 3594 7. Abbreviations 3594 8. Acknowledgments 3595 9. References 3595

Coinage Metal−N-Heterocyclic Carbene Complexes

The present paper review the drug-DNA interactions, their types and applications of experimental techniques used to study interactions between DNA and small ligand molecules that are potentially of pharmaceutical interest. DNA has been known to be the cellular target for many cytotoxic anticancer agents for several decades. Understanding how drug molecules interact with DNA has become an active research area at the interface between chemistry, molecular biology and medicine. In this review article, we attempt to bring together topics that cover the breadth of this large area of research. The interaction of drugs with DNA is a significant feature in pharmacology and plays a vital role in the determination of the mechanisms of drug action and designing of more efficient and specifically targeted drugs with lesser side effects. Several instrumental techniques are used to study such interactions. In the present review, we will discuss UV-Visible spectroscopy, fluorescence spectroscopy and cyclic voltammetry. The applications of spectroscopic techniques are reviewed and we have discussed the type of information (qualitative or quantitative) that can be obtained from the use of each technique. Not only have novel techniques been applied to study drug-DNA interactions but such interactions may also be the basis for the development of new assays. The interaction between DNA and drugs can cause chemical and conformational modifications and, thus, variation of the electrochemical properties of nucleobases.

Drug-DNA interactions and their study by UV-Visible, fluorescence spectroscopies and cyclic voltametry.

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

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.

Platinum anticancer drugs have been used for three decades despite their serious side effects and the emerging of resistance phenomena. Recently, a phosphine copper(I) complex, [Cu(thp)(4)][PF(6)] (CP), gained special attention because of its strong antiproliferative effects. CP killed human colon cancer cells more efficiently than cisplatin and oxaliplatin and it overcame platinum drug resistance. CP preferentially reduced cancer cell viability whereas non-tumour cells were poorly affected. Colon cancer cells died via a programmed cell death whose transduction pathways were characterized by the absence of hallmarks of apoptosis. The inhibition of 26S proteasome activities induced by CP caused intracellular accumulation of polyubiquitinated proteins and the functional suppression of the ubiquitin-proteasome pathway thus triggering endoplasmic reticulum stress. These data, providing a mechanistic characterization of CP-induced cancer cell death, shed light on the signaling pathways involved in paraptosis thus offering a new tool to overcome apoptosis-resistance in colon cancer cells.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1582-4934.2011.01292.x

A novel copper complex induces paraptosis in colon cancer cells via the activation of ER stress signalling.

Monocationic hydrophilic complexes [Cu(thp)4](+) 3 and [Cu(bhpe)2](+) 4 were synthesized by ligand exchange reactions starting from the labile [Cu(CH3CN)4][PF6] precursor in the presence of an excess of the relevant hydrophilic phosphine. Complexes 3 and 4 were tested against a panel of several human tumor cell lines. Complex 3 has been shown to be about 1 order of magnitude more cytotoxic than cisplatin. Chemosensitivity tests performed on cisplatin and multidrug resistance phenotypes suggested that complex 3 acts via a different mechanism of action than the reference drug. Different short-term proliferation assays suggested that lysosomal damage is an early cellular event associated with complex 3 cytotoxicity, probably mediated by an increased production of reactive oxygen species. Cytological stains and flow cytometric analyses indicated that the phosphine copper(I) complex is able to inhibit the growth of tumor cells via G2/M cell cycle arrest and paraptosis accompanied with the loss of mitochondrial transmembrane potential.

Maura Pellei

Papers

Advances in copper complexes as anticancer agents.

Copper complexes as anticancer agents

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

A novel copper complex induces paraptosis in colon cancer cells via the activation of ER stress signalling.

In vitro antitumor activity of the water soluble copper(I) complexes bearing the tris(hydroxymethyl)phosphine ligand.