Synthesis, Characterization, and in Vitro Antitumor Properties of Tris(hydroxymethyl)phosphine Copper(I) Complexes Containing the New Bis(1,2,4-triazol-1-yl)acetate Ligand

Marzano, Cristina; Pellei, Maura; Colavito, Davide; Alidori, Simone; Lobbia, Giancarlo Gioia; Gandin, Valentina; Tisato, Francesco; Santini, Carlo

doi:10.1021/jm0601248

Cited by 116 publications

(91 citation statements)

References 55 publications

(102 reference statements)

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“…229 Analogously, the choice for the hydrophilic tris(hydroxymethyl)phosphine (thp) allowed the preparation of perfectly aqueous soluble species with noteworthy cytotoxic properties. 230 In particular, the complex [HC(CO 2 )(pz Me2 ) 2 ]Cu(thp) 2 (13a) was found to possess markedly higher antiproliferative activity against different human tumor cell lines (HL60, A549, MCF-7, A375, and LoVo) than that shown by cisplatin. 230 Chemosensitivity tests performed on cisplatin sensitive and resistant human cancer cell lines established that (scorpionate)Cu(thp) 2 type compounds were able to overcome cisplatin resistance, supporting the hypothesis of a different mechanism of action compared to that exhibited by the reference drug (Scheme 13).…”

Section: Copper Complexes With Phosphine Ligandsmentioning

confidence: 99%

Copper in diseases and treatments, and copper‐based anticancer strategies

Tisato¹,

Marzano

Porchia³

et al. 2009

Medicinal Research Reviews

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419

402

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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.

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Section: Copper Complexes With Phosphine Ligandsmentioning

confidence: 99%

Copper in diseases and treatments, and copper‐based anticancer strategies

Tisato¹,

Marzano

Porchia³

et al. 2009

Medicinal Research Reviews

Self Cite

419

402

View full text Add to dashboard Cite

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“…It is hypothesized that the cytotoxic activity of the new copper(I) complex may be correlated to its ability to trigger paraptosis, a non-apoptotic mechanism of cell death. [24] 10. Cytotoxic effects are shown by copper(I) phosphane complexes of dihydridobis(3-nitro-1,2,4-triazolyl)borate, [25] copper(II) complex of N-Nicotinoyl-N′-o-hydroxythiobenzhydrazide, [26] copper(II)-doxorubicin chelate [27] and copper(I) complexes of 1,2-bis(diphenylphosphino) ethane (DPPE).…”

Section: Copper(ii) Complex Of N′-[(2-hydroxy Phenyl)mentioning

confidence: 99%

Role of chelates in treatment of cancer

Tripathi¹,

Kumar²,

Singhai³

2007

Indian J Cancer

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Chelates are used in cancer as cytotoxic agent, as radioactive agent in imaging studies and in radioimmunotherapy.Various chelates based on ruthenium, copper, zinc, organocobalt, gold, platinum, palladium, cobalt, nickel and iron are reported as cytotoxic agent. Monoclonal antibodies labeled with radioactive metals such as yttrium-90, indium-111 and iodine-131 are used in radioimmunotherapy. This review is an attempt to compile the use of chelates as cytotoxic drugs and in radioimmunotherapy.

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“…However, it has been recently shown that copper induces genes involved in the ubiquitin-proteasome system and in the oxidative stress response (24). In another study, copper complexes, other than A0, have been demonstrated to cause a cell death process with paraptotic features (25).…”

mentioning

confidence: 99%

The Thioxotriazole Copper(II) Complex A0 Induces Endoplasmic Reticulum Stress and Paraptotic Death in Human Cancer Cells

Tardito

Isella

Medico

et al. 2009

Journal of Biological Chemistry

120

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The copper(II) complex A0 induces a type of non-apoptotic cell death also known as paraptosis. Paraptosis involves extensive endoplasmic reticulum vacuolization in the absence of caspase activation. A wide panel of human cancer cell lines was used to demonstrate differences in cytotoxicity by the paraptosis-inducing drug A0 and the metal-based pro-apoptotic drug cisplatin. Gene expression profiling of the human fibrosarcoma HT1080 cells showed that, while cisplatin induced p53 targets, A0 up-regulated genes involved in the unfolded protein response (UPR) and response to heavy metals. The cytotoxic effects of A0 were associated with inhibition of the ubiquitinproteasome system and accumulation of ubiquitinylated proteins, in a manner dependent on protein synthesis. Cycloheximide inhibited the accumulation of ubiquitinylated proteins and hampered A0-induced cell death process. The occurrence of the UPR during A0-induced death process was shown by the increased abundance of spliced XBP1 mRNA, transient eIF2␣ phosphorylation, and a series of downstream events, including attenuation of global protein synthesis and increased expression of ATF4, CHOP, BIP, and GADD34. Mouse embryonic fibroblasts expressing a mutant eIF2␣, which could not be phosphorylated, were more resistant to A0 than wild type cells, pointing to a pro-death role of eIF2␣ phosphorylation. A0 may thus represent the prototypical member of a new class of compounds that cause paraptotic cell death via mechanisms involving eIF2␣ phosphorylation and the UPR.

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Synthesis, Characterization, and in Vitro Antitumor Properties of Tris(hydroxymethyl)phosphine Copper(I) Complexes Containing the New Bis(1,2,4-triazol-1-yl)acetate Ligand

Cited by 116 publications

References 55 publications

Copper in diseases and treatments, and copper‐based anticancer strategies

Copper in diseases and treatments, and copper‐based anticancer strategies

Role of chelates in treatment of cancer

The Thioxotriazole Copper(II) Complex A0 Induces Endoplasmic Reticulum Stress and Paraptotic Death in Human Cancer Cells

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