Metal-based coordination compounds have been used throughout the history of human medicine to treat various diseases, including cancer. Since the discovery of cisplatin in 1965, a great number of metal coordination complexes, such as platinum, ruthenium, gold or copper have been designed, synthesized and tested in order to develop clinically effective and safe drugs. Currently, many reviews cover applications of cytostatic metal complexes pointing out the most promising examples of platinum- and non-platinum-based compounds in preclinical and clinical trials. However, recent comprehensive reviews covering chemical and biological aspects of metal-based coordination compounds in cancer therapy are still rare. In this review we wish to provide an overview of the coordination chemistry of current and novel cytostatic compounds, including an outline of their design and rationale of synthesis, and summarize bio-chemical reactivity and physicochemical properties of candidate metal complexes.

• MeSH
• antitumorózní látky * farmakologie   terapeutické užití   MeSH
• cisplatina dějiny   farmakologie   terapeutické užití   MeSH
• galium dějiny   farmakologie   terapeutické užití   MeSH
• genomika metody   trendy   MeSH
• individualizovaná medicína metody   trendy   využití   MeSH
• kobalt dějiny   farmakologie   terapeutické užití   MeSH
• komplexní sloučeniny * farmakologie   terapeutické užití   MeSH
• lidé MeSH
• měď farmakologie   terapeutické užití   MeSH
• metabolomika metody   trendy   MeSH
• mezioborová komunikace MeSH
• proteomika metody   trendy   MeSH
• sloučeniny ruthenia dějiny   farmakologie   terapeutické užití   MeSH
• sloučeniny železa dějiny   farmakologie   terapeutické užití   MeSH
• sloučeniny zlata dějiny   farmakologie   terapeutické užití   MeSH
• statistika jako téma MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

The long-term objective of this proposal is to implement fundamental research leading to broadening of the theoretical backgroung needed for the design of new antitumor transition metal-based drugs. The working hypothesis will be tested experimentally that there is a correlation between inhibition of telomerase induced by DNA adducts of platinum and ruthenium complexes and antitumor activity of these compounds. Confirmation of this hypothesis will make it possible to define a new concept of antitumor effects of platinum and ruthenium compounds. This new concept will allow designing new antitumor drugs which will have better therapeutic properties than those already used in the clinic.

Obecným cílem tohoto projektu je realizovat základní výzkum vedoucí k rozšíření teoretického zázemí pro vývoj nových cytostatik odvozených od komplexů přechodných kovů. Experimentálně bude testována pracovní hypotéza, podle které existuje korelace mezi inhibicí telomerázy vyvolané poškozením DNA po její reakcí s komplexy platiny a ruthenia a jejich protinádorovou aktivitou. Potvrzení této hypotézy umožní definovat novou koncepci cytostatických účinků komplexů platiny a ruthenia, na základě které budou navržena léčiva, jejichž protinádorové účinky budou lepší ve srovnání s účinky cytostatik již využívaných v klinické praxi.

• MeSH
• cytostatické látky MeSH
• poškození DNA MeSH
• sloučeniny platiny farmakologie   MeSH
• sloučeniny ruthenia farmakologie   MeSH
• telomerasa antagonisté a inhibitory   MeSH

• Konspekt
• Biochemie. Molekulární biologie. Biofyzika
• NLK Obory
• biologie
• onkologie
• farmacie a farmakologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

Transition-metal-based compounds constitute a discrete class of chemotherapeutics, widely used in the clinic as antitumor and antiviral agents. Examples of established antitumor metallodrugs, routinely used in the clinic, are cisplatin [cis-diamminedichloroplatinum(II)] and its analogues carboplatin and oxaliplatin. However, drug resistance and side effects have limited their clinical utility. These limitations have prompted a search for more effective and less toxic metal-based antitumor agents. Some of the efforts have been directed in the design of non-platinum, transition-metal-based antitumor agents and ruthenium complexes have attracted much interest as alternative drugs to cisplatin in cancer chemotherapy. Ruthenium complexes demonstrate similar ligand exchange kinetics to those of platinum(II) antitumor drugs already used in the clinic while displaying only low toxicity. This is in part due to the ability of ruthenium complexes to mimic the binding of iron to molecules of biological significance, exploiting the mechanisms that the body has evolved for transport of iron. In addition, the redox potential between the different accessible oxidation states occupied by ruthenium complexes enables the body to catalyze oxidation and reduction reactions, depending on physiological environment. The biochemical changes that accompany cancer alter physiological environment, enabling ruthenium complexes to be selectively activated in cancer tissues. Due to differing ligand geometry between their complexes, ruthenium compounds bind to DNA affecting its conformation differently than cisplatin and its analogues. In addition, non-nuclear targets, such as the mitochondrion and the cell surface, have also been implicated in the antineoplastic activity of some ruthenium complexes. Thus, ruthenium compounds offer the potential over antitumor platinum(II) complexes currently used in the clinic of reduced toxicity, a novel mechanism of action, the prospect of non-cross-resistance and a different spectrum of activity. In other words, some chemical properties make ruthenium compounds well suited for medicinal applications and as an alternative to platinum antitumor drugs in the treatment of cancer cells resistant to cisplatin. Although the pharmacological target for antitumor ruthenium compounds has not been unequivocally identified, there is a large body of evidence indicating that the cytotoxicity of many ruthenium complexes correlates with their ability to bind DNA although few exceptions have been reported. This review summarizes results demonstrating that several ruthenium compounds that exhibit antitumor effects different from cisplatin or its analogues bind DNA and modify it differently than cisplatin or its analogues.

• MeSH
• antitumorózní látky farmakologie   chemická syntéza   MeSH
• dimethylsulfoxid MeSH
• DNA metabolismus   MeSH
• financování organizované MeSH
• lidé MeSH
• nádory farmakoterapie   patologie   MeSH
• organokovové sloučeniny farmakologie   chemie   metabolismus   MeSH
• racionální návrh léčiv MeSH
• sloučeniny ruthenia farmakologie   chemická syntéza   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• přehledy MeSH

• MeSH
• adukty DNA analýza   chemie   MeSH
• DNA chemie   metabolismus   účinky léků   MeSH
• ethidium MeSH
• fluorescenční barviva MeSH
• kultivační média farmakologie   MeSH
• plazmidy genetika   MeSH
• sloučeniny ruthenia farmakologie   MeSH