Herein, we describe and investigate biological activity of three octahedral ruthenium(II) complexes of the type [Ru(C∧N)(phen)2]+, RuL1-RuL3, containing a π-expansive cyclometalating substituted benzo[g]quinoxaline ligand (C∧N ligand) (phen = 1,10-phenanthroline). Compounds RuL1-RuL3 in cervical, melanoma, and colon human cancer cells exhibit high phototoxicity after irradiation with light (particularly blue), with the phototoxicity index reaching 100 for the complex RuL2 in most sensitive HCT116 cells. RuL2 accumulates in the cellular membranes. If irradiated, it induces lipid peroxidation, likely connected with photoinduced ROS generation. Oxidative damage to the fatty acids leads to the attenuation of the membranes, the activation of caspase 3, and the triggering of the apoptotic pathway, thus implementing membrane-localized photodynamic therapy. RuL2 is the first photoactive ruthenium-based complex capable of killing the hardly treatable colon cancer stem cells, a highly resilient subpopulation within a heterogeneous tumor mass, responsible for tumor recurrence and the metastatic progression of cancer.
- MeSH
- antitumorózní látky * farmakologie chemie chemická syntéza terapeutické užití MeSH
- apoptóza účinky léků MeSH
- buněčná membrána účinky léků metabolismus MeSH
- chinoxaliny * chemie farmakologie chemická syntéza MeSH
- fotochemoterapie * MeSH
- fotosenzibilizující látky * farmakologie chemie chemická syntéza terapeutické užití MeSH
- komplexní sloučeniny * farmakologie chemie chemická syntéza terapeutické užití MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádorové kmenové buňky * účinky léků patologie MeSH
- nádory tračníku * farmakoterapie patologie MeSH
- reaktivní formy kyslíku metabolismus MeSH
- ruthenium * chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Metastatic cancer remains a formidable challenge in anticancer therapy. Despite efforts to develop effective antimetastasis drugs over the past half-century, currently approved treatments fall short of expectations. This report highlights the promising antiproliferative activity of a ruthenium-based therapeutic agent, namely dichlorido(p-cymene)[2-amino-4-(pyridin-3-yl)-4H-benzo[h]-chromene-3-carbonitrile]ruthenium(II) (complex 1) against metastatic cell lines. Complex 1 shows significant efficacy in metastatic LoVo and Du-145 cell lines at nanomolar concentrations, being markedly more active than clinically used anticancer cisplatin. Studies on the MDA-MB-231 cell line, which displays invasive characteristics, demonstrated that 1 significantly reduces cell invasion. This efficacy was confirmed by its impact on matrix metalloproteinase production in MDA-MB-231 cells. Given that cell migration drives cancer invasion and metastasis, complex 1's effect on MDA-MB-231 cell migration was evaluated via wound healing assay and vimentin network analysis. Results indicated a strong reduction in migration. A re-adhesion assay further demonstrated that 1 significantly lowers the re-adhesion ability of MDA-MB-231 cells compared to cisplatin. To better simulate the human body environment, a 3D spheroid invasion assay was used. This method showed that 1 effectively inhibits tumor spheroids from infiltrating the surrounding extracellular matrix. This study underscores the potential of (arene)ruthenium(II) complexes with naphthopyran ligands as potent antimetastatic agents for chemotherapy.
- MeSH
- antitumorózní látky * farmakologie chemie terapeutické užití MeSH
- buněčná adheze účinky léků MeSH
- komplexní sloučeniny * farmakologie chemie terapeutické užití MeSH
- lidé MeSH
- metastázy nádorů prevence a kontrola farmakoterapie MeSH
- nádorové buněčné linie MeSH
- pohyb buněk * účinky léků MeSH
- proliferace buněk účinky léků MeSH
- ruthenium * chemie farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Terapia zhubných nádorových ochorení patrí medzi najstaršie a zároveň najperspektívnejšie oblasti aplikácie zlúčenín kovov v terapii. Druhá časť prehľadu o metalofarmakách sa zameriava na dejinný vývoj a súčasné využitie komplexných zlúčenín v terapii rakoviny. Najprv sa venuje najznámejšiemu a najúspešnejšiemu liečivu spomedzi metalofarmák – cisplatine. Po stručnom náčrte objavu antineoplastických vlastností tejto zlúčeniny sa zaoberá jej chemickými vlastnosťami, toxicitou, klinickými aplikáciami, mechanizmom účinku a vývojom rezistencie. V ďalšom sú diskutované tiež komplexy iných kovov ako potenciálne chemoterapeutiká, ako aj perspektívne smery výskumu v tejto oblasti. Tento stručný prehľad má za cieľ poskytnúť základnú orientáciu v tejto problematike pre farmaceutov i chemikov, ako aj ostatných záujemcov o danú oblasť z radov odbornej verejnosti.
Therapy of malignant tumors is among the oldest and at the same time the most promising application areas of therapeutic metal complexes. The second part of our survey on metallopharmaceuticals deals with historical development and current state of coordination compounds in cancer therapy. It starts with the most famous and most successful metallodrug – cisplatin. After a brief account of the discovery of the anticancer properties of this substance follows the discussion of its chemical properties, toxicity, clinical application and resistance. Hereafter, complexes of other metals along with innovative research directions are addressed. The aim of this brief survey is to provide basic overview of the area of metallopharmacy, aimed at specialists in pharmacy and chemistry as well as at the general educated public.
- MeSH
- chemie bioanorganická MeSH
- cisplatina terapeutické užití MeSH
- farmakoterapie metody MeSH
- komplexní sloučeniny terapeutické užití MeSH
- kovy * terapeutické užití MeSH
- lidé MeSH
- nádory * farmakoterapie MeSH
- platina terapeutické užití MeSH
- ruthenium terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
This minireview is devoted to the complexes of various transition metals, which contain azaindole ring coordinated to the metal centre, and whose cytotoxicity was studied. We decided to overview this interesting group of coordination compounds with the aim to highlight various structural types of complexes depending on the metal centre (i.e., Pt, Pd, Ru, Ir or Au) and type of the used co-ligand(s). The presented complexes are also reviewed in context of their toxicity, selectivity and processes connected with their mechanism of action. Some of complexes were also studied on in vivo models showing promising results comparable with the commonly used anticancer drug cisplatin. It can be deduced from the herein overviewed literature data regarding transition metal complexes containing azaindoles as ligands, that at least a few of them may represent suitable and promising candidates in the field of anticancer therapy. As one of the examples, the cis-[PtI2(2Me4Cl-7aza)2] complex (2Me4Cl-7aza = 2-methyl-4-chloro-7-azaindole) should be mentioned, which showed considerably higher in vitro cytotoxicity than cisplatin, the ability to overcome both the acquired and natural resistance of human cancer cells in comparison with the biological action of cisplatin, different mechanism of action than cisplatin and comparable in vivo anticancer activity with cisplatin.
- MeSH
- antitumorózní látky * chemická syntéza chemie terapeutické užití MeSH
- cytotoxiny * chemická syntéza chemie terapeutické užití MeSH
- indoly * chemická syntéza chemie terapeutické užití MeSH
- komplexní sloučeniny * chemická syntéza chemie terapeutické užití MeSH
- lidé MeSH
- nádory farmakoterapie metabolismus patologie MeSH
- přechodné kovy chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Kovy a ich zlúčeniny boli využívané v medicíne od úsvitu dejín a v súčasnosti predstavujú perspektívnu oblasť vývoja nových druhov liečiv. Všetky kovy (resp. ich zlúčeniny) vykazujú rôzne druhy biologickej aktivity. Koordinačné zlúčeniny majú v porovnaní s liečivami na báze organických molekúl množstvo unikátnych vlastností, súvisiacich s prítomnosťou centrálneho atómu kovu a so špecifickými možnosťami usporiadania ligandov okolo tohoto centrálneho atómu. Tento stručný prehľad má za cieľ poskytnúť základnú orientáciu v tejto problematike pre farmaceutov i chemikov, ako aj ostatných záujemcov o danú oblasť z radov odbornej verejnosti. Prvá časť prehľadu sa zaoberá historickým vývojom a aktuálnym využitím zlúčenín kovov v terapii infekčných ochorení, ako aj princípmi použitia komplexov kovov v diagnostike a ich súčasným významom, predovšetkým v moderných tomografických metódach.
Metals and their compounds have been exploited in medicine since the dawn of history. All metals (or their substances) exert some kind of biological activity. Metal complexes exhibit a number of unique properties as compared to purely organic substances, stemming from the presence of the metal atom and the variable arrangement of ligands around this central atom. The goal of this brief survey is to provide basic overview of the area of metallopharmacy, aimed at specialists in pharmacy and chemistry as well as at the general educated public. The first part concentrates on some historical aspects of metallopharmacy and on current application of metals in the therapy of infectious diseases and in diagnostics.
- Klíčová slova
- metalofarmaka,
- MeSH
- antibakteriální látky chemie klasifikace terapeutické užití MeSH
- antimon dějiny terapeutické užití MeSH
- arsen dějiny terapeutické užití MeSH
- bismut dějiny terapeutické užití MeSH
- chemie bioanorganická MeSH
- diagnostické techniky a postupy MeSH
- infekce farmakoterapie MeSH
- jednofotonová emisní výpočetní tomografie MeSH
- komplexní sloučeniny * dějiny chemie terapeutické užití MeSH
- kontrastní látky MeSH
- kovy dějiny klasifikace terapeutické užití MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- měď farmakologie terapeutické užití MeSH
- rtuť dějiny terapeutické užití MeSH
- ruthenium farmakologie terapeutické užití MeSH
- sloučeniny rtuti dějiny terapeutické užití MeSH
- sloučeniny ruthenia terapeutické užití MeSH
- sloučeniny stříbra dějiny farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
The platinum(II) iodido complexes 1-5 of the general formula cis-[PtI2(Ln)2], where Ln stands for O-substituted 9-deazahypoxanthine derivatives, were prepared and thoroughly characterized by various techniques, including multinuclear 1D and 2D NMR spectroscopy. The complexes were screened for their anticancer potential in vitro on ten human cancer cell lines, concretely breast adenocarcinoma (MCF7), osteosarcoma (HOS), lung carcinoma (A549), cervix epithelioid carcinoma (HeLa), malignant melanoma (G-361), prostate carcinoma (22Rv1, PC-3), hepatocellular carcinoma (HepG2), ovarian carcinoma (A2780) and cisplatin-resistant ovarian carcinoma (A2780R). The complexes exhibited significant wide-spectrum anticancer activity in vitro against all the employed cell lines, with IC50≈0.5-24.0μM. Very good correlation between the lipophilicity parameter log P and IC50 values of anticancer activity in vitro were obtained by simple QSAR analysis. The most lipophilic complexes 2, 4 and 5 showed the best results, as they reached the sub-micromolar IC50 values against the A2780 and A2780R sub-lines, with the best result equal 0.5±0.1μM on A2780 for complex 5. The in vivo testing of the representative complexes 1, 4 and 5 (applied at the same dose of Pt as 2mg/kg dose of cisplatin) on a L1210 leukaemia model revealed their positive effect on the prolongation of the mean survival time, even if it was lower than that of cisplatin. The 1H NMR interaction study revealed the ability of complexes to interact with glutathione (GSH) and 5'-guanosine monophosphate (GMP) and overall higher stability of the complexes 1-5 as compared to cisplatin. The electrospray-ionization mass spectrometry experiments with complex 1 identified the formation of a rich collection of hydrolytic species in water-containing media after 24h and the interaction intermediates with sulfur-containing biomolecule l-cysteine, but not with the reduced glutathione at physiologically relevant concentration levels.
- MeSH
- antitumorózní látky chemie terapeutické užití toxicita MeSH
- apoptóza účinky léků MeSH
- buňky Hep G2 MeSH
- HeLa buňky MeSH
- hypoxanthiny chemie MeSH
- jod chemie MeSH
- Kaplanův-Meierův odhad MeSH
- komplexní sloučeniny chemie terapeutické užití toxicita MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- myši inbrední DBA MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory farmakoterapie mortalita patologie MeSH
- platina chemie MeSH
- transplantace heterologní MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Prostate cancer cells control energy metabolism by chelating intracellular zinc. Thus, zinc delivery has been a popular therapeutic approach for prostate cancer. Here, we propose the use of the membrane-penetrating peptide Novicidin connected to zinc-Schiff base as a carrier vehicle for the delivery of zinc to prostate cells. Mass spectrometry, electrochemistry and spectrophotometry confirmed the formation/stability of this complex and provided insight regarding the availability of zinc for complex interactions. This delivery system showed minor toxicity in normal PNT1A cells and high potency towards PC3 tumor cells. The complex preferentially penetrated PC3 tumor cells in contrast to confinement to the membranes of PNT1A. Furthermore, zinc uptake was confirmed in both cell lines. Molecular analysis was used to confirm the activation of zinc stress (e.g., ZnT-1) and apoptosis (e.g., CASP-1). Our results strongly suggest that the zinc-Schiff base-Novicidin complex has great potential as a novel anticancer drug.
- MeSH
- antitumorózní látky chemie farmakologie terapeutické užití MeSH
- apoptóza účinky léků MeSH
- exprese genu účinky léků MeSH
- fluorescenční mikroskopie MeSH
- kaspasa 1 metabolismus MeSH
- kationické antimikrobiální peptidy chemie MeSH
- komplexní sloučeniny chemie farmakologie terapeutické užití MeSH
- lidé MeSH
- molekulární konformace MeSH
- nádorové buněčné linie MeSH
- nádory prostaty farmakoterapie MeSH
- proteiny přenášející kationty metabolismus MeSH
- Schiffovy báze chemie MeSH
- spektrometrie hmotnostní - ionizace laserem za účasti matrice MeSH
- zinek chemie metabolismus MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
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
DNA interstrand cross-linking (ICL) agents are an important group of cytotoxic drugs with the capability of binding covalently between two strands of DNA, thereby preventing vital processes such as replication or transcription in dividing cells. In anticancer therapy however, their potential is limited due to the resistance by various mechanisms. In order to develop highly effective antitumor drugs it is necessary to study both effective ICL formations and their subsequent repair mechanisms. This review presents an overview of development over the past decade and the use of both well-known and new DNA interstrand cross-linking agents. Their potential in applications especially as anticancer chemotherapeutics in the framework of current knowledge of repair mechanisms and development of combined chemotherapy is discussed.
- MeSH
- alkaloidy chemie terapeutické užití MeSH
- anthrachinony chemie terapeutické užití MeSH
- antitumorózní látky chemie terapeutické užití MeSH
- azepiny chemie terapeutické užití MeSH
- aziridiny chemie terapeutické užití MeSH
- DNA chemie metabolismus MeSH
- komplexní sloučeniny chemie terapeutické užití MeSH
- lidé MeSH
- mechlorethamin chemie terapeutické užití MeSH
- nádory farmakoterapie MeSH
- oprava DNA MeSH
- reagencia zkříženě vázaná chemie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
The idea of "repurposing" of existing drugs provides an effective way to develop and identify new therapies. Disulfiram (Antabuse), a drug commonly used for the treatment of alcoholism, shows promising anticancer activity in both preclinical and clinical studies. In the human body, disulfiram is rapidly converted to its reduced metabolite, diethyldithiocarbamate. If copper ions are available, a bis(diethyldithiocarbamate)-copper(II) complex is formed. Disulfiram's selective anticancer activity is attributed to the copper(II) complex's ability to inhibit the cellular proteasome. It is assumed that the complex inhibits the proteasome by a mechanism that is distinct to the clinically used drug bortezomib, targeting the 19S rather than the 20S proteasome. This difference could be explained by inhibition of the JAMM domain of the POH1 subunit within the lid of the 19S proteasome.
- MeSH
- antitumorózní látky chemie farmakologie terapeutické užití MeSH
- dithiokarb chemie MeSH
- inhibitory proteasomu chemie farmakologie terapeutické užití MeSH
- komplexní sloučeniny chemie farmakologie terapeutické užití MeSH
- kyseliny boronové chemie farmakologie terapeutické užití MeSH
- lidé MeSH
- měď chemie MeSH
- nádorové buněčné linie MeSH
- nádory prsu farmakoterapie metabolismus patologie MeSH
- oxidační stres účinky léků MeSH
- proteasomový endopeptidasový komplex chemie metabolismus MeSH
- pyraziny chemie farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
