Ten new vanadocene complexes bearing N,N'-chelating ligands were prepared, characterized, and their cytotoxicity toward a panel of cancer cells was measured. Structures of four vanadocene compounds were determined by single crystal X-ray diffraction analysis. Complexes containing 1,2-bis(phenylimino)acenaphthene (bian) and 1,2-bis(4-methoxyphenylimino)acenaphthene (4-MeO-bian) exhibit higher cytotoxicity than those with dipyrido[3,2-a:2',3'-c]phenazine (dppz) and (E)-N-((pyridin-2-yl)methylene)benzenamine (pyma). In light of the finding, cytotoxic mechanisms of two highly effective complexes [(η5-C5H4Me)2V(bian)][OTf]2 (3b) and [(η5-C5H4Me)2V(4-MeO-bian)][OTf]2 (4b) against human A549 lung adenocarcinoma cells were investigated by following membrane leakage of intracellular lactate dehydrogenase, Trypan Blue staining and activation of tumor protein p53 (p53). Evaluated complexes have a potent dose-dependent antiproliferative activity, causing cell cycle redistribution by the increased accumulation of cells in the G2 and S phase. In accord with the observed cell cycle deceleration, cyclin-dependent kinase inhibitor-interacting protein 1 (p21WAF1/Cip1), extracellular signal-regulated kinases 1 and 2 (ERK1/2), Checkpoint kinase 1 (Chk1), Checkpoint kinase 2 (Chk2) and their phosphorylated forms Chk1 at serine 345 and Chk2 at threonine 68 increased. In the cells exposed to complexes, dose- and time-dependent apoptotic process is initiated by the activation of the initiator caspase 8, followed by activation of effector caspase 3/7 and phosphatidylserine externalization. Moreover, because of treatment, A549 cells activate prosurvival mitogen-activated protein kinases (MAPK) signaling and up-regulate antiapoptotic protein B-cell lymphoma (Bcl-2), thereby promoting evasion of cell death. Both complexes exhibited considerably higher cytotoxic effect than the reference anticancer drug cis-platin and the cytotoxicity was more pronounced at higher treatment time.
- MeSH
- antitumorózní látky chemická syntéza chemie farmakologie MeSH
- apoptóza účinky léků MeSH
- chelátory chemická syntéza chemie farmakologie MeSH
- kaspasy metabolismus MeSH
- komplexní sloučeniny chemická syntéza chemie farmakologie MeSH
- kontrolní body fáze G2 buněčného cyklu účinky léků MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- ligandy MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- vanad chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting tens of million people. Currently marketed drugs have limited therapeutic efficacy and only slowing down the neurodegenerative process. Interestingly, it has been suggested that biometal cations in the amyloid beta (Aβ) aggregate deposits contribute to neurotoxicity and degenerative changes in AD. Thus, chelation therapy could represent novel mode of therapeutic intervention. Here we describe the features of chelators with therapeutically relevant mechanism of action. We have found that the tested compounds effectively reduce the toxicity of exogenous Aβ and suppress its endogenous production as well as decrease oxidative stress. Cholyl hydrazones were found to be the most active compounds. In summary, our data show that cation complexation, together with improving transport efficacy may represent basis for eventual treatment strategy in AD.
- MeSH
- Alzheimerova nemoc farmakoterapie metabolismus MeSH
- amyloidní beta-protein antagonisté a inhibitory metabolismus MeSH
- chelátory chemická syntéza chemie farmakologie MeSH
- chelátová terapie * MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie MeSH
- kationty chemie farmakologie MeSH
- kovy chemie farmakologie MeSH
- lidé MeSH
- molekulární struktura MeSH
- nádorové buňky kultivované MeSH
- proliferace buněk účinky léků MeSH
- proteinové agregáty účinky léků MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
In order to compare the coordination properties of 1,4,7-triazacyclononane (tacn) derivatives bearing varying numbers of phosphinic/carboxylic acid pendant groups towards 68Ga, 1,4,7-triazacyclononane-7-acetic-1,4-bis(methylenephosphinic) acid (NOPA) and 1,4,7- triazacyclononane-4,7-diacetic-1-[methylene(2-carboxyethyl)phosphinic] acid (NO2AP) were synthesized using Mannich reactions with trivalent or pentavalent forms of H-phosphinic acids as phosphorus components. Stepwise protonation constants logK1-3 12.06, 3.90 and 1.95, and stability constants with GaIII and CuII, logKGaL 24.01 and logKCuL 16.66, were potentiometrically determined for NOPA. Both ligands were labelled with 68Ga and compared with NOTA (tacn-N,N',N″-triacetic acid) and NOPO, a TRAP-type [tacn-N,N',N″- tris(methylenephosphinic acid)] chelator. At pH 3, NOPO and NOPA showed higher labelling efficiency (binding with lower ligand excess) at both room temperature and 95 °C, compared to NO2AP and NOTA. Labelling efficiency at pH = 0-3 correlated with a number of phosphinic acid pendants: NOPO > NOPA > NO2AP > NOTA; however, it was more apparent at 95 °C than at room temperature. By contrast, NOTA was found to be labelled more efficiently at pH > 4 compared to the ligands with phosphinic acids. Overall, replacement of a single phosphinate donor with a carboxylate does not challenge 68Ga labelling of TRAP-type chelators. However, the presence of carboxylates facilitates labelling at neutral or weakly acidic pH.
Molekulárne zobrazovacie techniky (PET, SPECT) zohrávajú dôležitú úlohu v nukleárnej medicíne. 64Cu sa javí ako významný rádionuklid, ktorý má potenciál si nájsť svoje uplatnenie v diagnostike ako aj v terapii. Avšak 64Cu musí byť do živého organizmu dopravená vo forme rádiofarmaka s cielenou biodistribúciou a dostatočnou in vivo stabilitou. Preto je často rozhodujúcou súčasťou celého rádiofarmaka polydentátny ligand, ktorý tvorí komplex s rádionuklidom medi. Tento prehľadový článok je venovaný najmä klasifikácii ligandov, ktoré dokážu tvoriť stabilné cheláty s 64Cu.
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- Klíčová slova
- bifunkční chelátory, polydentátní ligandy, 64Cu,
- MeSH
- chelátory * chemická syntéza chemie klasifikace MeSH
- izotopové značení MeSH
- jednofotonová emisní výpočetní tomografie MeSH
- měď MeSH
- organokovové sloučeniny * chemická syntéza chemie MeSH
- pozitronová emisní tomografie MeSH
- radiofarmaka chemická syntéza chemie MeSH
- radioizotopy mědi * klasifikace MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
A selected chemical library of six platinum(II) complexes having 1,2-bis(aminomethyl)carbobicyclic ligands were synthesized after a rational design in order to evaluate their antiproliferative activity and the structure-activity relationships. The cytotoxicity studies were performed using cancer cell lines sensitive (A2780) and resistant (A2780R) to cisplatin. Excellent cytotoxicity was observed for most of complexes, which presented better resistance factors than cisplatin against the A2780R cell line. The interaction of these complexes with DNA, as the target biomolecule, was evaluated by several methods: DNA-platinum binding kinetics, changes in the DNA melting temperature, evaluation of the unwinding angle of supercoiled DNA, evaluation of the interstrand cross-links, and replication mapping. The kinetics of the interaction with glutathione was also investigated to better understand the resistant factors observed for the new complexes.
- MeSH
- adukty DNA chemie MeSH
- antitumorózní látky * farmakologie chemická syntéza chemie MeSH
- chelátory chemická syntéza chemie MeSH
- chemorezistence MeSH
- cisplatina farmakologie MeSH
- diaminy * farmakologie chemická syntéza chemie MeSH
- DNA chemie MeSH
- glutathion chemie MeSH
- kinetika MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- ligandy MeSH
- můstkové bicyklické sloučeniny * farmakologie chemická syntéza chemie MeSH
- nádorové buněčné linie MeSH
- platina * MeSH
- reagencia zkříženě vázaná chemická syntéza chemie MeSH
- tranzitní teplota MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
