Two new compounds (E)-2-(5,7-dibromo-3,3-dimethyl-3,4-dihydroacridin-1(2H)-ylidene)hydrazinecarbothiomide (3) and (E)-2-(5,7-dibromo-3,3-dimethyl-3,4-dhihydroacridin-1(2H)-ylidene)hydrazinecarboxamide (4) were synthesized and evaluated for their anticholinesterase activities. In vitro tests performed by NMR and Ellman's tests, pointed to a mixed kinetic mechanism for the inhibition of acetylcholinesterase (AChE). This result was corroborated through further docking and molecular dynamics studies, suggesting that the new compounds can work as gorge-spanning ligands by interacting with two different binding sites inside AChE. Also, in silico toxicity evaluation suggested that these new compounds can be less toxic than tacrine.
- MeSH
- acetylcholinesterasa chemie MeSH
- Alzheimerova nemoc farmakoterapie enzymologie patofyziologie MeSH
- enzymatické testy MeSH
- exprese genu MeSH
- interakční proteinové domény a motivy MeSH
- katalytická doména MeSH
- kinetika MeSH
- lidé MeSH
- ligandy MeSH
- nootropní látky chemická syntéza farmakologie MeSH
- racionální návrh léčiv MeSH
- sekundární struktura proteinů MeSH
- semikarbazony chemická syntéza farmakologie MeSH
- simulace molekulární dynamiky * MeSH
- simulace molekulového dockingu MeSH
- takrin farmakologie MeSH
- termodynamika MeSH
- vazba proteinů MeSH
- vodíková vazba MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Catecholamines may undergo iron-promoted oxidation resulting in formation of reactive intermediates (aminochromes) capable of redox cycling and reactive oxygen species (ROS) formation. Both of them induce oxidative stress resulting in cellular damage and death. Iron chelation has been recently shown as a suitable tool of cardioprotection with considerable potential to protect cardiac cells against catecholamine-induced cardiotoxicity. However, prolonged exposure of cells to classical chelators may interfere with physiological iron homeostasis. Prochelators represent a more advanced approach to decrease oxidative injury by forming a chelating agent only under the disease-specific conditions associated with oxidative stress. Novel prochelator (lacking any iron chelating properties) BHAPI [(E)-Ń-(1-(2-((4-(4,4,5,5-tetramethyl-1,2,3-dioxoborolan-2-yl)benzyl)oxy)phenyl)ethylidene) isonicotinohydrazide] is converted by ROS to active chelator HAPI with strong iron binding capacity that efficiently inhibits iron-catalyzed hydroxyl radical generation. Our results confirmed redox activity of oxidation products of catecholamines isoprenaline and epinephrine, that were able to activate BHAPI to HAPI that chelates iron ions inside H9c2 cardiomyoblasts. Both HAPI and BHAPI were able to efficiently protect the cells against intracellular ROS formation, depletion of reduced glutathione and toxicity induced by catecholamines and their oxidation products. Hence, both HAPI and BHAPI have shown considerable potential to protect cardiac cells by both inhibition of deleterious catecholamine oxidation to reactive intermediates and prevention of ROS-mediated cardiotoxicity.
- MeSH
- adrenalin antagonisté a inhibitory toxicita MeSH
- biokatalýza MeSH
- buněčné linie MeSH
- chelátory železa farmakologie MeSH
- glutathion metabolismus MeSH
- hydroxylový radikál metabolismus MeSH
- isoprenalin antagonisté a inhibitory toxicita MeSH
- kardiotonika farmakologie MeSH
- katecholaminy antagonisté a inhibitory toxicita MeSH
- krysa rodu rattus MeSH
- kyseliny boronové farmakologie MeSH
- lidé MeSH
- membránový potenciál mitochondrií účinky léků MeSH
- oxidační stres účinky léků MeSH
- prekurzory léčiv farmakologie MeSH
- reaktivní formy kyslíku metabolismus MeSH
- semikarbazony farmakologie MeSH
- sloučeniny boru farmakologie MeSH
- železo chemie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Cancer cells have a high iron requirement and many experimental studies, as well as clinical trials, have demonstrated that iron chelators are potential anti-cancer agents. The ligand, 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT), demonstrates both potent anti-neoplastic and anti-retroviral properties. In this study, Bp4eT and its recently identified amidrazone and semicarbazone metabolites were examined and compared with respect to their anti-proliferative activity towards cancer cells (HL-60 human promyelocytic leukemia, MCF-7 human breast adenocarcinoma, HCT116 human colon carcinoma and A549 human lung adenocarcinoma), non-cancerous cells (H9c2 neonatal rat-derived cardiomyoblasts and 3T3 mouse embryo fibroblasts) and their interaction with intracellular iron pools. Bp4eT was demonstrated to be a highly potent and selective anti-neoplastic agent that induces S phase cell cycle arrest, mitochondrial depolarization and apoptosis in MCF-7 cells. Both semicarbazone and amidrazone metabolites showed at least a 300-fold decrease in cytotoxic activity than Bp4eT towards both cancer and normal cell lines. The metabolites also lost the ability to: (1) promote the redox cycling of iron; (2) bind and mobilize iron from labile intracellular pools; and (3) prevent 59Fe uptake from 59Fe-labeled transferrin by MCF-7 cells. Hence, this study demonstrates that the highly active ligand, Bp4eT, is metabolized to non-toxic and pharmacologically inactive analogs, which most likely contribute to its favorable pharmacological profile. These findings are important for the further development of this drug candidate and contribute to the understanding of the structure-activity relationships of these agents.
- MeSH
- antitumorózní látky chemie farmakologie MeSH
- buněčná smrt účinky léků MeSH
- buněčné linie MeSH
- chelátory železa chemie farmakologie MeSH
- kontrolní body fáze S buněčného cyklu účinky léků MeSH
- lidé MeSH
- metabolické sítě a dráhy účinky léků MeSH
- mitochondrie metabolismus patologie MeSH
- nádorové buněčné linie MeSH
- oxidace-redukce účinky léků MeSH
- proliferace buněk účinky léků MeSH
- reaktivní formy kyslíku metabolismus MeSH
- semikarbazony chemie metabolismus farmakologie toxicita MeSH
- thiosemikarbazony chemie metabolismus farmakologie toxicita MeSH
- železo chemie metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Oxidative stress is a common denominator of numerous cardiovascular disorders. Free cellular iron catalyzes the formation of highly toxic hydroxyl radicals, and iron chelation may thus be an effective therapeutic approach. However, using classical iron chelators in diseases without iron overload poses risks that necessitate more advanced approaches, such as prochelators that are activated to chelate iron only under disease-specific oxidative stress conditions. In this study, three cell-membrane-permeable iron chelators (clinically used deferasirox and experimental SIH and HAPI) and five boronate-masked prochelator analogs were evaluated for their ability to protect cardiac cells against oxidative injury induced by hydrogen peroxide. Whereas the deferasirox-derived agents TIP and TRA-IMM displayed negligible protection and even considerable toxicity, the aroylhydrazone prochelators BHAPI and BSIH-PD provided significant cytoprotection and displayed lower toxicity after prolonged cellular exposure compared to their parent chelators HAPI and SIH, respectively. Overall, the most favorable properties in terms of protective efficiency and low inherent cytotoxicity were observed with the aroylhydrazone prochelator BSIH. BSIH efficiently protected both H9c2 rat cardiomyoblast-derived cells and isolated primary rat cardiomyocytes against hydrogen peroxide-induced mitochondrial and lysosomal dysregulation and cell death. At the same time, BSIH was nontoxic at concentrations up to its solubility limit (600 μM) and in 72-h incubation. Hence, BSIH merits further investigation for prevention and/or treatment of cardiovascular disorders associated with a known (or presumed) component of oxidative stress.
- MeSH
- aldehydy chemie farmakologie MeSH
- apoptóza účinky léků MeSH
- benzoáty chemie farmakologie MeSH
- buněčné linie MeSH
- chelátory železa chemie farmakologie MeSH
- cytoprotekce * MeSH
- hydrazony chemie farmakologie MeSH
- kardiomyocyty účinky léků fyziologie MeSH
- krysa rodu rattus MeSH
- kyseliny boronové chemie farmakologie MeSH
- kyseliny isonikotinové chemie farmakologie MeSH
- membránový potenciál mitochondrií účinky léků MeSH
- oxidační stres účinky léků MeSH
- permeabilita buněčné membrány účinky léků MeSH
- peroxid vodíku metabolismus MeSH
- potkani Wistar MeSH
- semikarbazony chemie farmakologie MeSH
- sloučeniny boru chemie farmakologie MeSH
- srdeční mitochondrie účinky léků fyziologie MeSH
- triazoly chemie farmakologie MeSH
- železo chemie metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- srovnávací studie MeSH
- MeSH
- extenzivně rezistentní tuberkulóza imunologie komplikace MeSH
- farmaceutická technologie metody přístrojové vybavení MeSH
- financování organizované MeSH
- intracelulární infekce bakterií Mycobacterium avium MeSH
- léková rezistence imunologie účinky léků MeSH
- Mycobacterium avium patogenita účinky léků MeSH
- Mycobacterium fortuitum patogenita účinky léků MeSH
- Mycobacterium kansasii patogenita účinky léků MeSH
- Mycobacterium tuberculosis patogenita účinky léků MeSH
- semikarbazony farmakokinetika farmakologie terapeutické užití MeSH