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
This work describes cytotoxic effect of non-platinum metal-based compounds on the human T-leukemic cells with different p53 status (p53 wild-type MOLT-4 and p53-deficient Jurkat cells). The cytotoxic and apoptosis-inducing effect of the vanadium complex [(η(5)-C5H5)2V(5-NH2-phen)]OTf (V1) and molybdenum complex [(η(3)-C3H5)Mo(CO)2(phen)Cl] (Mo1) were studied using flow cytometry, spectrophotometry and Western blotting. We found that the cytotoxic effect of both tested complexes after 24 h is higher against the both examined cell lines than that of cis-platin (cis-DDP). At later investigated time intervals of 48 and 72 h, the cytotoxic effect of the cis-DDP increased but the values of the cytotoxicity of the tested V1 and Mo1 complexes remained unchanged, with the cytotoxicity of V1 comparable to that of cis-DDP. Furthermore we observed that the apoptotic process was induced by the activation of the caspases 9 (intrinsic pathway) and 8 (extrinsic pathway) in cells exposed to evaluated complexes. In case of the p53 wild-type MOLT-4 cells, the expression of the tumor-suppressor protein p53 and its form phosphorylated at the serine 15 increased after both V1 and Mo1 treatment, similar to the effect of cis-DDP.
- MeSH
- antitumorózní látky farmakologie MeSH
- apoptóza účinky léků MeSH
- fosforylace účinky léků MeSH
- kaspasy metabolismus MeSH
- léky antitumorózní - screeningové testy MeSH
- leukemie T-buněčná farmakoterapie metabolismus patologie MeSH
- lidé MeSH
- molybden chemie farmakologie MeSH
- nádorové buněčné linie MeSH
- nádorový supresorový protein p53 metabolismus MeSH
- organokovové sloučeniny chemie farmakologie MeSH
- proliferace buněk účinky léků MeSH
- serin metabolismus MeSH
- vanad chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Reaction of vanadocene dichlorides (Cp(2)VCl(2) and (eta(5)-C(5)H(4)Me)(2)VCl(2)) with amino acids containing secondary amino groups gives three types of complexes: a) compounds with N,O-bonded amino acid, b) O-bonded amino acids and c) O,O-bonded amino acid. The complexes with N,O-bonded amino acid and O-bonded amino acids were observed in the case of l-proline and N-methylglycine (NMG). Reactions with N-phenylglycine (NPG) give O,O-chelates as the sole products. All three types of the complexes were characterized by spectroscopic methods. Structures of [(eta(5)-C(5)H(4)Me)(2)V(O-Pro)][BPh(4)], [Cp(2)V(O-Pro)(2)][PF(6)](2), [Cp(2)V(N,O-NMG)][BPh(4)].MeOH, [(eta(5)-C(5)H(4)Me)(2)V(N,O-NMG)][BPh(4)].MeOH, [Cp(2)V(O-NMG)(2)][Cl](2).2H(2)O, [(eta(5)-C(5)H(4)Me)(2)V(O-NMG)(2)][Cl](2).H(2)O and [(eta(5)-C(5)H(4)Me)(2)V(O,O-NPG)][BPh(4)] were determined by X-ray crystallography.
