Cyclopentadienyl-Based Anticancer Drugs: Improvement of Cytotoxic Activity through Functionalisation of the π Ligand.

Cytotoxic complexes containing molybdenum are widely studied as a potential substitution for commercially used drugs that often suffer from pronounced side effects and cellular resistance. Compounds of the type [(η5 -Cp')Mo(CO)2 (N,N L)][BF4 ], where Cp is cyclopentadienyl and N,N L is a bidentate ligand, are well known for their strong anticancer activity. It is a generally accepted paradigm that the nature of the coordinated N,N L ligand has a major impact on the cytotoxicity. In this study, a series of new functionalised Cp complexes of molybdenum was synthesised from derivatised fulvenes as π-ligand precursors. Indeed, the coordination sphere's modulation by various N,N-chelating ligands afforded species active toward leukemic cell line MOLT-4 with IC50 values depending on the character of the N,N-chelator used. However, following study clearly showed that functionalisation of the Cp ring with an amine moiety considerably improved cytotoxicity. These results are of crucial importance for the future design of highly active cytotoxic drugs, as modification of cyclopentadienyl is believed to have a minor effect on biological activity.

Disruption of Cell Adhesion and Cytoskeletal Networks by Thiol-Functionalized Silica-Coated Iron Oxide Nanoparticles.

One of the major obstacles that limits the use of magnetic nanoparticles in biomedical applications is their potential toxicity. In the present study, we evaluated the cytotoxic effects of thiol-functionalized silica-coated iron oxide (Fe3O4@SiO2-SH) nanoparticles using human lung epithelial cells A549. We investigated the effect of Fe3O4@SiO2-SH nanoparticles on the cell viability, proliferation, cell cycle distribution, adhesion, apoptosis, and the orientation of the cytoskeletal networks, as well as on expression of proteins involved in cell death, cell survival, and cell adhesion. We demonstrated that exposure of A549 cells to Fe3O4@SiO2-SH nanoparticles resulted in severe disruption of the actin microfilaments and microtubule cytoskeleton and reduced the size of focal adhesions. Furthermore, cell adhesion was significantly affected as well as the phosphorylation of focal adhesion kinase (FAK), extracellular-signal-regulated kinase (ERK), and p38. Our findings highlight the need for in-depth cytotoxic evaluation of nanoparticles supporting their safer use, especially in biomedical applications.

Salt-washed graphene oxide and its cytotoxicity.

The carbon nanomaterials and congeners, e.g., graphene or graphene oxide (GO), dispose of numerous unique properties, which are not necessarily intrinsic but might be related to a content of impurities. The oxidation step of GO synthesis introduces a considerable amount of metallic species. Therefore, large-scale purification is an actual scientific challenge. Here we describe new purification technique (salt­washing), which is based on three consecutive steps: (a) aggregation of GO sheets with NaCl (b) washing of the aggregates and (c) removing of the salt to afford purified GO (swGO). The considerably improved purity of swGO was demonstrated by ICP and EPR spectroscopy. The microscopic methods (TEM with SEAD, AFM) proved that the salt-washing does not affect the morphology or concentration of defects, showing the aggregation of GO with NaCl is fully reversible. The eligibility of swGO for biomedical applications was tested using fibroblastic cell cultures. The determined IC50 values clearly show a strong correlation between the purity of samples and cytotoxicity. Although the purification decreases cytotoxicity of GO, the IC50 values are still low proving that cytotoxic effect is not only impurities-related but also an intrinsic property. These findings may represent a serious limitation for usage of GO in biomedical applications.

Enhanced cytotoxicity of indenyl molybdenum(ii) compounds bearing a thiophene function.

A series of six indenyl molybdenum compounds bearing a thiophenyl function in the side chain were prepared and characterized by analytical and spectroscopic methods. The structures of [(η5-C9H6CH2C4H3S)(η3-C3H5)Mo(CO)2] and [(η5-C9H6CH2C4H3S)Mo(CO)2(bpy)][BF4] were determined by single-crystal X-ray diffraction. The compounds bearing N,N-chelating ligands exhibit increased cytotoxic activity against human leukemia cell lines MOLT-4; up to two orders of magnitude lower IC50 values were observed compared to analogues with unsubstituted indenyl, which clearly demonstrates the strong effect of the indenyl ligand modification on the biological activity of the molybdenum(ii) compounds. The highest cytostatic potential was observed for the complex bearing 4,7-diphenyl-1,10-phenanthtoline [(η5-C9H6CH2C4H3S)Mo(CO)2(Ph2phen)][BF4] with IC50 (MOLT-4) = 0.19 ± 0.02 µM. Detailed regulation of the molecular and cellular mechanism by this derivative was investigated on the lung carcinoma cell line A549 and compared with the lung fibroblast cell line MRC-5. Rather unusual differences in the effects on tumor and non-tumor cell lines provide a unique insight into the cytostatic action of molybdenum(ii) complexes.

Vanadocene complexes bearing N,N'-chelating ligands: Synthesis, structures and in vitro cytotoxic studies on the A549 lung adenocarcinoma cell line.

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.