New insights on cytotoxic activity of group 3 and lanthanide compounds: complexes with [N,N,N]-scorpionate ligands.

OBJECTIVES: In this work was to evaluate the cytotoxic activity of a series of monomeric group 3 and lanthanide (N,N,N)-heteroscorpionate-triflate complexes (M (OTf) 2 (cybpamd) (THF)) (Ln = Sc (2), Y (3), La (4), Nd (5), Sm (6), Dy (7), Yb (8); OTf = SO3CF3; cybpamd = N, N'-dicyclohexyl-2,2-bis-(3,5-dimethyl-pyrazol-1-yl)-acetamidinate) having octahedral geometry around the metal atoms on the human epithelial lung adenocarcinoma (A549), human melanoma (A375), human cervical epithelial adenocarcinoma, human embryonic kidney (HEK-293) and murine macrophages (J774.A1) cell lines. METHODS: All the tested compounds were incubated with cells for 72 h and their growth inhibition assessed by using MTT assay. KEY FINDINGS: On the cell line HEK-293 complexes 5 and 7 show a reasonable activities, while the murine macrophage cell line (J774.A1), only the scandium 2 complex is not very active. All complexes tested are poorly active on human health adenocarcinoma lung epithelial (A549) and human melanoma (A375). CONCLUSIONS: The group 3 and lanthanide (N,N,N)-heteroscorpionate triflate-complexes (M(OTf)2(cybpamd)(THF)) on murine macrophage (J774.A1) cell line, except that of scandium, show a reasonable activity. On human epithelial cervix adenocarcinoma (HeLa) complexes 3, 5 and 6 are significantly more active than cis-platinum, as well as complex 5 is more active on human embryonic kidney (HEK-293) cell line. All the tested complexes are poorly active on human epithelial lung adenocarcinoma (A549) and human melanoma (A375). The different behaviour of the complexes examined (2-8) let us hypothesize that the cytotoxic activity is related to the molecule as a whole and not only to the ligand or the metal ion separately.

Enhanced in vitro antitumor activity of a titanocene complex encapsulated into polycaprolactone (PCL) electrospun fibers.

PURPOSE: The purpose of this work was to achieve detailed biomaterials characterization of a drug delivery system for local cancer treatment based on electrospun titanocene trichloride-loaded resorbable polycaprolactone (PCL) fibers. METHODS: The PCL fibers were characterized for their structural, morphologic and physical properties. The drug release kinetics of the titanocene complex was investigated at different concentrations, to obtain a set of correlations between structure and tuneable release. After exposing cancer cells directly onto the surface of PCL fibers, the anti-proliferative effects of titanocene-loaded PCL were assessed by: (i) counting viable cells via live/dead staining methods, and (ii) analyzing cell apoptosis. RESULTS AND CONCLUSIONS: Titanocene concentration influenced fiber diameters reduced for PCL filled with titanocene. X-ray analysis suggested that the titanocene, encapsulated into the PCL fibers, is not allowed to crystallize and exists as amorphous aggregates into the fibers. The titanocene release curves presented two stages unrelated to PCL degradation: an initial burst release followed by a release linear with time, extending for a very long time. All of the titanocene-loaded fibers revealed sustained drug release properties suggesting their potential clinical applicability for the treatment of local cancer diseases.

Synthesis and biological evaluation of new N-alkylcarbazole derivatives as STAT3 inhibitors: preliminary study.

The signalling pathway of Janus tyrosine Kinases-Signal Transducers and Activators of Transcription (JAK-STAT) is activated by a number of cytokines, hormones (GH, erythropoietin and prolactin), and growth factors. JAK-STAT signalling is involved in regulation of cell proliferation, differentiation and apoptosis. These activities are due to different members of JAK-STAT family consisting of: JAK1, JAK2, JAK3, Tyk2 and STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6. Recent studies suggest a key role for STAT family proteins, in particular for STAT3, in selectively inducing and maintaining a pro-carcinogenic inflammatory microenvironment, that promote tumour cells transformation. Moreover, a striking correlation between cancer development/progression and STAT3 persistent activation exists, probably due to STAT3 promoting of the pro-oncogenic inflammatory pathways, like NF-kB, IL-6 and JAK family kinases. Recent study demonstrated that carbazoles can inhibit STAT3 mediated transcription. From these evidences, STAT3 represents a therapeutic target, so we have synthesized a new set of N-alkylcarbazole derivatives substituted in positions 2, 4 and 6, to evaluate their activity on STAT3. Some of these compounds showed an interesting activity as STAT3 selective inhibitors; in particular, compounds 9a 9b and 9c revealed to inhibit the STAT3 activation for the 50%, 90% and 95%, respectively.

Synthesis, characterization and cytotoxicity studies of methoxy alkyl substituted metallocenes.

Five titanocene derivatives and one zirconium analogous, having cyclopentadienylethenylmethoxy ligand, were synthesized and fully characterized by NMR, FT-IR, and elemental analysis. Two of these complexes showed a good cytotoxic activity on human breast cancer (MCF-7) cell lines. Moreover, the half-titanocene disclosed also a good cytotoxic activity on human embryonic kidney (HEK-293). Additionally, a study on the rate of hydrolysis of these compounds showed that the leaving groups significantly affect the rate of hydrolysis of cyclopentadienyl groups too. The different activity of synthesized compounds was tentatively related to the rate of hydrolysis.

Synthesis and cytotoxic activities of group 3 metal complexes having monoanionic tridentate ligands.

Complexes of scandium, yttrium, samarium and neodymium bearing monoanionic tridentate ancillary ligands have been synthesized and characterized. The cytotoxic activities of novel compounds, as well as that of similar compounds previously reported have been evaluated on rat glioma (C6), murine fibrosarcoma (WHEI-164) and human embryonic kidney (HEK-293) cell lines. Scandium complex with quinolinephenoxyamine (NNHO) ligand showed very interesting activity against C6 cell line.