Unravelling the antitumoral potential of novel bis(thiosemicarbazonato) Zn(II) complexes: structural and cellular studies.

The development of pharmacologically active compounds based on bis(thiosemicarbazones) (BTSC) and on their coordination to metal centers constitutes a promising field of research. We have recently explored this class of ligands and their Cu(II) complexes for the design of cancer theranostics agents with enhanced uptake by tumoral cells. In the present work, we expand our focus to aliphatic and aromatic BTSC Zn(II) complexes bearing piperidine/morpholine pendant arms. The new complexes ZnL1-ZnL4 were characterized by a variety of analytical techniques, which included single-crystal X-ray crystallography for ZnL2 and ZnL3. Taking advantage of the fluorescent properties of the aromatic complexes, we investigated their cellular uptake kinetics and subcellular localization. Furthermore, we tried to elucidate the mechanism of action of the cytotoxic effect observed in human cancer cell line models. The results show that the aliphatic complexes (ZnL1 and ZnL2) have a symmetrical structure, while the aromatic counterparts (ZnL3 and ZnL4) have an asymmetrical nature. The cytotoxic activity was higher for the aromatic BTSC complexes, as well as the cellular uptake, evaluated by measurement of intracellular Zn accumulation. Among the most active complexes, ZnL3 presented the fastest uptake kinetics and lysosomal localization assessed by live-cell microscopy. Detailed studies of its impact on cellular production of reactive oxygen species and impairment of lysosomal membrane integrity reinforced the influence of the pendant piperidine in the biological performance of aromatic BTSC Zn(II) complexes.

Synthesis and characterization of the cyanobenzene-ethylenedithio-TTF donor.

A dissymmetric TTF-type electron donor, cyanobenzene-ethylenedithio-tetrathiafulvalene (CNB-EDT-TTF), was obtained in high yield, by a cross-coupling reaction with triethyl phosphite between 2-thioxobenzo[d][1,3]dithiole-5-carbonitrile and 5,6-dihydro-[1,3]dithiolo[4,5-b][1,4]dithiin-2-one. This new donor was characterized namely by single crystal X-ray diffraction, cyclic voltammetry, NMR, UV-visible and IR spectroscopy.

HOLZ rings in EBSD patterns of the UFeB4 compound: association with a random distribution of planar defects.

The UFeB4 phase present in different alloys of the B-Fe-U system was studied by powder X-ray diffraction (PXRD) and scanning electron microscopy complemented with energy-dispersive spectroscopy and electron backscattered diffraction (EBSD). The PXRD data showed that the ternary compound crystallized adopting essentially the YCrB4-type structure. However, microstructural observations revealed that under high undercooling conditions the UFeB4 phase exhibits a random distribution of defects parallel to, which are consistently associated with intense higher-order Laue zone rings in EBSD patterns. Indexation of the EBSD patterns showed that the defective structure is compatible with an intergrowth of YCrB4- and ThMoB4-type layers according to the (010)(YCrB4)//(110)(ThMoB4) and [001]YCrB4//[001](ThMoB4) orientation relation previously reported for an analogous compound. Magnetic studies indicated that the annealed UFeB4 compound has a paramagnetic behavior in the 2-300 K temperature range.

Biophysical characterization and antineoplastic activity of new bis(thiosemicarbazonato) Cu(II) complexes.

Aiming to explore alternative mechanisms of cellular uptake and cytotoxicity, we have studied a new family of copper(II) complexes (CuL1-CuL4) with bis(thiosemicarbazone) (BTSC) ligands containing pendant protonable cyclic amines (morpholine and piperidine). Herein, we report on the synthesis and characterization of these new complexes, as well as on their biological performance (cytotoxic activity, cellular uptake, protein and DNA binding), in comparison with the parental CuIIATSM (ATSM=diacetyl-bis(N4-methylthiosemicarbazonate) complex without pendant cyclic amines. The new compounds have been characterized by a range of analytical techniques including ESI-MS, IR spectroscopy, cyclic voltammetry, reverse-phase HPLC and X-ray spectroscopy. In vitro cytotoxicity studies revealed that the copper complexes are cytotoxic, unlike the corresponding ligands, with a similar potency to that of CuATSM. Unlike CuATSM, the new complexes were able to circumvent cisplatin cross-resistance. The presence of the protonable cyclic amines did not lead to an enhancement of the interaction of the complexes with human serum albumin or calf thymus DNA. However, CuL1-CuL4 showed a remarkably augmented cellular uptake compared with CuATSM, as proved by uptake, internalization and externalization studies that were performed using the radioactive congeners 64CuL1-64CuL4. The enhanced cellular uptake of CuL1-CuL4 indicates that this new family of CuIIBTSC complexes deserves to be further evaluated in the design of metallodrugs for cancer theranostics.

Pt(II) complexes with bidentate and tridentate pyrazolyl-containing chelators: synthesis, structural characterization and biological studies.

A series of four Pt(II) complexes anchored by bidentate or tridentate pyrazolyl-alkylamine chelators bearing different substituents at the azolyl rings has been prepared with the aim to assess their interest in the design of novel anticancer drugs. All complexes have been fully characterized by classical analytical methods and three of them were characterized also by X-ray diffraction analysis. Their solution behavior, together with lipophilicity measurements, cell uptake, antiproliferative properties, DNA interaction have been evaluated. Albeit all the complexes were less active than cisplatin on ovarian carcinoma A2780 cell line, greatly retained their activity in the cisplatin-resistant A2780cisR cell line and presented a lower resistance factor compared to cisplatin. Moreover, the Pt(II) complexes under investigation were less prone to undergo deactivation by glutathione, believed to be the major cellular target of cisplatin that inactivates the drug by binding to it irreversibly.

Tris(pyrazolyl)methane 99mtc tricarbonyl complexes for myocardial imaging.

Novel ether-containing tris(pyrazolyl)methane chelators stabilize thefac-[99mTc(CO)3]+ moiety providing complexes with significant, fast and stable heart uptake, together with a extremely fast liver clearance.

The uranium-nitrogen bond in U IV complexes supported by the hydrotris(3,5-dimethylpyrazolyl)borate ligand.

Insertion of benzonitrile and acetonitrile into the U-C bond of [U(Tp(Me2))Cl(2)(CH(2)SiMe(3))](Tp(Me2)= HB(3,5-Me(2)pz)(3)) gives the ketimide complexes [U(Tp(Me2))Cl(2){NC(R)(CH(2)SiMe(3))}](R = Ph (1); Me (2)). The identity of complex was ascertained by a single-crystal X-ray diffraction study. In the solid state exhibits octahedral geometry with a short U-N bond length to the ketimide ligand. We also report herein the synthesis and the X-ray crystal structures of the uranium amide complexes [U(Tp(Me2))Cl(2)(NR(2))](R = Et (3); Ph (4)). A detailed comparison of the U-N bond lengths in these compounds with other known U-N (and Th-N) distances in amide and ketimide actinide(IV) complexes is performed, confirming the short character of the U-N bond length in 1.