Triapine Derivatives Act as Copper Delivery Vehicles to Induce Deadly Metal Overload in Cancer Cells.

Thiosemicarbazones continue to attract the interest of researchers as potential anticancer drugs. For example, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, or triapine, is the most well-known representative of this class of compounds that has entered multiple phase I and II clinical trials. Two new triapine derivatives HL1 and HL2 were prepared by condensation reactions of 2-pyridinamidrazone and S-methylisothiosemicarbazidium chloride with 3-N-(tert-butyloxycarbonyl) amino-pyridine-2-carboxaldehyde, followed by a Boc-deprotection procedure. Subsequent reaction of HL1 and HL2 with CuCl2·2H2O in 1:1 molar ratio in methanol produced the complexes [CuII(HL1)Cl2]·H2O (1·H2O) and [CuII(HL2)Cl2] (2). The reaction of HL2 with Fe(NO3)3∙9H2O in 2:1 molar ratio in the presence of triethylamine afforded the complex [FeIII(L2)2]NO3∙0.75H2O (3∙0.75H2O), in which the isothiosemicarbazone acts as a tridentate monoanionic ligand. The crystal structures of HL1, HL2 and metal complexes 1 and 2 were determined by single crystal X-ray diffraction. The UV-Vis and EPR spectroelectrochemical measurements revealed that complexes 1 and 2 underwent irreversible reduction of Cu(II) with subsequent ligand release, while 3 showed an almost reversible electrochemical reduction in dimethyl sulfoxide (DMSO). Aqueous solution behaviour of HL1 and 1, as well as of HL2 and its complex 2, was monitored as well. Complexes 1-3 were tested against ovarian carcinoma cells, as well as noncancerous embryonic kidney cells, in comparison to respective free ligands, triapine and cisplatin. While the free ligands HL1 and HL2 were devoid of antiproliferative activity, their respective metal complexes showed remarkable antiproliferative activity in a micromolar concentration range. The activity was not related to the inhibition of ribonucleotide reductase (RNR) R2 protein, but rather to cancer cell homeostasis disturbance-leading to the disruption of cancer cell signalling.

New Water-Soluble Copper(II) Complexes with Morpholine-Thiosemicarbazone Hybrids: Insights into the Anticancer and Antibacterial Mode of Action.

Six morpholine-(iso)thiosemicarbazone hybrids HL1-HL6 and their Cu(II) complexes with good-to-moderate solubility and stability in water were synthesized and characterized. Cu(II) complexes [Cu(L1-6)Cl] (1-6) formed weak dimeric associates in the solid state, which did not remain intact in solution as evidenced by ESI-MS. The lead proligands and Cu(II) complexes displayed higher antiproliferative activity in cancer cells than triapine. In addition, complexes 2-5 were found to specifically inhibit the growth of Gram-positive bacteria Staphylococcus aureus with MIC50 values at 2-5 µg/mL. Insights into the processes controlling intracellular accumulation and mechanism of action were investigated for 2 and 5, including the role of ribonucleotide reductase (RNR) inhibition, endoplasmic reticulum stress induction, and regulation of other cancer signaling pathways. Their ability to moderately inhibit R2 RNR protein in the presence of dithiothreitol is likely related to Fe chelating properties of the proligands liberated upon reduction.

Crystal structure of N-hy-droxy-quinoline-2-carboxamide monohydrate.

The title compound, C10H8N2O2·H2O, consists of an N-hy-droxy-quinoline-2-carboxamide mol-ecule in the keto tautomeric form and a water mol-ecule connected through an O-H⋯O hydrogen bond. The N-hy-droxy-quinoline-2-carboxamide mol-ecule has a nearly planar structure [maximum deviation = 0.062 (1) Å] and only the hy-droxy H atom deviates significantly from the mol-ecule plane. In the crystal, π-π stacking between the aromatic rings [inter-centroid distance = 3.887 (1) Å] and inter-molecular O-H⋯O hydrogen bonds organize the crystal components into columns extending along the b-axis direction.

Copper(ii) thiosemicarbazone complexes induce marked ROS accumulation and promote nrf2-mediated antioxidant response in highly resistant breast cancer cells.

A series of water-soluble sodium salts of 3-formyl-4-hydroxybenzenesulfonic acid thiosemicarbazones (or sodium 5-sulfonate-salicylaldehyde thiosemicarbazones) containing different substituents at the terminal nitrogen atom (H, Me, Et, Ph) and their copper(ii) complexes have been prepared and characterised by elemental analysis, spectroscopic techniques (IR, UV-vis, 1H NMR), ESI mass spectrometry, X-ray crystallography and cyclic voltammetry. The proligands and their copper(ii) complexes exhibit moderate water solubility and good stability in aqueous environment, determined by investigating their proton dissociation and complex formation equilibria. The copper(ii) complexes showed moderate anticancer activity in established human cancer cell lines, while the proligands were devoid of cytotoxicity. The anticancer activity of the copper(ii) complexes correlates with their ability to induce ROS accumulation in cells, consistent with their redox potentials within the biological window, triggering the activation of antioxidation defense mechanisms in response to the ROS insult. These studies pave the way for the investigation of ROS-inducing copper(ii) complexes as prospective antiproliferative agents in cancer chemotherapy.

Crystal structure of bis-(µ-N-hy-droxy-picolin-amid-ato)bis-[bis-(N-hy-droxy-picolinamide)-sodium].

The title compound, [Na2(C6H5N2O2)2(C6H6N2O2)4], is a centrosymmetric coordination dimer based on the sodium(I) salt of N-hy-droxy-picolinamide. The mol-ecule has an {Na2O6(µ-O)2} core with two bridging carbonyl O atoms and two hydroxamate O atoms of two mono-deprotonated residues of N-hy-droxy-picolinamide, while two neutral N-hy-droxy-picolinamide mol-ecules are coordinated in a monodentate manner to each sodium ion via the carbonyl O atoms [the Na-O distances range from 2.3044 (2) to 2.3716 (2) Å]. The penta-coordinated sodium ion exhibits a distorted trigonal-pyramidal coordination polyhedron. In the crystal, the coordination dimers are linked into chains along the c axis via N-H⋯O and N-H⋯N hydrogen bonds; the chains are linked into a two-dimensional framework parallel to (100) via weak C-H⋯O and π-π stacking inter-actions.

Crystal structure of N-hy-droxy-picolinamide monohydrate.

The crystal structure of the title compound, C6H6N2O2·H2O, consists of N-hy-droxy-picolinamide and water mol-ecules connected through O-H⋯O and N-H⋯N hydrogen bonds. The O-H⋯O inter-actions and π-π stacking inter-actions between the pyridine rings [centroid-centroid distance = 3.427 (1) Å] organize the components into columns extending along the b axis and the N-H⋯N hydrogen bonds link these columns into a two-dimensional framework parallel to (100). The N-hy-droxy-picolinamide mol-ecule adopts a strongly flattened conformation and only the O-H group H atom deviates significantly from the mol-ecule best plane. The dihedral angle between the hydroxamic group and the pyridine ring is 5.6 (2)°. The conformation about the hydroxamic group C-N bond is Z and that about the C-C bond between the pyridine and hydroxamic groups is E.

Crystal structure of 2-{[(E)-(4-anilinophen-yl)iminium-yl]meth-yl}-5-(di-ethyl-amino)-phenolate.

The title compound, C23H25N3O, crystallized with one single mol-ecule in the asymmetric unit and is present in the zwitterionic form. There is an intra-molecular N-H⋯O hydrogen bond in the mol-ecule with the phenol ring being inclined to the central benzene ring by 20.67 (14)°. The terminal amino-phenyl ring forms a dihedral angle of 54.21 (14)° with the central benzene ring. The two outer aromatic rings are inclined to one another by 74.54 (14)°. In the crystal, the mol-ecules are connected by N-H⋯O hydrogen bonds, with adjacent molecules related by a 21 screw axis, generating -A-B-A-B- zigzag chains extending along [010]. The chains are linked via C-H⋯π and π-π inter-actions [with a centroid-centroid distance of 3.444 (3) Å] between the benzene ring and the imino group of symmetry-related mol-ecules, forming slabs lying parallel to (100).

2-[(Pyridin-2-yl)amino]-pyridinium 2,4,6-tri-nitro-phenolate.

In the cation of the title salt, C10H10N3 (+)·C6H2N3O7 (-), the pyridine and pyridinium rings are linked by an intra-molecular N-H⋯N hydrogen bond and are approximately coplanar, with a dihedral angle between their planes of 4.24 (6)°. In the crystal, the cations and anions are linked through N-H⋯O hydrogen bonds, forming supra-molecular chains propagating along the c-axis direction. π-π stacking is observed between neighbouring chains, the centroid-centroid distances being 3.7638 (11) (between pyridinium rings) and 3.5331 (11) Š(between benzene rings).