Jebiti Haribabu

Synthesis, DNA/protein binding, molecular docking, DNA cleavage and in vitro anticancer activity of nickel(II) bis(thiosemicarbazone) complexes

A series of N-substituted isatin thiosemicarbazone ligands (L1–L5) and their nickel(II) complexes [Ni(L)2] (1–5) were synthesized and characterized by elemental analyses and UV-Visible, FT-IR, 1H & 13C NMR, and mass spectroscopic techniques. The molecular structure of the ligands (L1 and L2) and complex 1 was confirmed by single crystal X-ray crystallography. The single crystal X-ray structure of 1 showed distorted octahedral geometry. The interaction of calf thymus (CT) DNA and bovine serum albumin (BSA) with the nickel(II) complexes was explored using absorption and emission spectral methods. A DNA cleavage study showed that the complexes cleaved DNA without any external agents. The alterations in the secondary structure of the protein by the nickel(II) complexes (1–5) were confirmed by synchronous and three dimensional fluorescence spectroscopic studies. The interaction of the complexes with DNA/protein also has been supported by molecular docking studies. An in vitro cytotoxicity study of the complexes found significant activity against human breast (MCF7) and lung (A549) cancer cell lines, with the best results for complexes 4 and 2 respectively, where the IC50 value is less than 0.1 μM concentration.

Synthesis of Ru(II)–benzene complexes containing aroylthiourea ligands, and their binding with biomolecules and in vitro cytotoxicity through apoptosis

The reaction of [RuCl2(η6-benzene)]2 with aroylthiourea resulted in the formation of Ru(II) complexes of the type [RuCl2(η6-benzene)L] (L = monodentate aroylthiourea ligand). The complexes were well characterized using UV-Visible, FT-IR, NMR and mass spectroscopic techniques. Single crystal X-ray diffraction confirmed the monodentate coordination of the ligand through a sulfur atom. The interaction of the Ru(II) complexes with calf thymus DNA (CT DNA) was investigated using UV-Visible and fluorescence spectroscopic methods, and viscosity measurements. The binding ability of the complexes with bovine serum albumin (BSA) was explored using UV-Visible and fluorescence experiments. The results showed that the complexes interact with the biomolecules with appreciable binding constants. The gel electrophoresis technique was used to demonstrate the unwinding of the supercoiled DNA to its nicked form. The cytotoxicity of the Ru(II) complexes was screened for a panel of cancer cell lines like HepG2, A549, MCF7 and SKOV3. Complexes 1, 2 and 3 showed modest activity at the concentration of 31.25 μg mL−1 against HepG2 cells. Complexes 1 and 3 displayed moderate cytotoxicity at the concentration of 62.5 μg mL−1 against A549 and SKOV3 respectively. Low cytotoxicity was observed for all the complexes against MCF7. Advantageously, complexes exhibited only less toxicity against Vero normal cells. Further DNA fragmentation, flow cytometry and fluorescence staining [DAPI (blue), FITC (green) and PI (red)] for the detection of apoptosis in HepG2 cells were carried out. The above methods demonstrated that the complexes have a significant ability to induce cell death by apoptosis.

Crystal structures of two hydrazinecarbo­thio­amide derivatives: (E)-N-ethyl-2-[(4-oxo-4H-chromen-3-yl)methyl­idene]hydrazinecarbo­thio­amide hemi­hydrate and (E)-2-[(4-chloro-2H-chromen-3-yl)methyl­idene]-N-phenyl­hydrazinecarbo­thio­amide

The title compounds, (I) and (II), are hydrazinecarbothioamide derivatives. In the crystal of (I), two independent molecules are linked by bifurcated N—H⋯O and C—H⋯O hydrogen bonds, forming two (6) ring motifs, and (10) and (14) ring motifs. In the crystal of (II), molecules are linked by pairs of N—H⋯S hydrogen bonds, forming inversion dimers with an (8) ring motif.

Nickel(II) bis(isatin thiosemicarbazone) complexes induced apoptosis through mitochondrial signaling pathway and G0/G1 cell cycle arrest in IM-9 cells

Three novel complexes (1, 3 and 4) ligating N-substituted isatin thiosemicarbazone derivatives have been synthesized and their structural and biological characteristics have been compared with those of the known analogs (2, 5-7 and 8). In addition, the structure of the representative ligands (L1, L3 and L4) and complex (4) was confirmed by single crystal X-ray diffraction method. All the complexes (1-8) were assessed for their cytotoxic property against a panel of four human cancer cells such as HepG-2 (liver), MOLM-14 (acute monocytic leukemia), U937 (histiocytic lymphoma). and IM-9 (myeloma). Complex 4 exhibited prominent cytotoxic property against MOLM-14, U937 and IM-9 cell lines. Moreover, the results were compared with the well-known anticancer drugs like doxorubicin, cisplatin and daunorubicin. Besides, complex 4 enhanced the apoptotic cell death in IM-9 cell line and induced cell cycle arrest at G1 phase. Western blot analysis revealed the down-regulation of Bcl-2 (b-cell lymphoma-2), up-regulation of Bax (bcl-2 associated X protein), release of cytochrome c and activation of caspases-3 in IM-9 cells by complex 4. Importantly, complex 4 was not toxic to the normal Vero cell line (IC50 > 300 μM). In addition, complex 4 showed the concentration dependent cleavage of supercoiled (SC) DNA to its nicked circular (NC) form.

Crystal structure of (E)-2-[(4-chloro-2H-chromen-3-yl)methyl-idene]-N-cyclo-hexyl-hydrazinecarbo-thio-amide.

In the title compound, C17H20ClN3OS, the mean plane of the central thiourea core makes dihedral angles of 26.56 (9) and 47.62 (12)° with the mean planes of the chromene moiety and the cyclohexyl ring, respectively. The cyclohexyl ring adopts a chair conformation. The N–H atoms of the thiourea unit adopt an anti conformation. The chromene group is positioned trans, whereas the cyclohexyl ring lies in the cis position to the thione S atom, with respect to the thiourea C—N bond. In the crystal, molecules are linked by N—H⋯S hydrogen bonds, forming inversion dimers enclosing R 2 2(8) ring motifs. The dimers are linked by C—H⋯Cl hydrogen bonds, enclosing R 6 6(44) ring motifs, forming sheets lying parallel to (010).

Crystal structure of (2E)-N-methyl-2-[(4-oxo-4H-chromen-3-yl)methyl-idene]hydrazine-carbo-thio-amide.

In the title compound, C12H11N3O2S, the dihedral angle between the 4H-chromen-4-one ring system and the –CH=N—NH—CS—NH– unit is 6.22 (1)°. In the crystal, inversion dimers linked by pairs of N—H⋯O hydrogen bonds generate R 2 2(14) loops. The dimers are reinforced by a pair of C—H⋯O interactions, which generate R 2 2(10) loops.

Crystal structures of the Schiff base derivatives (E)-N′-[(1H-indol-3-yl)methyl­idene]isonicotino­hydrazide ethanol monosolvate and (E)-N-methyl-2-[1-(2-oxo-2H-chromen-3-yl)ethyl­idene]hydrazinecarbo­thio­amide

In the two title Schiff base derivatives, the (E)-N′-[(1H-indol-3-yl)methylidene]isonicotinohydrazide molecules and (E)-N-methyl-2-[1-(2-oxo-2H-chromen-3-yl)ethylidene]hydrazinecarbothioamide molecules form a tape structure and a helical chain structure, respectively, through hydrogen bonds.

Crystal structure of (Z)-2-(1-benzyl-2-oxoindolin-3-yl­idene)-N-phenyl­hydra­zine-1-carbo­thio­amide

The title compound, C22H18N4OS, crystallized with four independent molecules (A, B, C and D) in the asymmetric unit. All four molecules have a Z conformation about the C=N bond with the benzyl ring being inclined to the indoline ring mean planes by 73.4 (2), 77.9 (2), 73.2 (2) and 77.2 (2)° in molecules A, B, C and D, respectively. In molecules A and B, the phenyl ring is inclined to the mean plane of the indoline ring mean plane by 12.0 (2) and 12.2 (2)°, respectively. However, in molecules C and D, the same dihedral angles are larger, viz. 37.3 (2) and 36.4 (2)°, respectively. Consequently, the benzyl and phenyl rings are almost normal to one another in molecules A and B [dihedral angles = 80.3 (3) and 87.1 (3)°, respectively], while in molecules C and D, the same dihedral angles are only 48.8 (2) and 43.8 (3)°, respectively. There is an intramolecular N—H⋯O hydrogen bond in each molecule with an S(6) ring motif. There are also short intramolecular N—H⋯N and C—H⋯S contacts in each molecule. In the crystal, molecules are linked via C—H⋯S hydrogen bonds and C—H⋯π interactions, forming a three-dimensional structure. The crystal was refined as a non-merohedral twin with a final BASF value of 0.110 (1).

Crystal structure of N-[(naphthalen-1-yl)carbamo-thio-yl]cyclo-hexa-necarboxamide.

The title compound, C18H20N2OS, displays whole-molecule disorder over two adjacent sets of sites with an occupancy ratio of 0.630 (11):0.370 (11). In each disorder component, the cyclohexyl ring shows a chair conformation with the exocyclic C—C bond in an equatorial orientation. The dihedral angles between the cyclohexyl ring (all atoms) and the naphthyl ring system are 36.9 (6) for the major component and 20.7 (12)° for the minor component. Each component features an intramolecular N—H⋯O hydrogen bond, which closes an S(5) ring. In the crystal, inversion dimers linked by pairs of N—H⋯S hydrogen bonds generate R 2 2(8) loops for both components. Aromatic π–π stacking interactions [shortest centroid–centroid separation = 3.593 (9) Å] and a C—H⋯π interaction are also observed.

Synthesis, structures and mechanistic pathways of anticancer activity of palladium(II) complexes with indole-3-carbaldehyde thiosemicarbazones

New PdII complexes of the types [PdCl(L)(PPh3)] (1–5) and [Pd(L)2] (6 and 7) (HL = indole-3-carbaldehyde thiosemicarbazones, HL1–HL5) have been synthesized in order to ascertain the effect of substitution at the terminal nitrogen of thiosemicarbazones on the biological properties of their PdII complexes. The compounds were characterized by elemental analyses, and UV-visible, FT-IR, 1H NMR, 13C NMR, DEPT-135 NMR, 31P NMR, 1H–1H COSY, 1H–13C HSQC, 1H–13C HMBC, 1H–31P HMBC and mass spectroscopic techniques. The solid state structures of the ligand (HL3) and complexes (2–5 and 6) were determined by single crystal X-ray diffraction analysis. Spectroscopic and crystallographic studies revealed that thiosemicarbazone is coordinated to the PdII ion as a monobasic bidentate (NS−) ligand by forming a five membered ring. To determine the potential of the PdII complexes towards biomolecular interactions, additional experiments involving interaction with calf thymus DNA (CT DNA) and bovine serum albumin (BSA) were carried out. Further, the complexes cleaved DNA (pUC19 and pBR322) without any co-oxidant at pH 7.2 and temperature 37 °C. The effect of substitution on the DNA and BSA binding ability of the complexes was revealed through molecular docking studies. In addition, in vitro anticancer activity was examined by using MTT assay in three cancer cell lines (HepG-2, A549 and MCF7) and one normal cell line (L929). Complexes 4 and 5 which contain triphenylphosphine showed better activity (HepG-2) with an IC50 value of 22.8 and 67.1 μM respectively. The anticancer activity of the complexes was compared with that of the well-known anticancer drug cisplatin and it was inferred that complex 4 exhibited comparable activity. All the complexes displayed moderate anticancer activity against A549 and MCF7 cancer cell lines and less toxicity towards the normal cell line. The morphological changes assessed by staining methods and DNA fragmentation revealed that the cell death occurred by apoptosis.