Effective inhibition of insulin amyloid fibril aggregation by nickel(II) complexes containing heterocyclic thiosemicarbazones.

The sensitivity of protein molecular structures makes them susceptible to aggregation in conditions unfavorable for the maintenance of their native folds. The aggregation of proteins leads to many disorders, but the inhibition of amyloid fibril formation using metal-containing small molecules is gaining popularity. Herein we report the effect of nickel(II) complexes (N1, N2, N3, and N4) bearing thiosemicarbazones on the inhibition of amyloid fibril formation by insulin. The interactions of the complexes with amyloid fibrils were investigated using various biophysical techniques, including light scattering, intrinsic fluorescence assay, thioflavin T (ThT) assay, and Fourier transform-infrared spectroscopy. The results revealed that the phenyl-substituted N3 was an efficient inhibitor of amyloid fibril formation and maintained the insulin in its native structure despite conditions promoting fibrillation. Nickel(II) complexes containing indole based thiosemicarbazones were efficient in inhibiting the amyloid fibril formation and maintaining the insulin in its native structure in unfavorable conditions.

N-substitution in isatin thiosemicarbazones decides nuclearity of Cu(II) complexes - Spectroscopic, molecular docking and cytotoxic studies.

The mono- (1) and bi-nuclear (2) copper(II) complexes containing N-substituted isatin thiosemicarbazone(s) were synthesized, and characterized by analytical and spectroscopic (UV-Visible, FT-IR and EPR) techniques. Bimetallic nature of complex 2 was confirmed by single crystal X-ray crystallography. The structures predicted by spectroscopic and crystallographic methods were validated by computational studies. From the spectroscopic, crystallographic and computational data, the structures were found to be distorted square planar for 1 and distorted square pyramidal for 2. Molecular docking studies showed hydrogen bonding and hydrophobic interactions of the complexes with tyrosinase kinase receptors. Complex 1 exhibited promising cytotoxic activity against Jurkat (leukemia) cell line, and complex 2 displayed more activity against HeLa S3 (cervical) and Jurkat cell lines with the IC50 values of 3.53 and 3.70 µM, respectively. Cytotoxicity of 1 (Jurkat) and 2 (Jurkat and HeLa S3) was better than that of cisplatin. Morphological changes in A549 (lung), HeLa S3 and Jurkat cell lines were examined in presence of the active complexes with the co-staining of Hoechst, AO (acridine orange) and EB (ethidium bromide) by fluorescence microscope.

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.

Synthesis of Ni(II) complexes bearing indole-based thiosemicarbazone ligands for interaction with biomolecules and some biological applications.

A series of new Ni(II) complexes containing indole-based thiosemicarbazone ligands was synthesized and characterized by elemental analyses, and UV-visible, FT-IR, 1H & 13C NMR and mass spectroscopic techniques. The Ni(II) complexes (1-4) bear the general formula [Ni{C10H9N2NHCSNH(R)}2] where R = hydrogen (1), 4-methyl (2), 4-phenyl (3) and 4-cyclohexyl (4). Molecular structure of ligands (L3 and L4) and complexes (2, 3 and 4) was confirmed by single crystal X-ray crystallography. Four coordinated Ni(II) complexes showed square planar geometry. The interaction of the Ni(II) complexes with calf thymus DNA (CT-DNA) has been evaluated by absorption spectroscopic and ethidium bromide (EB) competitive binding studies, which revealed the intercalative interaction of the complexes with CT-DNA. Gel electrophoresis experiments showed the cleavage of DNA by the complexes without any external agent. Further, the interaction of the complexes with bovine serum albumin (BSA) was investigated using UV-visible, fluorescence and synchronous fluorescence spectroscopic methods, which showed that the complexes could bind strongly with BSA. Molecular docking was employed to understand the binding of the Ni(II) complexes with the molecular target B-DNA, human DNA topoisomerase I and BSA. All the Ni(II) complexes possess high antioxidant activity against 2-2-diphenyl-1-picrylhydrazyl (DPPH) radical and antihaemolytic activity. In addition, in vitro cytotoxicity of the Ni(II) complexes against lung cancer (A549), human breast cancer (MCF7) and mouse embryonic fibroblasts (L929) cell lines was investigated. Complex 4 has high cytotoxicity. The mode of cell death effected by complex 4 has been explored using Hoechst 33258 staining. Nickel(II) complexes of thiosemicarbazone ligands were synthesized and their DNA/protein binding, DNA cleavage and cytotoxicity abilities were studied.

Half-sandwich RuCl2(η(6)-p-cymene) core complexes containing sulfur donor aroylthiourea ligands: DNA and protein binding, DNA cleavage and cytotoxic studies.

A series of Ru(ii)(η(6)-p-cymene) complexes (1-4) bearing the general formula [RuCl2(η(6)-p-cymene)L] (L = monodentate aroylthiourea ligand) has been synthesized and characterized by analytical and various spectroscopic techniques. The neutral monodentate coordination of aroylthiourea with Ru via an S atom was confirmed by single crystal X-ray diffraction study. The complexes were tested for their ability to interact with DNA and protein. The complexes bound with calf thymus DNA (CT DNA) with the intrinsic binding constant value in the order of 10(4) M(-1). The intercalative mode of binding was confirmed by the ethidium bromide (EB) displacement study. The interaction of the complexes with CT DNA was further supported by viscosity measurements and circular dichroic (CD) spectra. The Ru(ii) complexes cleaved the supercoiled DNA without the need of any external agent. The spectroscopic evidence showed good binding efficacy of the complexes with BSA (Bovine Serum Albumin). The alterations in the secondary structure of BSA by the Ru(ii) complexes were confirmed by synchronous fluorescence spectra. Cytotoxicity examination by MTT assay was carried out in two cancer cell lines (MCF7 and A549) and one non-cancerous cell line (L929). Complex 4 showed significant activity [IC50 = 52.3 (MCF7) and 54.6 (A549) µM] which was comparable with that of similar known complexes. The morphological changes assessed by Hoechst staining revealed that the cell death occurred by apoptosis.