A significantly non-toxic novel Cobalt(III) Schiff base complex induces apoptosis via G2-M cell cycle arrest in human breast cancer cell line MCF-7.

AIMS: Metal complexes have ignited considerable interest in the field of chemotherapy after the serendipitous discovery of cisplatin but the severe toxicity of these platinum-based drugs compelled researchers to search for newer, more effective lesser toxic anticancer drugs. MATERIALS AND METHODS: Structural analysis is done by different physicochemical techniques including X-ray single crystallography. Toxicity study has been done in normal Swiss albino mice. MTT assay assessed cell viability. Apoptosis, cell cycle arrest, and cell proliferation were assessed by FACS using Annexin V-PI, PI, and CFSE staining respectively. Western blot quantifies protein expression. While cell migration was studied by wound healing assay. KEY FINDINGS: One-pot synthesis of a novel mononuclear cobalt(III)-Schiff base complex (1) (>99 % purity) and its complete characterization have been done. Cell viability assay showed that 1 (IC50 = 16.81 ± 1.33 µM) exhibits cytotoxicity at much lower concentration in comparison to oxaliplatin (IC50 = 31.4 ± 0.69 µM) against MCF-7 cells for 24 h of therapy without being overly toxic to human PBMCs (IC50 ≥ 60 µM). Additional in vitro studies demonstrated that 1 induces apoptosis via G2-M cell cycle arrest and reduces cell proliferation as well as cell migration in MCF-7 cells. In vivo subacute toxicity (28 days) and systemic chronic toxicity (40 days) studies were carried out in normal Swiss albino mice showed 1 is significantly nontoxic to the host. SIGNIFICANCE: The readily synthesizable, significantly nontoxic cobalt complex with appreciable anticancer activity implies that it might be an effective chemotherapeutic agent for new-age anti-tumor medication.

Designing of novel zinc(ii) Schiff base complexes having acyl hydrazone linkage: study of phosphatase and anti-cancer activities.

Three asymmetric tridentate acyl hydrazone Schiff base ligands namely L1, L2 and L3 were prepared via condensation of 4-methoxybenzohydrazide with picolinaldehyde, 1-(pyridin-2-yl)ethanone and phenyl(pyridin-2-yl)methanone respectively. Three bio-relevant mononuclear zinc(ii) complexes [Zn(L1)Cl2]·2H2O (1), [Zn(L2)Cl2] (2) and [Zn(L3)Cl2] (3) were synthesized by treatment of zinc(ii) chloride with the corresponding Schiff base ligands and characterised by the usual physicochemical techniques. The solid state structures of complexes 1 and 3 were evaluated by single crystal X-ray analysis. All complexes were able to hydrolyse the P-O bond of the phosphate monoester in 90% (v/v) DMSO-water medium using 4-nitrophenylphosphate (4-NPP) as the model substrate and the trend in their activity is 1≈2 > 3. On considering the highly efficient hydrolysis properties, complexes 1-3 were tested as potential therapeutic agents for cancer using HCT116 (human colorectal carcinoma), HepG2 (human hepatocellular carcinoma) and A549 (human non-small lung carcinoma) cells. Complex 2 showed the highest IC50 values for anti-cancer activity towards all three cell lines among the three complexes and complex 3 showed the least activity as observed in the phosphatase activity study. The internucleosomal degradation of DNA during apoptosis can be detected by cell death detection ELISA. DNA fragmentation that leads to cell death was examined and when induced by complex 2 in HepG2 cells a significant level of DNA fragmentation was observed at regular intervals of time.

Anion-mediated bio-relevant catalytic activity of dinuclear nickel(ii) complexes derived from an end-off compartmental ligand.

Four dinuclear nickel(ii) complexes, namely [Ni4(L)2(H2O)8(µ2-H2O)2](NO3)6(H2O)6 (1), [Ni2(L)Cl2(µ-Cl)(CH3OH)] (2), [Ni2(L)(OAc)2(H2O)2]Br (3) and [Ni2(L)(H2O)4(µ2-OH)] (H2O)X(I)X (4), have been synthesized using a template synthesis technique by adding nickel(ii) salts (nitrate/chloride/bromide/iodide) to the N4O donor end-off compartmental ligand (HL) obtained via the condensation of 2-(2-pyridyl)ethylamine and 2,6-diformyl-4-isopropyl phenol in methanol. All complexes were characterized with the help of typical physicochemical techniques, and their solid-state structures were assigned from single crystal X-ray analysis. The variable temperature magnetic study reveals that the two nickel centers are antiferromagnetically coupled with J values ranging from -5 to -15 cm-1 in the complexes. The catecholase-like activity of complexes 1-4 was studied using 3,5-di-tert-butylcatechol (3,5-DTBC) as the model substrate in N,N-dimethylformamide (DMF) medium. Complex 1 shows the catecholase activity, while the other complexes were found to be inactive. The phosphatase-like activity of the complexes was also investigated in a 97.5% (v/v) DMF-water mixture using the disodium salt of 4-nitrophenylphosphate (4-NPP) as the model substrate and the reactivity trend was 4 > 1 > 3 > 2. The reasons behind the activity, inactivity and activity trend have been explored. It has been assumed that the anions associated with the complexes are supposed to play a crucial role in the whole event. Complex 1 showed catalytic promiscuity, whereas complexes 2, 3 and 4 should be considered only as the potential hydrolytic catalyst.

Unveiling the effects of the in situ generated arene anion radical and imine radical on catecholase like activity: a DFT supported experimental investigation.

Two new dinuclear nickel(ii) complexes namely [Ni2(L1)2(OAc)2(H2O)2]·CH3CN (1) and [Ni2(L2)2(SCN)2(CH3OH)2]·CH3OH (2) have been synthesized from the designed Schiff-base ligand 4-bromo-2-[(2-hydroxy-1,1-dimethyl-ethylimino)-methyl]-phenol (HL1) and its reduced analogue 4-bromo-2-[(2-hydroxy-1,1-dimethyl-ethylamino)-methyl]-phenol (HL2), respectively. Both 1 and 2 have been characterised by usual physicochemical techniques (UV-Vis, FT-IR, ESI-MS study and single crystal XRD) and their variable temperature magnetic study has been performed. The nickel(ii) centres in the dinuclear complexes 1 and 2 are antiferromagnetically coupled through participation of the bridging phenoxyl oxygen. In acetonitrile solution both 1 and 2 retain their dinuclear structural integrity as is evident from the ESI-MS study. The catecholase-like activity of 1 and 2 has been performed in acetonitrile medium using 3,5-di-tert-butylcatechol (3,5-DTBC) as a model substrate. Complex 1 shows a higher catalytic activity than that of complex 2. The ESI-MS study suggests that dinuclear species undergo cleaving into a mononuclear entity in the presence of 3,5-DTBC and that mononuclear species are supposed to act as active catalysts in the catalytic cycle. The EPR study of catalytic reactions confirms that organic radicals have been generated during catalysis in both cases. However, in the case of complex 1 catalyzed reaction a single isotropic signal at g = 1.97 is obtained which is most likely due to imine radical formation. On the other hand, for complex 2 catalyzed reaction the spectrum shows a signal with hyperfine splitting (g = 2.11, 2.05 and 1.9), thereby suggesting the generation of a new radical i.e. an arene anion radical in this study on catecholase activity. Extensive DFT calculations have been performed to support the experimental observation and thus to put forward the most probable mechanistic pathways operating in the two cases. The higher efficiency of the imine radical pathway over the arene anion radical has been rationalized by DFT calculations.