Synthesis and antitumor activity of copper(II) complexes of imidazole derivatives.

Complexes [Cu(PI)2(H2O)](NO3)2 (1), [Cu(PBI)2(NO3)]NO3 (2), [Cu(TBI)2(NO3)]NO3 (3), [Cu(BBIP)2](ClO4)2 (4) and [Cu(BBIP)(CH3OH)(ClO4)2] (5) were synthesized from the reactions of Cu(II) salts with 2-(2'-pyridyl)imidazole (PI), (2-(2'-pyridyl)benzimidazole (PBI), 2-(4'-thiazolyl)-benzimidazole (TBI), 2,6-bis(benzimidazol-2-yl)-pyridine (BBIP), respectively. Their compositions and crystal structures were determined. Their in-vitro antitumor activities were screened on four cancer cell lines and one normal cell line (HL-7702) using cisplatin as the positive control. Complexes 2 and 4 show higher cytotoxicity than the other three complexes. The cytotoxicity of complex 2 are comparable to those for cisplatin, and the cytotoxicity for 4 are much higher than those for cisplatin. From a viewpoint of antitumor, 2 might be a nice choice on the tumor cell line of T24 because its IC50 values on T24 and HL-7702 are 15.03 ± 1.10 and 21.34 ± 0.35, respectively. Thus, a mechanistic study for complexes 2 and 4 on T24 cells was conducted. It revealed that they can reduce mitochondrial membrane potential and increase mitochondrial membrane permeability, resulting in increased intracellular ROS levels, Ca2+ inward flow, dysfunctional mitochondria and the eventual cell apoptosis. In conclusion, they can induce cell apoptosis through mitochondrial dysfunction. These findings could be useful in the development of new antitumor agents.

Antitumor Activities for Two Pt(II) Complexes of Tropolone and 8-Hydroxyquinoline Derivative.

The reactions of cis-Pt(DMSO)2Cl2 and tropolone (HL) with 8-hydroxyquinoline (HQ) or 2-methyl-8-hydroxyquinoline (HMQ) gave [Pt(Q)(L)] (1) and [Pt(MQ)(L)] (2), which present mononuclear structures with their Pt(II) ions four-coordinated in square planar geometries. Their in vitro biological properties were evaluated by MTT assay, which showed a remarkable cytotoxic activity on the cancer cell lines. 1 shows higher cytotoxic activities on tumor cells such as T24, HeLa, A549, and NCI-H460 than complex 2 and cisplatin, with IC50 values <16 µM. Among them, an IC50 value of 3.6 ± 0.63 µM was found for complex 1 against T24 cells. It presented a tuning cytotoxic activity by substitution groups on 8-hydroxyquinoline skeleton. In our case, the substitution groups of -H are much superior to -CH3 against tumor cells. It revealed that both complexes can induce cell apoptosis by decreasing the potential of a mitochondrial membrane, enhancing reactive oxygen species and increasing Ca2+ levels of T24 cells. The T24 cell cycle can be arrested at G2 and G1 phases by complexes 1 and 2, respectively, with an upregulation for P21 and P27 expression levels and a down-regulation for cyclin A, CDK1, Cdc25A, and cyclin B expression levels. Furthermore, complex 1 exhibits satisfactory in vivo antitumor activity as revealed by the tumor inhibitory rate and the tumor weight change as well as by the cute toxicity assay and renal pathological examinations, which is close to cisplatin and much better than complex 2. All of these suggest that 1 might be a potential candidate for developing into a safe and effective anticancer agent.

Synthesis and anticancer activity of mixed ligand 3d metal complexes.

Our previously reported copper-based complexes of tropolone show nice antitumor effects, but with high cytotoxicity to normal cells, which is presumably caused by copper ions. Here, we managed to achieve this challenge by using other 3D metals to replace copper ions. We thus prepared four mononuclear 3D metal complexes [M(phen)L2] (M = Mn, Co, Ni, and Zn for 1-4, respectively). Complexes 1 and 4 show selectivity on different cancer cell lines with much lower cytotoxicity to normal cells than cisplatin. The anticancer effects for complexes 2 and 3 on the tested cancer cell lines are very poor. It revealed a tuning effect of different metal ions on the anticancer activities with those for Mn(II) and Zn(II) being much higher than those for Co(II) and Ni(II) in this system. Among them, complex 1 presents a best anticancer effect on HeLa cells comparable to cisplatin. It overcame the afore-mentioned shortage of high cytotoxicity to normal cells for the reported Cu(II) complexes. It revealed from the mechanistic studies that complex 1 mainly induces apoptosis through the mitochondrial pathway by increasing intracellular reactive oxygen species, releasing Ca2+, and activating Caspase 9 and proapoptotic gene Bax.

Structure and anticancer activities of four Cu(ii) complexes bearing tropolone.

Agents inducing apoptosis and autophagic death could be effective chemotherapeutic drugs. In this work, four novel Cu(ii) complexes formulated as [CuL2] (1), [Cu(phen)LCl]·0.5H2O (2), [Cu2(MQ)2L2] (3) and [Cu(2,2'-bpy)LCl]·H2O (4) (phen = 1,10-Phenanthroline, HMQ = 8-hydroxy-2-methylquinoline, 2,2'-bpy = 2,2'-bipyridine) were prepared from the reactions of copper(ii) chloride with tropolone (HL) in the absence or presence of different ancillary ligands. The solution state structures of 1, 2 and 4 agree well with their solid state structures. Complex 3 presents a dimer structure in the solid state, however, a monomer structure in the solution state. It was shown that all of these complexes are stable under experimental conditions and bind to DNA in an intercalative mode with the binding constant Kb values of 1.05 × 103, 2.57 × 103, 2.53 × 103 and 2.26 × 103 L mol-1 for complexes 1, 2, 3 and 4, respectively. The anti-proliferative tests against cultured human cancer cell lines (A549, Bel-7402, MGC80-3, T24, SK-OV-3, and NCI-H460) in vitro revealed cytotoxic activities for these complexes, which are much better than those for all ligands in these complexes, as well as that for cis-platin. After a careful comparison, the cytotoxic activity of complex 2 against MGC80-3 cells in vitro (IC50 = 3.5 ± 0.9 µM for 2 and 18.0 ± 1.2 for cis-platin) was further investigated in detail as an example. 2 induces the apoptosis of MGC80-3 through a caspase-dependent mitochondrion pathway and can also induce autophagy, which revealed a certain anticancer activity for complex 2.