Bi-Qun Zou

Synthesis and antioxidant activities of novel 4-Schiff base-7-benzyloxy-coumarin derivatives

4-Schiff base-7-benzyloxy-coumarins 5a(1)-5h(2) and its derivative 6 were designed and synthesized based on the 7-benzyloxy-coumarin structure as novel antioxidants. The in vitro antioxidant activities screening revealed that 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activities of compounds 5b(1), 5d(1), 5f(1), 5f(2), 5g(1) and 5g(2), and 2,2-azinobis-(3-ethylbenzthiazoline-6-sulfonate) cation (ABTS(+)) radical scavenging activities of compounds 5a(1), 5b(1), 5c(1), 5c(2), 5d(1), 5e(1), 5e(2), 5f(2), 5g(1), 5g(2) and 5h(1) were better than that of the commercial antioxidant butylated hydroxytoluene (BHT), while the superoxide anion radical scavenging activities of 5a(2) and 5g(2) were stronger than that of the commercial antioxidant butylated hydroxyanisole (BHA), and the hydroxyl radical scavenging activity of 5e(1) was much better than that of the common antioxidant ascorbic acid.

Cytotoxicity, DNA binding and cell apoptosis induction of a zinc(II) complex of HBrQ

A new zinc(II) complex (1) of 5-bromo-8-hydroxyquinoline (HBrQ) was prepared and structurally characterized using IR, ESI-MS, elemental analysis, 1H and 13C NMR, as well as single crystal X-ray diffraction analysis. The DNA binding study on complex 1, which was performed using UV-vis, fluorescence and circular dichroism (CD) spectral analyses, suggested that complex 1 interacts with ct-DNA mainly via an intercalative binding mode. The in vitro cytotoxicity of complex 1, compared with Zn(OAc)2·H2O, HBrQ and cisplatin, was screened against a series of tumor cell lines as well as the normal liver cell line HL-7702 using the MTT assay. Complex 1 showed much higher cytotoxicity than Zn(OAc)2·H2O and HBrQ against most of the tumor cell lines, in which BEL-7404 was the most sensitive tumor cell line towards 1, with an IC50 value of 8.69 ± 0.04 μM. Complex 1 was found to greatly induce cell cycle arrest in the BEL-7404 cells at the G2 phase, and consequently to induce cell apoptosis in a dose-dependent mode, which is suggested by the cell apoptosis analysis via the Hoechst 33258 and AO/EB staining assays. Targeting the mitochondria pathway due to the redox activity of Zn, the apoptotic mechanism in the BEL-7404 cells treated by 1 was investigated using reactive oxygen species (ROS) detection, intracellular calcium concentration measurement and caspase-9/3 activity assay, which showed that the cell apoptosis induced by 1 was closely related to the loss of mitochondrial membrane potential, ROS production and enhancement of intracellular [Ca2+], which trigger caspase-9/3 activation via the mitochondrial dysfunction pathway.

Synthesis, crystal structure and biological evaluation of a new dasatinib copper(II) complex as telomerase inhibitor.

A new copper(II) complex of dasatinib (DAS) was synthesized and characterized via ESI-MS, UV-Vis, IR, single-crystal X-ray diffraction analysis, 1H and 13C NMR spectroscopy, and elemental analysis. The composition of the new complex (1) was found to be [Cu(DASxa0+xa0H)(NO3)2(H2O)]NO3·(H2O)·(CH3OH). Through MTT assay, it was found that 1 had high cytotoxicity towards A549, HeLa, BEL-7402, Hep-G2, NCI-H460, and MGC80-3 tumor cell lines, with IC50 values in 4.04-13.04xa0μM. The Hep-G2 cells were the most sensitive to 1. It is worth noting that compared with DAS and cisplatin, 1 not only had higher inxa0vitro anticancer activity but also exhibited greater selective toxicity towards Hep-G2 cells than for normal HL-7702xa0cells. Experimental results from cell apoptosis analysis, cellular uptake, TRAP-silver staining assay, RT-PCR, western blot, and transfection assays showed that 1 was most likely a telomerase inhibitor that targeted c-myc G-quadruplex DNA. The high cytotoxicity and biological behaviors of 1 could be correlated with the central copper(II) atom in the coordinated mode with DAS.

Antioxidant activities and transition metal ion chelating studies of some hydroxyl Schiff base derivatives

Several hydroxyl Schiff base (HSB) compounds (1–10) with good radical scavenging activity (RSA) were designed. Compounds 6, 7, and 10 showed better RSAs than the common synthetic antioxidant 2,6-diter-butyl-4-methylphenol (BHT) in DPPH• and ABTS• assays. To probe whether these HSB compounds may exert their antioxidant effect through transition metal ion chelation, the copper and ferrous chelating abilities of them were investigated. It was found by fluorescence quenching spectra that the binding constants Ka were in the range of 0.85×103–7.30×104xa0M−1. Further study was carried out by the complexation of a representative compound 5 with ferrous ion in mass spectrum. A 2:1 5-ferrous complex was readily formed in a methanol–water solution (v:v, 8:2), which confirmed that the chelation happened when the HSB compounds were treated with transition metal ions. The above results indicated that the transition metal ion chelation play an important role in their antioxidant abilities.

Three novel transition metal complexes of 6-methyl-2-oxo-quinoline-3-carbaldehyde thiosemicarbazone: synthesis, crystal structure, cytotoxicity, and mechanism of action

Three novel 6-methyl-2-oxo-quinoline-3-carbaldehyde thiosemicarbazone (H-L) transition metal complexes, [Cu(H-L)NO3H2O]·NO3 (1), [Zn(H-L)NO3H2O]·NO3 (2) and [CoL2] (3), were synthesized. In vitro antitumor screening revealed that complex 1 exhibited better inhibitory activities than the commercial anticancer drug cisplatin against SK-OV-3 and MGC80-3 tumor cell lines, with IC50 values of 10.35 ± 1.26 μM and 10.17 ± 0.95 μM, respectively. All three complexes showed low cytotoxicity toward the normal human liver HL-7702 cells compared with cisplatin. Their binding properties to DNA were investigated by various methods. It was found that the complexes interacted with DNA mainly through intercalation, and their binding affinities ranked in the order of 3 > 1 > 2. Complex 1 induced the highest apoptosis rate of MGC80-3 cells, and it caused cell arrest in the S phase according to flow cytometry. Further experiments confirmed that complex 1 triggered MGC80-3 cells apoptosis via a mitochondrial dysfunction pathway.

Cobalt(II) 8-hydroxyquinoline complexes: structure, cytotoxicity and action mechanism

Three cobalt(II) complexes, [Co(NOQ)2(C5H5N)2]C2H5OH (1), [Co(BrQ)2(C5H5N)2] (2) and [Co(NQ)2(C5H5N)2] (3) (NOQ = 5-nitro-8-hydroxyquinoline, BrQ = 5-bromo-8-hydroxyquinoline, NHQ = 2-amino-8-hydroxyquinoline), were synthesized and characterized. Their in vitro cytotoxicity against T-24, BEL-7404, HepG2, HeLa, MGC-803, SKOV-3, HL-7702 and WI-38 cell lines was evaluated. Complexes 1–3 exhibited the highest proliferation inhibition activity against the T-24 tumor cell line with IC50 values in the range between 7.00 and 16.70 μM. They also displayed selectivity towards T-24 tumor cell lines compared to the normal liver cell line HL-7702 and human fetal lung fibroblast WI-38 cell line. The action mechanism of complex 1 was investigated. It caused apoptotic death of the T-24 cells via G1 cell cycle arrest. Further investigation revealed that complex 1 induced overproduction of reactive oxygen species, which led to mitochondrion-mediated apoptosis. DNA binding studies suggested that intercalation might be the most probable binding mode of the Co(II) complexes with ct-DNA.

Studies on the structures, cytotoxicity and apoptosis mechanism of 8-hydroxylquinoline rhodium(III) complexes in T-24 cells

Two rhodium(III) complexes (Rh(OQ)3 (1) and Rh(BrQ)2(CH3OH)Cl (2), HOQ = 8-hydroxyquinoline, HBrQ = 5-bromo-8-hydroxyquinoline) of 8-hydroxylquinoline were synthesized and characterized. By MTT assay, the in vitro cytotoxicity of complexes 1 and 2, compared with HOQ, HBrQ and cisplatin, was evaluated towards a series of tumor cell lines as well as the normal liver cell line HL-7702. Complexes 1 and 2 showed higher cytotoxicity against the tested tumor cell lines than the corresponding ligands, among which T-24 was the most sensitive cell line for complexes 1 and 2 (IC50 = 13.42 μM for 1, 18.91 μM for 2). Compared with cisplatin, complex 1 exhibited higher cytotoxicity against T-24 cells but lower cytotoxicity against HL-7702(IC50 = 15.93 μM). Considering the better cytotoxicity of complex 1 than complex 2 against T-24 cells, the underlying anticancer molecular mechanisms were also investigated. DNA interaction studies revealed that complex 1 interacted with ct-DNA mainly via an intercalative binding mode. Further investigation of intracellular mechanisms revealed that complex 1 caused G2 phase cell cycle arrest and induced T-24 cell apoptosis in a dose-dependent mode. Targeting the mitochondrial pathway, the apoptotic mechanism in T-24 cells treated with 1 was studied by ROS detection, intracellular Ca2+ concentration measurements and caspase-9/3 activity assay, which suggested that complex 1 induced T-24 cell apoptosis by the disruption of mitochondrial-related mechanisms.

Synthesis and in vitro biological evaluation of three 4′-(4-methoxyphenyl)-2,2′:6′,2″-terpyridine iridium(III) complexes as new telomerase inhibitors

There iridium(III) complexes, [Ir(3-MeO-Phtpy)Cl3] (1), [Ir(2-MeO-Phtpy)Cl3] (2) and [Ir(4-MeO-Phtpy)Cl3] (3) with 4-(3-methoxyphenyl)-2,2:6,2″-terpyridine (3-MeO-Phtpy), 4-(2-methoxyphenyl)-2,2:6,2″-terpyridine (2-MeO-Phtpy) and 4-(4-methoxyphenyl)-2,2:6,2″-terpyridine (4-MeO-Phtpy) as ligands, respectively, were synthesized and evaluated for their antiproliferative activities. In these complexes, the iridium(III) center adopts a six-coordinate distorted octahedral geometry. Among them, complex 1 exhibited the most potent activity, with IC50 values of 3.19-27.77xa0μM against four cancer cell lines (BEL-7404, Hep-G2, NCI-H460 and MGC80-3xa0cells). Cellular mechanism studies suggested that complexes 1-3 directly targeted c-myc promoter elements and inhibited the telomerase activity. In addition, complexes 1-3 may trigger cell apoptosis via a mitochondrial dysfunction pathway. We postulated that the difference in the inxa0vitro antitumor activities of complexes 1-3 is mainly dependent on the position of the methoxy group on the phenyl ring of the iridium ligand.

Synthesis of two platinum(II) complexes with 2-methyl-8-quinolinol derivatives as ligands and study of their antitumor activities

Two platinum(II) complexes, [Pt(ClQ)(DMSO)Cl] (ClQ-Pt) and [Pt(BrQ)(DMSO)Cl] (BrQ-Pt), with 5,7-dichloro-2-methyl-8-quinolinol (H-ClQ) and 5,7-dibromo-2-methyl-8-quinolinol (H-BrQ) as ligands, respectively, have been synthesized and characterized. The single-crystal X-ray diffraction characterization as well as other spectroscopic and analytical studies of ClQ-Pt and BrQ-Pt revealed that the coordination geometry of Pt(II) can be described as a four-coordinated square planar geometry. By MTT assay, ClQ-Pt displayed the most potent activity, with IC50 values of 5.02-34.38u202fμM against MGC80-3, T-24, Hep-G2 and BEL-7402 tumor cells. Among them, the T-24u202fcells the highest sensitivity to ClQ-Pt and BrQ-Pt with IC50 value of 5.02u202f±u202f0.62u202fμM and 18.02u202f±u202f1.05u202fμM, respectively. In addition, ClQ-Pt caused a higher percentage of apoptotic T-24u202fcells (ca. 33.75%) than that of BrQ-Pt (ca. 23.85%) and cisplatin (ca. 12.82%). Mechanistic studies revealed that ClQ-Pt and BrQ-Pt caused T-24u202fcell cycle arrest at the S phase, as shown by the down-regulation of cyclin A and CDK2 expression levels. In addition, ClQ-Pt and BrQ-Pt also caused mitochondrial dysfunction. Interestingly, the inxa0vitro anticancer activity of ClQ-Pt was higher than those of BrQ-Pt and cisplatin, more selective for T-24 tumor cells than for normal HL-7702u202fcells. Taken together, we concluded that the 5- and 7-substitution groups of the ClQ ligands play an important role in determining the anti-proliferation activity of the corresponding Pt(II) complexes.

Tryptanthrin derivative copper(II) complexes with high antitumor activity by inhibiting telomerase activity, and inducing mitochondria-mediated apoptosis and S-phase arrest in BEL-7402

The copper(II) complexes of tryptanthrin (Try) and 8-bromo-tryptanthrin (BrTry), [CuII(Try)2Cl2] (Try-Cu) and [CuII(BrTry)2Cl2] (BrTry-Cu), were synthesized and fully characterized by spectroscopic methods and single-crystal X-ray diffraction analysis. The copper(II) centers in the Try-Cu and BrTry-Cu complexes adopted an approximately six-coordinated distorted octahedral geometry. The anticancer activities of Try-Cu and BrTry-Cu were evaluated in vitro against four human cancer cell lines (BEL-7402, T-24, MGC80-3, and HepG2 cells) and one normal human liver cell line (HL-7702 cells). It was found that Try-Cu exhibited selective cytotoxicity against the four selected cancer cells (IC50 = 4.02–9.03 μM) but low cytotoxicity toward the normal human liver HL-7702 cells. Further studies revealed that Try-Cu exhibited its cytotoxic activity mainly by inducing DNA damage and thus causing cell cycle arrest in the S phase, as well as stimulating mitochondrial dysfunction and inhibiting telomerase by interacting with the c-myc promoter.