Alkaloids from Zanthoxylum nitidum and their anti-proliferative activity against A549 cells by regulating the EGFR/AKT/mTOR pathway.

Zanthoxylum nitidum is frequently used as a traditional Chinese medicine and food supplement. Our previous study revealed that its constituent compounds were able to inhibit cancer cell proliferation. In our continuous exploration of bioactive compounds in Z. nitidum, we isolated ten alkaloids (1-10), including one new natural compound (1), and nine known alkaloids (2-10), from an ethanolic extract of the whole plant. The chemical structures were elucidated based on a combination of comprehensive NMR and HRESIMS analyses. Compounds 5, 8 and 10 exhibited significant antiproliferative effects against A549 cancer cell lines. We further elucidated the underlying molecular mechanisms of the antiproliferative activity of compound 8 in A549 human lung cancer cells. Compound 8 was found to induce cell cycle arrest in the G0/G1 phase via p53 activation and CDK4/6 suppression. Compound 8 also effectively inhibited cell migration through the modulation of the epithelial-mesenchymal transition (EMT), as indicated by the expression of biomarkers, such as N-cadherin downregulation and E-cadherin upregulation. Compound 8 significantly suppressed the activation of the EGFR/AKT/mTOR signalling pathway in A549 cells. These results indicate that alkaloid 8 from Z. nitidum has potential to be a lead antiproliferative compound in cancer cells.

In vitro and in vivo anticancer activity of novel Rh(III) and Pd(II) complexes with pyrazolopyrimidine derivatives.

Six pyrazolopyrimidine rhodium(III) or palladium(II) complexes, [Rh(L1)(H2O)Cl3] (1), [Rh(L2)(CH3OH)Cl3] (2), [Rh(L3)(H2O)Cl3] (3), [Rh2(L4)Cl6]·CH3OH (4), [Rh(L5)(CH3CN)Cl3]·0.5CH3CN (5), and [Pd(L5)Cl2] (6), were synthesized and characterized. These complexes showed high cytotoxicity against six tested cancer cell lines. Most of the complexes showed higher cytotoxicity to T-24 cells in vitro than cisplatin. Mechanism studies indicated that complexes 5 and 6 induced G2/M phase cell cycle arrest through DNA damage, and induced apoptosis via endoplasmic reticulum stress response. In addition, complex 5 also induced cell apoptosis via mitochondrial dysfunction. Complexes 5 and 6 showed low in vivo toxicity and high tumor growth inhibitory activity in mouse tumor models. The inhibitory effect of rhodium complex 5 on tumor growth in vivo was more pronounced than that of palladium complex 6.

Rhodium(III)-Picolinamide Complexes Act as Anticancer and Antimetastasis Agents via Inducing Apoptosis and Autophagy.

As a continuation of our endeavors in discovering metal-based drugs with cytotoxic and antimetastatic activities, herein, we reported the syntheses of 11 new rhodium(III)-picolinamide complexes and the exploration of their potential anticancer activities. These Rh(III) complexes showed high antiproliferative activity against the tested cancer cell lines in vitro. The mechanism study indicated that Rh1 ([Rh(3a)(CH3CN)Cl2]) and Rh2 ([Rh(3b)(CH3CN)Cl2]) inhibited cell proliferation by multiple modes of action via cell cycle arrest, apoptosis, and autophagy and inhibited cell metastasis via FAK-regulated integrin ß1-mediated suppression of EGFR expression. Furthermore, Rh1 and Rh2 significantly inhibited bladder cancer growth and breast cancer metastasis in a xenograft model. These rhodium(III) complexes could be developed as potential anticancer agents with antitumor growth and antimetastasis activity.

In vitro and in vivo antitumor activities of Ru and Cu complexes with terpyridine derivatives as ligands.

Six terpyridine ligands(L1-L6) with chlorophenol or bromophenol moiety were obtained to prepare metal terpyridine derivatives complexes: [Ru(L1)(DMSO)Cl2] (1), [Ru(L2)(DMSO)Cl2] (2), [Ru(L3)(DMSO)Cl2] (3), [Cu(L4)Br2]·DMSO (4), Cu(L5)Br2 (5), and [Cu(L6)Br2]⋅CH3OH (6). The complexes were fully characterized. Ru complexes 1-3 showed low cytotoxicity against the tested cell lines. Cu complexes 4-6 exhibited higher cytotoxicity against several tested cancer cell lines compared to their ligands and cisplatin, and lower toxicity towards normal human cells. Copper(II) complexes 4-6 arrested T-24 cell cycle in G1 phase. The mechanism studies indicated that complexes 4-6 accumulated in mitochondria of T-24 cells and caused significant reduction of the mitochondrial membrane potential, increase of the intracellular ROS levels and the release of Ca2+, and the activation of the Caspase cascade, finally inducing apoptosis. Animal studies showed that complex 6 obviously inhibited the tumor growth in a mouse xenograft model bearing T-24 tumor cells without significant toxicity.

Copper(II) complex enhanced chemodynamic therapy through GSH depletion and autophagy flow blockade.

Three copper(II) complexes C1-C3 were synthesized and fully characterized as chemodynamic therapy (CDT) anticancer agents. C1-C3 showed greater cytotoxicity than their ligands toward SK-OV-3 and T24 cells. Particularly, C2 showed high cytotoxicity toward T24 cells and low cytotoxicity toward normal human HL-7702 and WI-38 cells. Mechanistic studies demonstrated that C2 oxidized GSH to GSSG and produced ˙OH, which induced mitochondrial dysfunction and ER stress, finally leading to apoptosis of T24 cells. In addition, C2 inhibited autophagy by blocking autophagy flow, thereby closing the self-protection pathway of oxidative stress to enhance CDT. Importantly, C2 significantly inhibited T24 tumor growth with 57.1% inhibition in a mouse xenograft model. C2 is a promising lead as a potential CDT anticancer agent.

Arene-Ruthenium(II)/Osmium(II) Complexes Potentiate the Anticancer Efficacy of Metformin via Glucose Metabolism Reprogramming.

Targeting metabolic reprogramming to treat cancer could increase overall survival and reduce side effects. Here, we put forward a strategy using arene-ruthenium(II)/osmium(II) complexes to potentiate the anticancer effect of metformin (Met.) via glucose metabolism reprogramming. Complexes 1-6 with oxoglaucine derivatives as ligands were synthesized and their anti-tumor activities were tested under hypoglycemia. Results indicated that 2 and 5 potentiated the anticancer effects of Met. under hypoglycemia, exhibiting lower toxicity, slower blood glucose decline and inhibition of early tumor liver metastasis. Combination of 5 with Met. could be used as a new strategy to treat cancer under hypoglycemia through glucose metabolism reprogramming.

Terpyridine copper(II) complexes as potential anticancer agents by inhibiting cell proliferation, blocking the cell cycle and inducing apoptosis in BEL-7402 cells.

Four mononuclear terpyridine complexes [Cu(H-La)Cl2]·CH3OH (1), [Cu(H-La)Cl]ClO4 (2), [Cu(H-Lb)Cl2]·CH3OH (3), and [Cu(H-Lb)(CH3OH)(DMSO)](ClO4)2 (4) were prepared and fully characterized. Complexes 1-4 exhibited higher cytotoxic activity against several tested cancer cell lines especially BEL-7402 cells compared to cisplatin, and they showed low toxicity towards normal human liver cells. ICP-MS detection indicated that the copper complexes were accumulated in mitochondria. Mechanistic studies demonstrated that the copper complexes induced G0/G1 arrest and altered the expression of the related proteins of the cell cycle. All copper complexes reduced the mitochondrial membrane potential while increasing the intracellular ROS levels and the release of Ca2+. They also up-regulated Bax and down-regulated Bcl-2 expression levels, caused cytochrome c release and the activation of the caspase cascade, and induced mitochondrion-mediated apoptosis. Animal studies demonstrated that complex 1 suppressed tumor growth in a mouse xenograft model bearing BEL-7402 tumor cells.

Ru(III) complexes with pyrazolopyrimidines as anticancer agents: bioactivities and the underlying mechanisms.

Three ruthenium(III) complexes with pyrazolopyrimidine [Ru(Ln)(H2O)Cl3] (1-3, n = 1-3) were prepared and characterized. These Ru(III) compounds show strong cytotoxicity against six cancer cell lines and low toxicity to normal human liver cells. Particularly, they exhibited stronger cytotoxicity to SK-OV-3 cells than cisplatin. Mechanism studies revealed that complex 1 inhibited tumor cell invasion and suppressed cell proliferation, induced apoptosis by elevating the levels of intracellular ROS (reactive oxygen species) and free calcium (Ca2+), and reduced mitochondrial membrane potential (ΔΨ). It also activated the caspase cascade, accompanied with upregulation of cytochrome c, Bax, p53, Apaf-1 and downregulation of Bcl-2. Moreover, complex 1 caused cell cycle arrest at S phase by inhibiting the expression of CDC 25, cyclin A2 and CDK 2 proteins, and induced DNA damage by interacting with DNA and inhibiting the topoisomerase I enzyme. Complex 1 exhibited efficient in vivo anticancer activity in a model of SK-OV-3 tumor xenograft.

A pyrazolopyrimidine based fluorescent probe for the detection of Cu2+ and Ni2+ and its application in living cells.

A fluorescent sensor L based on a pyrazolopyrimidine core simultaneously detects Cu2+ and Ni2+ ions by photoluminescence quenching, even in the presence of other metal cations. Sensor L possesses high association constants of 5.24 × 103 M-1 and 2.85 × 104 M-1 and low detection limits of 0.043 µM and 0.038 µM for Cu2+ and Ni2+, respectively. The binding stoichiometry ratios of L to Cu2+ or Ni2+ is 1:1 as determined by Benesi-Hildebrand and Job's plots, and by crystal structures. DFT calculations on L-Cu2+ indicated reduced electron donation from the coordinated pyrazolopyridine to the fused pyrimidine and pendant phenyl group which, together with a smaller HOMO-LUMO orbital gap could favour non-radiative decay and explain the observed fluorescence quenching. Sensor L possessed low cytotoxicity and good imaging characteristics for Cu2+ and Ni2+ in living cells, suggesting potential applications for detecting Cu2+ and Ni2+in vivo.

Dual-response detection of Ni2+ and Cu2+ ions by a pyrazolopyrimidine-based fluorescent sensor and the application of this sensor in bioimaging.

Herein, a dual-response fluorescent sensor, L, based on pyrazolopyrimidine was designed and developed for the simultaneous detection of Ni2+ and Cu2+ ions in the presence of other metal ions; the structural characterization of L was carried out by FTIR spectroscopy, NMR spectroscopy, HRMS and X-ray diffraction analysis. The sensor L effectively displayed fluorescence quenching towards the Ni2+ and Cu2+ ions with high sensitivity without interference from other metal ions. The results reveal that L binds to Ni2+ and Cu2+ in a 2 : 1 pattern, which matches well with the result of the Job's plot. The association constants of L with Ni2+ and Cu2+ were 3.2 × 104 M-1 and 7.57 × 104 M-1, respectively. The detection limits (DLs) are down to 8.9 nM for Ni2+ and 8.7 nM for Cu2+. The fluorescence imaging of L in T-24 cells was investigated because of the low cytotoxicity of L, indicating that L could be used to detect Ni2+ and Cu2+ in living cells.

Platinum(ii) complexes with rutaecarpine and tryptanthrin derivatives induce apoptosis by inhibiting telomerase activity and disrupting mitochondrial function.

Four new platinum(ii) complexes, [Pt(Rut)(DMSO)Cl2] (Rut-Pt), [Pt(Try)(DMSO)Cl2] (Try-Pt), [Pt(ITry)(DMSO)Cl2] (ITry-Pt) and [Pt(BrTry)(DMSO)Cl2] (BrTry-Pt), with rutaecarpine (Rut), tryptanthrin (Try), 8-iodine-tryptanthrin (ITry) and 8-bromo-tryptanthrin (BrTry) as ligands were synthesized and fully characterized. In these complexes, the platinum(ii) adopts a four-coordinated square planar geometry. The inhibitory activity evaluated by the MTT assay showed that BrTry-Pt (IC50 = of 0.21 ± 0.25 µM) could inhibit the growth of T-24 tumor cells (human bladder cancer cell line) more so than the other three complexes. In addition, all of these Pt complexes exhibited low toxicity against non-cancerous HL-7702 cells. BrTry-Pt induced cell cycle arrest in the S phase, leading to the down-regulation of cyclin A and CDK2 proteins. BrTry-Pt acts as a telomerase inhibitor targeting the c-myc promoter. In addition, BrTry-Pt also caused mitochondrial dysfunction. Importantly, the in vitro anticancer activity of BrTry-Pt was higher than those of Rut-Pt, Try-Pt and ITry-Pt, and it was more selective for T-24 cells than for non-cancerous HL-7702 cells.

Novel FeII and CoII Complexes of Natural Product Tryptanthrin: Synthesis and Binding with G-Quadruplex DNA.

Tryptanthrin is one of the most important members of indoloquinoline alkaloids. We obtained this alkaloid from Isatis. Two novel FeII and CoII complexes of tryptanthrin were first synthesized. Single-crystal X-ray diffraction analyses show that these complexes display distorted four-coordinated tetrahedron geometry via two heterocyclic nitrogen and oxygen atoms from tryptanthrin ligand. Binding with G-quadruplex DNA properties revealed that both complexes were found to exhibit significant interaction with G-quadruplex DNA. This study may potentially serve as the basis of future rational design of metal-based drugs from natural products that target the G-quadruplex DNA.

The antitumor activity of zinc(II) and copper(II) complexes with 5,7-dihalo-substituted-8-quinolinoline.

[Zn2(ClQ)4(CH3OH)2] (1), [Zn(BrQ)2(H2O)2] (2), [Zn2(ClIQ)4] (3) and [Cu(BrQ)2] (4) (H-ClQ = 5,7-dichloro-8-hydroxylquinoline, H-BrQ = 5,7-dibromo-8-hydroxylquinoline, and H-ClIQ = 5-chloro-7-iodo-8-hydroxylquinoline) were synthesized. Compounds 1-4 showed high anti-proliferative cytotoxicities against BEL-7404, SK-OV-3, NCI-H460 tumor cells, and HL-7702 normal cells in vitro, with IC50 values in the 1.4 nM to 32.13 µM range. Compounds 2-4 exhibited significantly enhanced cytotoxicity against BEL-7404 cell line, comparing with free 5,7-dihalo-8-quinolinol. Western blotting analysis showed that 2, 3 depleted mutant p53 protein in MDA-MB-231, and compound 2 decreased the ratio of Bcl-2/Bax in NCI-H460 significantly. The binding abilities of 1-4 to DNA were stronger than that of free quinolinol ligand. Intercalation is the probable binding mode for the complexes and free quinolinol ligands with DNA.

High antitumor activity of 5,7-dihalo-8-quinolinolato cerium complexes.

Three cerium complexes: [Ce(ClQ)4] (1) (H-ClQ=5,7-dichloro-8-hydroxylquinoline), [Ce(ClIQ)4]·CH2Cl2·0.5H2O (2) (H-ClIQ=5-chloro-7-iodo-8-hydroxylquinoline) and [Ce2(BrQ)4(H-BrQ)(H2O)3Cl2]·1.5H2O (3) (H-BrQ=5,7-dibromo-8-hydroxylquinoline) were synthesized. The structures of 1 and 2 are mononuclear whereas 3 has a binuclear structure. Compared with the H-ClQ, H-ClIQ and H-BrQ, complexes 1-3 exhibited significantly higher cytotoxicity (IC50=0.09-5.23 µM) to SK-OV-3 and BEL-7404, 1 and 2 exhibited higher cytotoxicity to NCI-H460. Most the complexes and ligands exhibited higher cytotoxicity than cisplatin. Complexes 1-3 are much more sensitive to SK-OV-3 than to human normal liver cell HL-7702. Their antitumor activities were achieved through cell apoptosis and arrest at G0/G1-phase. Studies on the binding properties of 1-3 to DNA indicate that intercalation is the most probable binding mode.

High antitumor activity of 5,7-dihalo-8-quinolinolato tin(IV) complexes.

Three tin(IV) complexes [Sn(ClQ)2Cl2] (1), [Sn(BrQ)2Cl2] (2) and [Sn(ClIQ)2Cl2] (3) were prepared (H-ClQ = 5,7-dichloro-8-hydroxylquinoline, H-BrQ = 5,7-dibromo-8-hydroxylquinoline, H-ClIQ = 5-chloro-7-iodo-8-hydroxylquinoline) and their in vitro cytotoxicities against BEL7404, SKOV-3, NCI-H460, HL-7702 cell lines were evaluated. The complexes showed high anti-proliferative activity toward the tested cell lines with IC50 values ranging from 20 nM to 5.11 µM. Compared with 5,7-dihalo-8-quinolinol, most complexes exhibited significantly enhanced cytotoxicity (except 2 against SKOV-3 and NCI-H460). They also displayed some selective cytotoxicity favoring the tested tumor cells over the normal human liver HL-7702 cells. Compared with their quinolinol ligands, complexes 1-3 bind more strongly with DNA. Intercalation is the most probable binding mode for both the complexes and their quinolinol ligands.

Synthesis, crystal structure, cytotoxicity and DNA interaction of 5,7-dichloro-8-quinolinolato-lanthanides.

Four isostructural lanthanide complexes with 5,7-dichloro-8-quinolinoline (H-ClQ): [Sm(ClQ)(3)(H(2)O)(2)]·1.33EtOH·0.33H(2)O (1), [Eu(ClQ)(3)(H(2)O)(2)]·0.5EtOH, (2), [Tb(ClQ)(3)(H(2)O)(2)]·0.5EtOH (3) and [Ho(ClQ)(3)(H(2)O)(2)]·H(2)O (4) were synthesized, in which the lanthanide was coordinated by three ClQ(-) anions and two aqua ligands. The in vitro cytotoxicities of complexes 1-4 against five human tumor cells were evaluated. The IC(50) values of complexes 1-4 against BEL7404, HeLa and A549 were in the range 1.2-6.3, 3.5-6.6 and 10.8-25.2 µM, respectively; except for complex 3 toward BEL7404, they all exhibited enhanced cytotoxicity in comparison to H-ClQ. The binding properties of complexes 1-4 to DNA examined by various methods indicated that complexes 1-4 interacted with DNA more strongly than free quinolinoline, and intercalation was the most probable binding mode for both the complexes and quinolinoline.

Bis[4-amino-N-(pyrimidin-2-yl)benzene-sulfonamidato](2,2'-bipyridine)manganese(II).

The title compound, [Mn(C(10)H(9)N(4)O(2)S)(2)(C(10)H(8)N(2))], contains a distorted octa-hedral [Mn(sdz)(2)(bpy)] (sdz is the sulfadiazine anion and bpy is 2,2'-bipyridine) complex mol-ecule. A three-dimensional network is generated by N-H⋯N, N-H⋯O and C-H⋯O hydrogen bonds from the sulfadiazine ligands.