In recent years, energy metabolism in cancer has received increasing attention as an important component of tumor biology, and the functions of transcription factors, mitochondria, reactive oxygen species (ROS) and the autophagy-lysosome system in which have been elucidated. G-quadruplex (G4) is a molecular switch that regulates gene transcription or translation. As an anticancer target, the effect of G4 on cancer cell proliferation, apoptosis, cycle and autophagy has been recognized. The energy metabolism system is a unified whole composed of transcription factors, metabolic regulators, metabolites and signaling pathways that run through the entire cancer process. However, the role of G4 in this complex metabolic network has not been systematically elucidated. In this review, we analyze the close correlation between G4 and transcription factors, mitochondria, ROS and the autophagy-lysosome system and suggest that G4 can exert a marked effect on cancer energy metabolism by regulating the above mentioned key regulatory elements. The anticancer effects of some G4 ligands through regulation of energy metabolism have also been summarized, confirming the clear involvement of G4 in energy metabolism. Although much more research is needed, we propose that G4 may play a critical role in the complex energy metabolism system of cancer, which is a promising target for anticancer strategies focusing on energy metabolism.

In this contribution, a terpyridine-based ligand bearing a thioether functionality is used to prepare a new cobalt(II) spin crossover complex: [Co(TerpyPhSMe)2](PF6)2 (1), where TerpyPhSMe is 4'-(4-methylthiophenyl)-2,2':6',2''-terpyridine. Its structure, determined by single crystal X-ray diffraction, reveals a mer coordination of the tridentate terpyridine ligands, leading to a tetragonally compressed octahedron. Intermolecular interactions in the crystal lattice freeze the complex in the high spin state in the solid state at all temperatures, as indicated by magnetometry and Electron Paramagnetic Resonance (EPR) spectra. When dissolved in acetonitrile, however, temperature dependent electronic, 1H-NMR and EPR spectra highlight an entropy-driven spin crossover transition, whose thermodynamics parameters have been determined. This is the first report of a cobalt(II) SCO complex featuring a thioether group, allowing its implementation in chemically grown bistable monolayers and may open important perspectives for the use of such systems in molecular spintronics.

With the aim of developing potential anticancer drug candidates, a series of Fe(II) complexes were synthesized using nine 2,2':6',2''-terpyridine ligands functionalized with substituted-phenyl groups, and their biological activities were systematically investigated. Their bis-terpyridine sandwich-like structures were determined by single crystal X-ray crystallography. In vitro antiproliferative experiments based on three human cancer cell lines, including human hepatoma cancer cell line (Bel-7402), human esophageal cancer cell line (Eca-109), and human cervical squamous cancer cell line (SiHa), indicate the high antiproliferation activities of these complexes compared with commercial cisplatin. And their toxicity to normal cells was estimated based on human normal hepatocyte (HL-7702) cell line. In particular, when the phenyl in terpyridine ligand was modified by a carboxyl group, the corresponding complex 3 exhibited much higher antiproliferation to cancer Bel-7402 cells (IC50 = 3.653 μmol L-1) than cisplatin and low toxicity to normal HL-7702 cells (IC50 = 99.92 μmol L-1), implying a significant selectivity for 3 in killing hepatoma cancer cells. Combined with the fact that iron element is more accessible than platin, this series of Fe(II) complexes comprises potential candidates for anticancer drugs with specific inhibition of hepatoma cancer. UV titration experiments and circular dichroism (CD) showed a strong binding affinity between these nine complexes and CT-DNA. However, molecular docking simulation revealed the competitive binding of DNA and protein to these complexes. Further, the interactions between these complexes and bovine serum albumin (BSA) have been studied by fluorescence titration and CD spectroscopy.

A series of Ni(II) sandwich-like coordinated compounds were synthesized by the reaction of nickel dichloride and ten 4'-(4-substituent phenyl)-2',2':6',2″-terpyridine ligands, and their structures were confirmed by elemental analysis, FT-IR, ESI-MS, solid state ultraviolet spectroscopy and X-ray single crystal diffraction analysis. Three human cancer cell lines and a normal human cell line were used for anti-proliferation potential study: human lung cancer cell line (A549), human esophageal cancer cell line (Eca-109), human liver cancer cells (Bel-7402) and normal human liver cells (HL-7702). The results show that these nickel complexes possess good inhibitory effects on the cancer cells, outperforming the commonly used clinical chemotherapy drug cisplatin. Especially, complexes 3 (-methoxyl) and 7 (-fluoro) have strong inhibitory ability against Eca-109 cell line with IC50 values of 0.223 μM and 0.335 μM, complexes 4 and 6 showed certain cell selectivity, and complex 6 can inhibit cancer cells and slightly poison normal cells when the concentration was controlled. The ability of these complexes binding to CT-DNA was studied by UV titration and CD spectroscopy, and CD spectroscopy was also used to study the secondary structural change of BSA under the action of the complexes. The binding of these complexes with DNA, DNA-Topo I and bovine serum protein has been simulated by molecular docking software, and the docking results and optimal binding conformation data showed that they interacted with DNA in the mode of embedded binding, which is consistent with the experimental results. These complexes are more inclined to move to the cleavage site when docking with DNA-Topo I, so as to play a role of enzyme cleavage, while BSA promotes the action of the complexes by binding to effective binding sites.

Genomic instability and inflammation are considered to be two enabling characteristics that support cancer development and progression. G-quadruplex structure is a key element that contributes to genomic instability and inflammation. G-quadruplexes were once regarded as simply an obstacle that can block the transcription of oncogenes. A ligand targeting G-quadruplexes was found to have anticancer activity, making G-quadruplexes potential anticancer targets. However, further investigation has revealed that G-quadruplexes are widely distributed throughout the human genome and have many functions, such as regulating DNA replication, DNA repair, transcription, translation, epigenetics, and inflammatory response. G-quadruplexes play double regulatory roles in transcription and translation. In this review, we focus on G-quadruplexes as novel targets for the treatment of gastrointestinal cancers. We summarize the application basis of G-quadruplexes in gastrointestinal cancers, including their distribution sites, structural characteristics, and physiological functions. We describe the current status of applications for the treatment of esophageal cancer, pancreatic cancer, hepatocellular carcinoma, gastric cancer, colorectal cancer, and gastrointestinal stromal tumors, as well as the associated challenges. Finally, we review the prospective clinical applications of G-quadruplex targets, providing references for targeted treatment strategies in gastrointestinal cancers.

Ten new palladium(II) complexes [PdCl(L^1-10)]Cl have been synthesized by the reaction of palladium(II) chloride and ten 4'-(substituted-phenyl)-2,2':6',2''-terpyridine ligands bearing hydrogen(L¹), p-hydroxyl(L²), m-hydroxyl (L³), o-hydroxyl (L⁴), methyl (L⁵), phenyl (L⁶), fluoro (L⁷), chloro (L⁸), bromo (L⁹), or iodo (L¹⁰). Their structures were confirmed by FT-IR, ¹H NMR, elemental analysis and/or single crystal X-ray diffraction analysis. Their in vitro anticancer activities were investigated based on five cell lines, including four cancer cell lines (A549, Eca-109, Bel-7402, MCF-7) and one normal cell line (HL-7702). The results show that these complexes possess a strong killing effect on the cancer cells but a weak proliferative inhibition on the normal cells, implying their high inhibitory selectivity for the proliferation of the cancer cell lines. Flow cytometry characterization reveals that these complexes affect cell proliferation mainly in the G0/G1 phase and induce the late apoptotic of the cells. The quantity of palladium(II) ion in extracted DNA was determined by ICP-MS, which proved that these complexes target genomic DNA. And the strong affinity of the complexes with CT-DNA were confirmed by UV-Vis spectrum and circular dichroism (CD). The possible binding modes of the complexes with DNA were further explored by molecular docking. As the concentration of complexes 1-10 gradually increases, the fluorescence intensity of bovine serum albumin (BSA) decreases by a static quenching mechanism.

Eleven manganese 4'-substituted-2,2':6',2″-terpyridine complexes (1a-1c and 2a-2h) with three non-oxygen-containing substituents (L^1a-L^1c: phenyl, naphthalen-2-yl and naphthalen-1-yl, L^1a-L^1c) and eight oxygen-containing substituents (L^2a-L^2h: 4-hydroxyl-phenyl, 3-hydroxyl-phenyl, 2-hydroxyl-phenyl, 4-methoxyl-phenyl, 4-carboxyl-phenyl, 4-(methylsulfonyl)phenyl, 4-nitrophenyl and furan-2-yl) were prepared and characterized by IR, elemental analysis or single crystal X-ray diffraction. In vitro data demonstrate that all of these show higher antiproliferative activities than cisplatin against five human carcinoma cell lines: A549, Bel-7402, Eca-109, HeLa and MCF-7. Compound 2d presents the strongest antiproliferative effect against A549 and HeLa cells, with IC₅₀ values being 0.281 μM and 0.356 μM, respectively. The lowest IC₅₀ values against Bel-7402 (0.523 μM) Eca-109 (0.514 μM) and MCF-7 (0.356 μM) were obtained for compounds 2h, 2g and 2c, respectively. Compound 2g with a nitro group showed the best results on the whole, with relevantly low IC₅₀ values against all the tested tumor cells. The DNA interactions with these compounds were studied by circular dichroism spectroscopic and molecular modeling methods. Spectrophotometric results revealed that the compounds have strong affinities in binding with DNA as intercalators, and the binding induces DNA conformational transition. Molecular docking studies indicate that the binding is contributed by the π-π stacking and hydrogen bonds. The anticancer activities of the compounds are correlated with their DNA binding ability, and the modification of oxygen-containing substituents significantly enhanced the anticancer activity, which could provide a new rationale for the future design of terpyridine-based metal complexes with antitumor potential.

Metal terpyridine complexes have gained substantial interest in many application fields, such as catalysis and supramolecular chemistry. In recent years, the biological activity of terpyridine and its metal complexes has aroused considerable regard. On this basis, we synthesised new terpyridine derivatives of trehalose and glucose to improve the water solubility of terpyridine ligands and target them in cancer cells through glucose transporters. Glucose derivative and its copper(II) and iron(II) complexes showed antiproliferative activity. Interestingly, trehalose residue reduced the cytotoxicity of terpyridine. Moreover, we tested the ability of parent terpyridine ligands and their copper complexes to inhibit proteasome activity as an antineoplastic mechanism.

Based on the previous research, we found that the magnetic nanocomposite Fe₃O₄/rGO (reduced graphene oxide) has a good drug loading effect. Therefore, in this paper, we studied the positive role of Fe₃O₄/rGO as a drug carrier in the interaction between resveratrol (RES) and calf-thymus DNA (ct-DNA). The fluorescence experiment is used to evaluate by the Stern-Volmer equation, the quenching constant of RES - ct-DNA system with and without Fe₃O₄/rGO decreases with the increasing temperature. It was found the quenching mode of RES - ct-DNA and Fe₃O₄/rGO - RES - ct-DNA systems were all static quenching, but the binding constant of RES -ct-DNA increased from 4.14 ± 0.21 × 10⁴ L mol^-1 to 10.12 ± 0.02 × 10⁴ L mol^-1. It was found that Fe₃O₄/rGO formed a ternary complex with RES and ct-DNA by ultraviolet spectrum (UV-vis), resonance light scattering experiments (RLS) and scanning electron microscope (SEM). Meanwhile, Fourier transform infrared (FT-IR) and circular dichroism (CD) experiments show that Fe₃O₄/rGO and Fe₃O₄/rGO loaded with RES have effect on the secondary structure of ct-DNA and change the conformation of ct-DNA. On the cellular level, the comet assay shows that Fe₃O₄/rGO and Fe₃O₄/rGO - RES could not cause DNA strand break to the mouse hepatocytes after 24 co-incubation. These results confirm that Fe₃O₄/rGO nanocomposites have good application potential, which can be used as a good drug carrier in a wide range of therapeutic methods.

Based on the ability of terpyridines to react with G-quadruplex DNA (G4) structures along with the interest aroused by Zn as an essential metal centre in many biological processes, we have synthesized and characterized six Zn chloride or nitrate complexes containing terpyridine ligands with different 4'-substituents. In addition, we have studied their interaction with G4 and their cytotoxicity. Our experimental results revealed that the leaving group exerts a strong influence on the cytotoxicity, since the complexes bearing chloride were more cytotoxic than their nitrate analogues and an effect of the terpyridine ligand was also observed. The thermal stabilization profiles showed that the greatest stabilization of hybrid G4, Tel22, was observed for the Zn complexes bearing the terpyridine ligand that contained one or two methylated 4-(imidazol-1-yl)phenyl substituents, 3Cl and 3(L)2, respectively, probably due to their extra positive charge. Stability and aquation studies for these complexes were carried out and no ligand release was detected. Complexes 3Cl and 3(L)2 were successfully internalized by SW480 cells and they seemed to be localized mainly in the nucleolus. The highest cytotoxicity, G4 selectivity and G4 affinity determined by fluorescence and ITC experiments, and subcellular localization quantified by ICP-MS measurements, rendered 3Cl a very interesting complex from a biological standpoint.