Platinum (Pt)-based anticancer drugs such as cisplatin have been used to treat various cancers. However, they have some limitations including poor selectivity and toxicity towards normal cells and increasing chemoresistance. Therefore, there is a need for novel metallo-anticancers, which has not been met for decades. Since the initial introduction of ruthenium (Ru) polypyridyl complex, a number of attempts at structural evolution have been conducted to improve efficacy. Among them, half-sandwich Ru-arene complexes have been the most prominent as an anticancer platform. Such complexes have clearly shown superior anticancer profiles such as increased selectivity toward cancer cells and ameliorating toxicity against normal cells compared to existing Pt-based anticancers. Currently, several Ru complexes are under human clinical trials. For improvement in selectivity and toxicity associated with chemotherapy, Ru complexes as photodynamic therapy (PDT), and photoactivated chemotherapy (PACT), which can selectively activate prodrug moieties in a specific region, have also been investigated. With all these studies on these interesting entities, new metallo-anticancer drugs to at least partially replace existing Pt-based anticancers are anticipated. This review covers a brief description of Ru-based anticancer complexes and perspectives.

/pdf/ruthenium-complexes-as-anticancer-agents-a-brief-history-and-14ksxw06l5.pdf

Ruthenium Complexes as Anticancer Agents: A Brief History and Perspectives.

Although cisplatin and its analogues have been widely utilized as anticancer metallodrugs in clinics, their serious side effects and damage to normal tissues cannot be avoided because cisplatin kills cancer cells by attacking genomic DNA. Thus the design of metallodrugs possessing different actions of anti-cancer mechanism is promising. G-quadruplex nucleic acid, which is formed by self-assembly of guanine-rich nucleic acid sequences, has recently been considered as an attractive target for anticancer drug design. The basic unit of a G-quadruplex is a G-quartet, a planar motif generated from four guanine residues pairing together through Hoogsteen like hydrogen bonds. DNA G-quadruplex (G4) structures exist in the chromosomal telomeric sequences and the promoter regions of numerous genes, including oncogenetic promoters. Formation of G4 structures within the 3′-overhang of telomeric DNA can inhibit the telomerase activity, which is silent in normal cells but up-regulated in most cancer cells, thus significantly shortening telomeres and preventing cancer cell proliferation and immortalization. Intramolecular G4 structures formed within the oncogene promoter regions can effectively inhibit oncogenen transcription and expression. Thus rational design of small molecular ligands to selectively interact, stabilize or cleave G4 structures is a promising strategy for developing potent anti-cancer drugs with selective toxicity towards cancer cells over normal ones. This review will highlight the recent development of G4-interacting metal complexes, termed G4-ligands, discussing their binding modes with G-quadruplex DNA and their potential to serve as anticancer drugs in the medical field.
 Introduction to the international collaboration
 The collaboration between Prof. Zong-Wan Mao from Sun Yat-Sen University, P. R. China and Prof. Roland K. O. Sigel from the University of Zurich, Switzerland officially began in January, 2014. The international collaborative research project titled “Chemical Biology Research of New Metallodrugs for Cancer Therapy” is supported by the Science and Technology Program of Guangdong Provincial Government [20130501c]. With the rapid development of tumor molecular pharmacology, molecular targeted anti-tumor drugs have become a hot spot in the research of cancer therapy. This international collaborative research project combines the computer simulation and in vitro drug screening platform to design a series of metallodrugs that are systematic and have structural diversity, which can target specific nucleic acid structures (e.g. G-quadruplexes), key proteins (DNA topoisomerase, telomerase, CDK kinase) associated with the occurrence and development of tumor. With the advantages of both laboratories, the structural–functional relationship, interaction modes, co-crystallization, and mechanisms of action of these newly designed metallodrugs are intensively studied, and their in vitro and in vivo anti-tumor activities are comprehensively evaluated.

/pdf/g-quadruplex-dna-targeted-metal-complexes-acting-as-4o0om9rh43.pdf

G-quadruplex DNA targeted metal complexes acting as potential anticancer drugs

Three water-soluble ruthenium(II) complexes with chiral 4-(2,3-dihydroxypropyl)-formamide oxoaporphine (FOA) were synthesized and characterized. It was found that these ruthenium(II) complexes exhibited considerable in vitro anticancer activities and that they were the effective stabilizers of telomeric and G-quadruplex-DNA (G4-DNA) in promoter of c-myc, which acted as a telomerase inhibitor targeting G4-DNA and induced cell senescence and apoptosis. Interestingly, the in vitro anticancer activity of 6 (LC-003) was higher than those of 4 (LC-001) and 5 (LC-002), more selective for BEL-7404 cells than for normal HL-7702 cells, and preferred to activate caspases-3/9. The different biological behaviors of the ruthenium complexes could be correlated with the chiral nature of 4-(2,3-dihydroxypropyl)-formamide oxoaporphine. More significantly, 6 exhibited effective inhibitory on tumor growth in BEL-7402 xenograft mouse model and higher in vivo safety than cisplatin. These mechanistic insights indicate that 6 di...

Water-Soluble Ruthenium(II) Complexes with Chiral 4-(2,3-Dihydroxypropyl)-formamide Oxoaporphine (FOA): In Vitro and in Vivo Anticancer Activity by Stabilization of G-Quadruplex DNA, Inhibition of Telomerase Activity, and Induction of Tumor Cell Apoptosis

Electrooxidation of 5‐hydroxymethylfurfural (HMF) into 2,5‐furandicarboxylic acid (FDCA) is a highly promising approach for producing value‐added chemicals from biomass. However, developing highly efficient electrocatalysts for HMF oxidation (HMFOR) with high current density in large‐scale productions remains a challenge. Herein, it is demonstrated that the Mn‐doped NiS nanosheet electrocatalysts grown directly on 3D graphite felt (GF) substrates can efficiently perform electrooxidation of HMF into FDCA at industrial‐level current density (500 mA cm−2) in the H‐cell. The Mn0.2NiS/GF exhibits excellent HMFOR performance with high selectivity (98.3%), yield (97.6%), faradaic efficiency (94.2%), and robust stability (10 cycles). Especially, FDCA production rate up to 4.56 g h−1 can be achieved, superior to those reported in HMFOR literatures. Furthermore, by scaling up the Mn0.2NiS/GF electrode area and assembling it in a continuous‐flow electrolyzer, high FDCA production rate of 44.32 g h−1 is achieved. The high activity of Mn0.2NiS/GF for HMFOR can be attributed to incorporation of Mn into NiS material, theoretical calculation results indicate that the Mn and Ni as both the adsorption sites for HMF oxidation, thereby effectively facilitate the HMF electro‐oxidation performance. This work provides a strategy for developing potential industrial‐grade electrocatalysts at a large current density.

Doped Mn Enhanced NiS Electrooxidation Performance of HMF into FDCA at Industrial‐Level Current Density

An original strategy was reported to manipulate ORR selectivity of N-doped hollow mesoporous carbon spheres (N-HMCS) via heteroatom (P and S) doping. Heteroatom doping can not only modulate electronic structure of N-HMCS and proportion/configuration of doped N, but also regulate ORR pathway. Specifically, rich-graphitic N sites and electron-rich C–P bond domains in N,P-HMCS act as electron donors, making *OOH more unstable and easier to desorb into H2O2. This severely distorts the sp2 lattice of graphene, catalyzing a two-electron ORR synergistically. Conversely, a strong interaction between electron-deficient C–S bond domain and *OOH intermediate due to the introduction of highly electronegative S hinders the desorption of *OOH, leading to the breakage of the O–O bond and promoting four-electron ORR along with the rich-pyridinic N receptor site. The reaction activity and kinetics mechanism present a positive correlation with proportion of graphitic N, revealing graphitic N is the primary active site with a much faster electron transfer capacity. 

Steering the Oxygen Reduction Reaction Pathways of N-Carbon Hollow Spheres by Heteroatom Doping

DeePMD-kit is a powerful open-source software package that facilitates molecular dynamics simulations using machine learning potentials (MLP) known as Deep Potential (DP) models. This package, which was released in 2017, has been widely used in the fields of physics, chemistry, biology, and material science for studying atomistic systems. The current version of DeePMD-kit offers numerous advanced features such as DeepPot-SE, attention-based and hybrid descriptors, the ability to fit tensile properties, type embedding, model deviation, Deep Potential - Range Correction (DPRc), Deep Potential Long Range (DPLR), GPU support for customized operators, model compression, non-von Neumann molecular dynamics (NVNMD), and improved usability, including documentation, compiled binary packages, graphical user interfaces (GUI), and application programming interfaces (API). This article presents an overview of the current major version of the DeePMD-kit package, highlighting its features and technical details. Additionally, the article benchmarks the accuracy and efficiency of different models and discusses ongoing developments.

pdf/deepmd-kit-v2-a-software-package-for-deep-potential-models-11b27oys.pdf

DeePMD-kit v2: A software package for Deep Potential models

Three ruthenium(II) complexes [Ru(bpy)2(biim)]2+ (1), [Ru(phen)2(biim)]2+ (2) and [Ru(p-mopip)2-(biim)]2+ (3) (where bpy is 2,2′-bipyridine, phen is 1,10-phenanthroline, biim is 2,2′-bisimidazole and p-mopip is 2-(4-methoxyphenyl)-imidazo-[4,5f]phenanthroline), have been synthesized and characterized. The interactions of human telomeric DNA oligomers 5′-G3(T2AG3)3-3′ (HTG21) with ruthenium(II) complexes were investigated via UV-vis, fluorescence resonance energy transfer (FRET) melting assay, polymerase chain reaction (PCR) stop assay, and circular dichroism (CD) measurements. The results indicated that the three ruthenium(II) complexes could stabilize the formation of human telomeric G-quadruplex DNA, and complex 2 was found to be the most efficient. In vitro cytotoxicity assay by MTT also showed that complex 2 was superior to complexes 1 and 3 in inhibiting the growth of cancer cells. Telomeric repeat amplification protocol (TRAP) showed that complexes 2 and 3 led to an inhibition of the telomerase activity, and complex 2 was the significantly better inhibitor. Flow cytometric analysis and evaluation of mitochondrial membrane potential demonstrated that complex 2 inhibited the growth of HeLa cells through induction of apoptotic cell death, as evidenced by the depletion of mitochondrial membrane potential in HeLa cells.

Studies of ruthenium(II)-2,2′-bisimidazole complexes on binding to G-quadruplex DNA and inducing apoptosis in HeLa cells

Developing high-performance anode electrocatalysts is desirable in electrocatalytic energy devices powered by sustainable electricity. Compared to water oxidation using Ni-based anodes, electro-oxidation upgrading of biomass molecule with larger size lacks dynamics driving due to increased thickness and decreased electron transfer kinetics of insulating NiOOH amorphous layer (>50 nm) from uncontrollable in-depth reconstruction. Herein, a self-confined surface reconstruction strategy is proposed to construct ∼5 nm-thick NiOOH layers on NiMo3S4 with superior activity and stability for 5-hydroxymethylfurfural oxidation reaction (HMFOR). In-situ high-valence Mo-O coordination and sulfate-terminated anion groups effectively prevent in-depth surface oxidation, leading to the ultra-thin active layers with increased electron transfer kinetics. The surface self-reconstructed NiMo3S4 (NiMo3S4-R) exhibits nearly 100% of HMF conversion, FDCA selectivity and Faradaic efficiency, much better than sulfate-modified NiOOH and pure NiOOH. Moreover, a paired electrolyzer of NiMo3S4-R||NiMo3S4 for HMFOR||HER is also assembled with an ultralow voltage of 1.414 V at 10 mA cm−2. 

Surface-confined self-reconstruction to sulfate-terminated ultrathin layers on NiMo3S4 toward biomass molecule electro-oxidation

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DeePMD-kit v2: A software package for Deep Potential models

Studies of ruthenium(II)-2,2′-bisimidazole complexes on binding to G-quadruplex DNA and inducing apoptosis in HeLa cells

Surface-confined self-reconstruction to sulfate-terminated ultrathin layers on NiMo3S4 toward biomass molecule electro-oxidation