When transition-metal catalysis meets electrosynthesis: a recent update.

While aiming at sustainable synthesis, organic electrosynthesis has attracted increasing attention in the past few years. In parallel, with a deeper understanding of catalyst and ligand design, 3d transition-metal catalysis allows the conception of more straightforward synthetic routes in a cost-effective fashion. Owing to their intrinsic advantages, the merger of organic electrosynthesis with 3d transition-metal catalysis has offered huge opportunities for conceptually novel transformations while limiting ecological footprint. This review summarizes the key advancements in this direction published in the recent two years, with specific focus placed on strategy design and mechanistic aspects.

Zinc and p53 disrupt mitochondrial binding of HK2 by phosphorylating VDAC1.

Many cell death regulators physically or functionally interact with metabolic enzymes. These interactions provide insights into mechanisms of anticancer treatments from the perspective of tumor cell metabolism and apoptosis. Recent studies have shown that zinc and p53 not only induce tumor cell apoptosis, but also regulate tumor cell metabolism. However, the underlying mechanism is complex and remains unclear, making further research imperative to provide clues for future cancer treatments. In this study, we found that hexokinase 2 (HK2), which has dual metabolic and apoptotic functions, is downstream of zinc and p53 in both prostate cancer patient tissue and prostate cancer cell lines. Notably, the mitochondrial location of HK2 is crucial for its function. We demonstrate that zinc and p53 disrupt mitochondrial binding of HK2 in prostate cancer cells by phosphorylating VDAC1, which is mediated by protein kinase B (Akt) inhibition and glycogen synthase kinase 3ß (GSK3ß) activation. In addition, we found that zinc combined with p53 significantly inhibited tumor growth in a prostate cancer cell xenograft model. Therefore, interference of the mitochondrial localization of HK2 by zinc and p53 may provide a new treatment approach for cancer.

Zinc promotes prostate cancer cell chemosensitivity to paclitaxel by inhibiting epithelial-mesenchymal transition and inducing apoptosis.

BACKGROUND: Paclitaxel (PTX) is a first-line chemotherapeutic drug for the treatment of prostate cancer. However, most patients develop resistance and metastasis, and thus new therapeutic approaches are urgently required. Recent studies have identified widespread anti-tumor effects of zinc (Zn) in various tumor cell lines, especially prostate cancer cells. In this study, we examined the effects of Zn as an adjuvant to PTX in prostate cancer cells. METHODS: PC3 and DU145 cells were treated with different concentrations of Zn and/or PTX. MTT assay was used to detect cell viability. Real-time cell analysis (RTCA) and microscopy were used to observe morphological changes in cells. Western blotting was used to detect the expression of epithelial-mesenchymal transition (EMT)-related proteins. qPCR (reverse transcription-polymerase chain reaction) was used to examine changes in TWIST1 mRNA levels. Cell invasion and migration were detected by scratch and transwell assays. shRNA against TWIST1 was used to knockdown TWIST1. Colony formation assay was used to detect cell proliferation, while Annexin V and propidium iodide (PI) staining was used to detect cell apoptosis. RESULTS: Zn and PTX increased proliferation inhibition in a dose- and time-dependent manner in prostate cancer cells, while Zn increased prostate cancer cell chemosensitivity to PTX. Combined Zn and PTX inhibited prostate cancer cell invasion and migration by downregulating the expression of TWIST1. Furthermore, knockdown of TWIST1 increased the sensitivity of prostate cancer cells to PTX. In addition, Zn and PTX reduced cell proliferation and induced apoptosis in prostate cancer cells. CONCLUSIONS: Our results demonstrated that Zn and PTX combined therapy inhibits EMT by reducing the expression of TWIST1, which reduces the invasion and migration of prostate cancer cells. SiTWIST1 increased the sensitivity of prostate cancer cells to PTX. In addition, with prolonged treatment, Zn and PTX inhibited proliferation and led to prostate cancer cell apoptosis. Therefore, Zn may be a potential adjuvant of PTX in treating prostate cancer and combined treatment may offer a promising therapeutic strategy for prostate cancer.

Exploring the ancestry differentiation and inference capacity of the 28-plex AISNPs.

Inferring an unknown DNA's ancestry using a set of ancestry-informative single nucleotide polymorphisms (SNPs) in forensic science is useful to provide investigative leads. This is especially true when there is no DNA database match or specified suspect. Thus, a set of SNPs with highly robust and balanced differential power is strongly demanded in forensic science. In addition, it is also necessary to build a genotyping database for estimating the ancestry of an individual or an unknown DNA. For the differentiation of Africans, Europeans, East Asians, Native Americans, and Oceanians, the Global Nano set that includes just 31 SNPs was developed by de la Puente et al. Its ability for differentiation and balance was evaluated using the genotype data of the 1000 Genomes Phase III project and the Stanford University HGDP-CEPH. Just 402 samples were genotyped and analyzed as a reference set based on statistical methods. To validate the differentiating capacity using more samples, we developed a single-tube 28-plex SNP assay in which the SNPs were chosen from the 31 allelic loci of the Global AIMs Nano set. Three tri-allelic SNPs used to differentiate mixed-source DNA contribute little to population differentiation and were excluded here. Then, 998 individuals from 21 populations were typed, and these genotypes were combined with the genotype data obtained from 1000 Genomes Phase III and the Stanford University HGDP-CEPH (3090 total samples,43 populations) to estimate the power of this multiplex assay and build a database for the further inference of an individual or an unknown DNA sample in forensic practice.

Praseodymium(III)-Catalyzed Regioselective Synthesis of C3-N-Substituted Coumarins with Coumarins and Azides.

A series of C3-N-substituted coumarins were synthesized in good yields directly from coumarins and azides in the presence of Pr(OTf)3 without any additives or ligands needed. The selected compounds 3a, 3c-e, 3g, 3i, 3q, 3u, and 3v exhibited good anticancer activities against MGC-803, A549, and NCI-H460 cell lines with IC50 in the range 8.75-38.54 µmol L-1.

Zinc cooperates with p53 to inhibit the activity of mitochondrial aconitase through reactive oxygen species accumulation.

Metabolic reprogramming is a central hallmark of cancer. Therefore, targeting metabolism may provide an effective strategy for identifying promising drug targets for cancer treatment. In prostate cancer, cells undergo metabolic transformation from zinc-accumulating, citrate-producing cells to citrate-oxidizing malignant cells with lower zinc levels and higher mitochondrial aconitase (ACO2) activity. ACO2 is a Krebs cycle enzyme that converts citrate to isocitrate and is sensitive to reactive oxygen species (ROS)-mediated damage. In this study, we found that the expression of ACO2 is positively correlated with the malignancy of prostate cancer. Both zinc and p53 can lead to an increase in ROS. ACO2 can be a target for remodeling metabolism by sensing changes in the ROS levels of prostate cancer. Our results indicate that targeting ACO2 through zinc and p53 can change prostate cancer metabolism, and thus provides a potential new therapeutic strategy for prostate cancer.

Global analysis of population stratification using a smart panel of 27 continental ancestry-informative SNPs.

Over the last decade, several panels of ancestry-informative markers have been proposed for the analysis of population genetic structure. The differentiation efficiency depends on the discriminatory ability of the included markers and the reference population coverage. We previously developed a small set of 27 autosomal single nucleotide polymorphisms (SNPs) for analyzing African, European, and East Asian ancestries. In the current study, we gathered a high-coverage reference database of 110 populations (10,350 individuals) from across the globe. The discrimination power of the panel was re-evaluated using four continental ancestry groups (as well as Indigenous Americans). We observed that all the 27 SNPs demonstrated stratified population specificity leading to a striking ancestral discrimination. Five markers (rs728404, rs7170869, rs2470102, rs1448485, and rs4789193) showed differences (δ > 0.3) in the frequency profiles between East Asian and Indigenous American populations. Ancestry components of all involved populations were accurately accessed compared with those from previous genome-wide analyses, thereafter achieved broadly population separation. Thus, our ancestral inference panel of a small number of highly informative SNPs in combination with a large-scale reference database provides a high-resolution in estimating ancestry compositions and distinguishing individual origins. We propose extensive usage in biomedical studies and forensics.

Palladium(ii)-catalyzed C-C and C-O bond formation for the synthesis of C1-benzoyl isoquinolines from isoquinoline N-oxides and nitroalkenes.

C1-Benzoyl isoquinolines can be generated via a palladium(ii)-catalyzed C-C and C-O coupling of isoquinoline N-oxides with aromatic nitroalkenes. The reaction proceeds through remote C-H bond activation and subsequent intramolecular oxygen atom transfer (OAT). In this reaction, the N-O bond was designed as a directing group in the C-H bond activation as well as the source of an oxygen atom.

A facile synthesis of 2,5-disubstituted oxazoles via a copper-catalyzed cascade reaction of alkenes with azides.

A novel and efficient approach to the synthesis of 2,5-disubstituted oxazoles is developed via a 1,3-dipolar cycloaddition/ring cleavage/1,2-H migration/denitrogenation/copper-catalyzed aerobic oxidative dehydrogenative cyclization cascade. The desired products can be obtained from readily available aromatic terminal alkenes and azides employing air as the oxidant under mild conditions, and it offers an attractive alternative method for the synthesis of oxazole derivatives.

Synthesis and pharmacological evaluation of novel bisindole derivatives bearing oximes moiety: identification of novel proapoptotic agents.

In an effort to develop potent anti-cancer chemopreventive agents, a novel series of bisindole derivatives bearing oxime moiety were synthesized. Structures of all compounds were characterized by NMR and HRMS. Anti-proliferative activities for all of these compounds were investigated by the method of MTT assay on 7 human cancer lines and the normal cell lines (HUVEC). Most of them showed a noteworthy anti-cancer activity in vitro, the half maximal inhibitory concentration (IC50) value is 4.31 µM of 4e against T24. The results from Hoechst 33258 and acridine orange/propidium iodide staining as well as annexinV-FITC assays provided evidence for an apoptotic cell death. The further mechanisms of compound 4e-induced apoptosis in T24 cells demonstrated that compound 4e induced the productions of ROS, and altered anti- and pro-apoptotic proteins, leading to mitochondrial dysfunction and activations of caspase-9 and caspase-3 for causing cell apoptosis. Moreover, the cell cycle analysis and western-blot analysis indicated that compound 4e effectively arrested T24 cells in G1 stage and possibly has an effect on cell cycle regulatory proteins particularly cyclin D1.