Nickel-Catalyzed Reductive Borylation of Enaminones via C(sp2)-N Bond Cleavage.

The cleavage and transformation of alkenyl C(sp2)-N bonds is a significant synthetic challenge. Herein we described an unprecedented nickel-catalyzed reductive borylation of enaminones to synthesize ß-ketone boronic esters. Notably, B2pin2 played the dual role in this process, and water served as a hydrogen source, which was transferred to target products. The air-stable nickel catalyst was applied to the cleavage of alkenyl C(sp2)-N bonds, concomitant with the reductive process of the alkenyl boronic ester intermediates, on the basis of the mechanism study.

Recent Advances on Natural Aryl-C-glycoside Scaffolds: Structure, Bioactivities, and Synthesis-A Comprehensive Review.

Aryl-C-glycosides, of both synthetic and natural origin, are of great significance in medicinal chemistry owing to their unique structures and stability towards enzymatic and chemical hydrolysis as compared to O-glycosides. They are well-known antibiotics and potent enzyme inhibitors and possess a wide range of biological activities such as anticancer, antioxidant, antiviral, hypoglycemic effects, and so on. Currently, a number of aryl-C-glycoside drugs are on sale for the treatment of diabetes and related complications. This review summarizes the findings on aryl-C-glycoside scaffolds over the past 20 years, concerning new structures (over 200 molecules), their bioactivities-including anticancer, anti-inflammatory, antioxidant, antivirus, glycation inhibitory activities and other pharmacological effects-as well as their synthesis.

Sensitive detection of picric acid in an aqueous solution using fluorescent nonconjugated polymer dots as fluorescent probes.

Nonconjugated polymer dots (NPDs) were successfully used as fluorescent probes to selectively and sensitively detect picric acid (PA). The NPDs were prepared from polyethylenimine and 1,4-phthalaldehyde under mild conditions and had excitation and emission maxima of 351 and 474 nm, respectively. Fluorescence of the NPDs was efficiently quenched by PA through the inner filter effect because of the overlapping PA absorption band and NPD excitation spectrum. The NPDs allowed PA to be determined with a high degree of sensitivity. The linear range was 0-140µM and the detection limit was 0.5µM. The work involved developing a novel method for synthesizing NPDs and a promising platform for determining PA in environmental media.

Preparation of nonconjugated fluorescent polymer nanoparticles for use as a fluorescent probe for detection of 2,4,6-trinitrophenol.

Water-soluble nonconjugated fluorescent polymer nanoparticles (NFPNs) were prepared from branched polyethylenimine (PEI) and citric acid through an amide condensation reaction in the aqueous phase. The NFPNs were characterized using a transmission electron microscope, Fourier transform infrared (FTIR) spectroscopy, and X-ray photoelectron spectra (XPS). The NFPN fluorescence (with excitation/emission peaks at 360/450 nm) was quenched by 2,4,6-trinitrophenol (TNP) at trace concentrations through the inner filter effect and the formation of self-assembled non-fluorescent Meisenheimer complexes of TNP on the NFPN surfaces through acid-base interactions. The complexes effectively enriched TNP from the bulk solution on the NFPN surfaces through acid-base interactions, and the strong overlap between NFPN excitation and TNP absorption peaks contributed to NFPNs having good sensitivity and selectivity for TNP. The method was selective for TNP and was not sensitive to other interfering species. The calibration plot of log(F0/F) versus TNP concentration shows a linear relationship (R2 = 0.999) for TNP concentration in the range of 0.5-150 µM. The detection limit for TNP was 0.7 µM. The assay was successfully used to determine TNP in spiked lake water samples, and the recoveries were 96.6-102.7%.

"Turn-on" fluorometric probe for α-glucosidase activity using red fluorescent carbon dots and 3,3',5,5'-tetramethylbenzidine.

A turn-on method for determining α-glucosidase activity is described using a chemical redox strategy in which the fluorescence of red fluorescent carbon dots (CDs) is modulated. The red fluorescent CDs were prepared using a solvothermal method with p-phenylenediamine and sodium citrate. The excitation and emission maxima of the CDs were 490 and 618 nm, respectively. Ce4+ ions catalyze the oxidation of the colorless substrate 3,3',5,5'-tetramethylbenzidine (TMB) to give a blue oxidized TMB product (oxTMB). Absorption by oxTMB overlaps with the red light emitted by the CDs because of the fluorescence inner filter effect; therefore the presence of oxTMB decreases the intensity of fluorescence emission by the CDs. However, hydrolysis of L-ascorbic acid-2-O-α-D-glucopyranosyl by the enzyme α-glucosidase causes formation of ascorbic acid . Ascorbic acid reduces oxTMB to TMB, so that the inner filter effect disappeared and the fluorescence recovered. The strategy allows α-glucosidase activity to be successfully determined down to 0.02 U mL-1 and gives a dynamic linear range of 0-5.5 U mL-1. The strategy is very selective for α-glucosidase activity in the presence of potentially interfering substances. The method has been successfully applied to the determination of α-glucosidase activity in spiked human serum samples and gave satisfactory results. Graphical Abstract Schematic of the method used to prepare the carbon dots and the mechanisms involved in determining α-glucosidase activity.

A turn-on fluorescent sulfide probe prepared from carbon dots and MnO2 nanosheets.

A turn-on fluorescent sulfide probe was prepared from carbon dots (CDs; synthesized using an environmentally friendly method) and MnO2 nanosheets. In this composite probe, the fluorescence of the CDs (with excitation/emission peaks at 330/430 nm) is quenched by the MnO2 nanosheets through an inner filter effect. Introducing sulfide causes the MnO2 nanosheets to be disintegrated through a redox reaction between sulfide and MnO2. Hence, the blue fluorescence of the CDs is restored. Under the optimum conditions, fluorescence increases linearly in the 2-25 µM sulfide concentration range. The detection limit is 0.8 µM. The method was used to analyze spiked real water samples, and satisfactory results were achieved. Graphical abstract Schematic of the detecting sulfide ions using the carbon dots/MnO2 fluorescence probe based on the recovery of carbon dot fluorescence when sulfide ions are added.

A G-quadruplex-selective luminescent iridium(III) complex and its application by long lifetime.

BACKGROUND: The G-quadruplex motif has been widely used for the construction of analytical detection platforms due to its rich structural polymorphism and flexibility. Luminescent assays are often limited due to the interference from endogenous fluorophores in biological samples. METHODS: To address this challenge, a novel long lifetime iridium(III) complex 1 was synthesized and used to construct a G-quadruplex-based assay for detecting prostate specific antigen (PSA) in aqueous solution. PSA is a common biomarker in serum and used as a model for demonstration in this work. RESULTS: The PSA assay has achieved a detection limit of 40.8pg·mL-1, and shows high selectivity towards PSA over other proteins. Additionally, the assay could function in diluted human serum by using time-resolved luminescent spectroscopy, with good linearity from 1 to 10ng·mL-1 of PSA, which is adequate to detect the PSA levels for physiological (<4ng·mL-1) and clinical (4-10ng·mL-1) applications. CONCLUSIONS: The assay was successfully constructed. As revealed from time-resolved method, the long lifetime property of iridium(III) complex 1 plays an important role in distinguishing phosphorescence signals from short-life auto-fluorescence of human serum. GENERAL SIGNIFICANCE: Luminescent transition metal complexes offer several advantages over other widely used organic fluorophores, such as long phosphorescence lifetime, large Stokes shift and modular syntheses. In addition, the assay could work effectively in diluted human serum using time-resolved luminescent spectroscopy, it therefore could be potentially developed to monitor PSA in biological samples. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio.

"Ring opening-ring closure" strategy for the synthesis of aryl-C-glycosides.

A new "ring-opening-ring closure" strategy for the synthesis of aryl-C-glycosides was described. This strategy exploited the nickel-catalyzed regioselective ß-O elimination of glycals by reactions with various aryl boronic acids or potassium aryltrifluoroborates to yield the ring-opened products, which underwent the Lewis acid, protonic acid, PhSeCl, or NBS mediated ring closure reactions to afford diverse aryl-C-glycosides. After Lewis acids and protonic acids were screened, it was found that, starting from the ring-opened substrates, the Ph3PHBr or Sc(OTf)3 mediated ring closure reaction provided α- or ß-preferred aryl-C-Δ(2,3)-glycosides, respectively. Furthermore, ß-D-phenyl-C-glycosides were successfully prepared via the PhSeCl-mediated cyclization reaction, whereas the α-D-phenyl-C-glycoside was obtained via the NBS-mediated cyclization reaction. After removal of the 2-substituted functionalities by Bu3SnH/AIBN, the synthesis of 2-deoxy-aryl-C-glycosides was ultimately realized in a stereoselective manner.

Current status of drugs targeting PDGF/PDGFR.

As an important proangiogenic factor, platelet-derived growth factor (PDGF) and its receptor PDGFR are highly expressed in a variety of tumors, fibrosis, cardiovascular and neurodegenerative diseases. Targeting the PDGF/PDGFR pathway is therefore a promising therapeutic strategy. At present, a variety of PDGF/PDGFR targeted drugs with potential therapeutic effects have been developed, mainly including PDGF agonists, inhibitors targeting PDGFR and proteolysis targeting chimera (PROTACs). This review clarifies the structure, biological function and disease correlation of PDGF and PDGFR, and it discusses the current status of PDGFR-targeted drugs, so as to provide a reference for subsequent research.

Ratiometric luminescence detection of H2O2 in food samples using a terbium coordination polymer sensitized with 3-carboxyphenylboronic acid.

A ratiometric luminescent probe was fabricated using adenosine monophosphate (AMP) as a bridging ligand and 3-carboxyphenylboronic acid (3-CPBA) as the sensitizer and functional ligand that allowed the probe to recognize hydrogen peroxide (H2O2). The probe was labeled AMP-Tb/3-CPBA. Adding H2O2 caused the nonluminescent 3-CPBA to be converted into 3-hydroxybenzoic acid, which strongly luminesces at 401 nm. This meant that adding H2O2 decreased the AMP-Tb/3-CPBA luminescence intensity at 544 nm and caused luminescence at 401 nm. The 401 and 544 nm luminescence intensity ratio (I401/I544) was strongly associated with the H2O2 concentration between 0.1 and 60.0 µM, and the detection limit was 0.23 µM. Dual emission reverse-change ratio luminescence sensing using the probe allowed environmental effects to be excluded and the assay to be very selective. We believe that the results pave the way for the development of new functionalized lanthanide coordination polymers for use in luminescence assays.

A New Dawn for Targeted Cancer Therapy: Small Molecule Covalent Binding Inhibitor Targeting K-Ras (G12C).

K-Ras is a frequently mutated oncogene in human malignancies, and the development of inhibitors targeting various oncogenic K-Ras mutant proteins is a major challenge in targeted cancer therapy, especially K-Ras(G12C) is the most common mutant, which occurs in pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and other highly prevalent malignancies. In recent years, significant progress has been made in developing small molecule covalent inhibitors targeting K-Ras(G12C), thanks to the production of nucleophilic cysteine by the G12C mutant, breaking the "spell" that K-Ras protein cannot be used as a drug target. With the successful launch of sotorasib and adagrasib, the development of small molecule inhibitors targeting various K-Ras mutants has continued to gain momentum. In recent years, with the popularization of highly sensitive surface plasmon resonance (SPR) technology, fragment-based drug design strategies have shown great potential in the development of small molecule inhibitors targeting K-Ras(G12C), but with the increasing number of clinically reported acquired drug resistance, addressing inhibitor resistance has gradually become the focus of this field, indirectly indicating that such small molecule inhibitors still the potential for the development of these small molecule inhibitors are also indirectly indicated. This paper traces the development of small molecule covalent inhibitors targeting K-Ras(G12C), highlighting and analyzing the structural evolution and optimization process of each series of inhibitors and the previous inhibitor design methods and strategies, as well as their common problems and general solutions, in order to provide inspiration and help to the subsequent researchers.

Anti-angiogenic Agents: A Review on Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) Inhibitors.

Tumor growth inhibition can be achieved by inhibiting angiogenesis, which has been a field of great concern in recent years. Important targets to inhibit angiogenesis include vascular endothelial growth factor receptor (VEGFR) and its homologous tyrosine kinase receptor. Anti-angiogenic therapy based on inhibition of VEGFR-2 is an effective clinical treatment strategy. The research progress of VEGFR-2 inhibitors is reviewed in this paper from the aspects of drug development and chemical synthesis.

A Review on Poly (ADP-ribose) Polymerase (PARP) Inhibitors and Synthetic Methodologies.

Poly (ADP-ribose) polymerase (PARP) acts as an essential DNA repair enzyme. PARP inhibitors are novel small molecule targeted drugs based on the principle of "Synthetic Lethality", which affect DNA repair process by competitively inhibiting the activity of PARP enzyme and thereby kill cancer cells. Currently, four PARP inhibitors including olaparib, rucaparib, niraparib, and talazoparib have been approved by FDA for cancer treatment and have achieved great success in the treatment of ovarian cancer, breast cancer, and pancreatic cancer, etc. This paper provides a general overview of the research progress of PARP inhibitors including the major structure types, structure-activity relationship (SAR), and synthetic routes, with the aim of providing ideas for the discovery and synthesis of novel PARP inhibitors.

Monoclonal Antibodies, Small Molecule Inhibitors and Antibody-drug Conjugates as HER2 Inhibitors.

Overexpression of human epidermal growth factor receptor (HER)-2 is found in a variety of cancers, often portending poor clinical outcomes. Therefore, HER2 is an attractive target for treatment. This review describes the research progress of HER2 targeted inhibitors in recent years. Excellent reviews are available, so we focus on the development, mechanisms of action, and structure-activity relationships of different types of inhibitors, including monoclonal antibodies, small molecule inhibitors, and antibody-drug conjugates (ADCs). In addition, the differences among them are compared.

Structure-based identification of a NEDD8-activating enzyme inhibitor via drug repurposing.

NEDD8-activating enzyme (NAE) is an essential player of the NEDD8 conjugation pathway that regulates protein degradation. Meanwhile, drug repurposing is a cost-efficient strategy to identify new therapeutic uses for existing scaffolds. In this report, mitoxantrone (1) was repurposed as an inhibitor of NAE by virtual screening of an FDA-approved drug database. Compound 1 inhibited NAE activity in cell-free and cell-based systems with high selectivity and was competitive with ATP. Furthermore, compound 1 induced apoptosis of colorectal adenocarcinoma cancer cells through inhibiting the degradation of the neddylation substrate p53.

Luminescent iridium(iii) complexes as COX-2-specific imaging agents in cancer cells.

Two luminescent iridium(iii) complexes, 1 and 2, were synthesized and evaluated for their ability to probe COX-2 in human cancer cells. This is the first application of iridium(iii) complexes as imaging agents for COX-2. We demonstrate that complex 1 differentiates cancer cells from normal cells with high stability and low cytotoxicity.

Antagonizing STAT5B dimerization with an osmium complex.

Targeting STAT5 is an appealing therapeutic strategy for the treatment of hematologic malignancies and inflammation. Here, we present the novel osmium(II) complex 1 as the first metal-based inhibitor of STAT5B dimerization. Complex 1 exhibited superior inhibitory activity against STAT5B DNA binding compared to STAT5A DNA binding. Moreover, 1 repressed STAT5B transcription and blocked STAT5B dimerization via binding to the STAT5B protein, thereby inhibiting STAT5B translocation to the nucleus. Furthermore, 1 was able to selectively inhibit STAT5B phosphorylation without affecting the expression level of STAT5B.