<i>N</i>‑Heterocyclic Carbene Catalyzed Enantioselective [3 + 2] Dearomatizing Annulation of Saturated Carboxylic Esters with <i>N</i>‑Iminoisoquinolinium Ylides

The dearomatizing annulation reaction is a significant challenge in organic chemistry. The direct activation of α-carbons of simple saturated esters, as nucleophiles, is an important synthesis strategy. In the present study, we disclose [3 + 2] dearomatizing annulation reactions with direct activating α-carbons of saturated carboxylic esters and <i>N</i>-iminoisoquinolinium ylides, which possess highly enantioselective characteristics, catalyzed by <i>N</i>-heterocyclic carbenes (NHCs). The protocol achieves isoquinoline dearomatization and the construction of tricyclic chiral products under mild conditions with good yield, substrate tolerance, and diastereoselectivity as well as excellent enantioselectivity

Understanding the value of tourism to seniors’ health and positive aging

The value of tourism has been included in studies of active aging, and the existing public health implications of the physical and mental health effects of tourism among seniors are recognized as important issues. This study uses a mixed methods research approach to explore the effects of tourism value on the health and mortality risk of older adults, referred to in this paper as seniors. Survival analysis and cohort analysis are combined with the narrative analysis of in-depth interviews with eight convenience-sampled seniors to construct a narrative framework of seniors’ active aging tourism and its intrinsic drivers. The study found that the intrinsic framework of active aging tourism values for seniors has a three-stage continuum, an interaction, and orientation characteristics. There are six intrinsic key value drivers of tourism value and public health for seniors. In addition, this study identifies the personal characteristics and strengths of seniors as important influences on tourism value practices for active aging and public health. This study provides a positive psychological and behavioral research direction for existing research on the value of tourism in active aging. It provides an empirical basis for exploring the intrinsic mechanisms of tourism and public health

Terahertz Phase Shift and Its Modulation in NdGaO₃ Single Crystals

Finding appropriate materials to shape the terahertz (THz) wave is highly desired due to the increasing development of practical devices and application systems. In this work, the THz phase shifts of four typical oxide crystals, i.e., NdGaO3 (NGO), quartz, (LaAlO3)0.3(Sr2AlTaO6)0.35, and sapphire, have been investigated by using THz time-domain spectroscopy. It is interesting to find that the NGO crystal is the only one that shows a distinct phase shift. The phase shift (Δφ) of a ∼500 μm-thick NGO crystal is almost linearly dependent on the THz frequency and it reaches as large as ∼94° at 1.5 THz with a temperature variation from 100 to 400 K. Moreover, the THz phase shift of NGO possesses crystal anisotropy and Δφ(100) > Δφ(001) > Δφ(110). In addition, the effects of both electric field and laser illumination on the THz phase shift in the NGO crystal have also been explored. It is found that the electric field (∼260 V/cm) has negligible effect, while the laser illumination can efficiently cause a noticeable THz shift and Δφ ∼ 78° with good manipulation stability can be achieved with 20 J/cm2 light fluence. These findings suggest that NGO crystals are an appropriate candidate for THz phase modulator and their sensitivity and stability are expected to have a great technological impact and offer prospects for their applications in THz optics

Concise Total Synthesis of (±)-Deguelin and (±)-Tephrosin Using a Vinyl Iodide as a Key Building Block

A concise and protecting-group-free total synthesis of the antiproliferative natural product (±)-deguelin (<b>2</b>) was accomplished in four steps and 62% overall yield from commercially available precursors. The key transformation employed a vinyl iodide as the pivotal building block to construct the 4-acylchromene substructure present in deguelin. Subsequent Cu₂O-mediated α-hydroxylation of deguelin (<b>2</b>) afforded tephrosin (<b>3</b>) in 90% yield

<i>N</i>‑Heterocyclic Carbene Catalytic [4 + 2] Cyclization of 3‑Alkylenyloxindoles with Enals: γ‑Carbon Activation for Enantioselective Assembly of Spirocarbocyclic Oxindoles

The ubiquitous structure of all-carbospirocyclic oxindoles makes the development of new methods for their enantioselective and stereoselective synthesis a significant ongoing challenge. Herein, we disclose a formal [4 + 2] annulation through <i>N</i>-heterocyclic carbene (NHC) catalysis for highly enantioselective synthesis of intriguing spirocarbocyclic oxindoles in the presence of Lewis acids. This protocol features good substrates tolerance, good yields, and excellent diastereoselectivities and enantioselectivities (up to 97% ee) under mild conditions

Solvent-Controlled Switchable C–H Alkenylation of 4‑Aryl‑1<i>H</i>‑pyrrole-3-carboxylates: Application to the Total Synthesis of (±)-Rhazinilam

A solvent-controlled switchable C–H alkenylation of 4-aryl-1<i>H</i>-pyrrole-3-carboxylates via a Pd­(OAc)₂ catalyzed oxidative Heck reaction was first realized. The corresponding C2 and C5 alkenylation products were obtained in good yields with high regioselectivities, respectively. The selective C5-alkenylation was successfully applied to the total synthesis of (±)-rhazinilam

Solvent-Controlled Switchable C–H Alkenylation of 4‑Aryl‑1<i>H</i>‑pyrrole-3-carboxylates: Application to the Total Synthesis of (±)-Rhazinilam

A solvent-controlled switchable C–H alkenylation of 4-aryl-1<i>H</i>-pyrrole-3-carboxylates via a Pd­(OAc)₂ catalyzed oxidative Heck reaction was first realized. The corresponding C2 and C5 alkenylation products were obtained in good yields with high regioselectivities, respectively. The selective C5-alkenylation was successfully applied to the total synthesis of (±)-rhazinilam

Discovery of hematopoietic progenitor kinase 1 inhibitors using machine learning-based screening and free energy perturbation

Hematopoietic progenitor kinase 1 (HPK1) is a key negative regulator of T-cell receptor (TCR) signaling and a promising target for cancer immunotherapy. The development of novel HPK1 inhibitors is challenging yet promising. In this study, we used a combination of machine learning (ML)-based virtual screening and free energy perturbation (FEP) calculations to identify novel HPK1 inhibitors. ML-based screening yielded 10 potent HPK1 inhibitors (IC50 DW21302, revealed that a single key atom change could trigger activity cliffs. The resulting DW21302-A was a potent HPK1 inhibitor (IC50 = 2.1 nM) and potently inhibited cellular HPK1 signaling and enhanced T-cell function. Molecular dynamics (MD) simulations and ADME predictions confirmed DW21302-A as candidate compound. This study provides new strategies and chemical scaffolds for HPK1 inhibitor development. Communicated by Ramaswamy H. Sarma</p

Novel Hybrids of Natural Oridonin-Bearing Nitrogen Mustards as Potential Anticancer Drug Candidates

A series of novel hybrids from natural product oridonin and nitrogen mustards were designed and synthesized to obtain more efficacious and less toxic antitumor agents. The antiproliferative evaluation showed that most conjugates were more potent than their parent compounds oridonin and clinically used nitrogen mustards against four human cancer cell lines (K562, MCF-7, Bel-7402, and MGC-803). Furthermore, the representative compounds <b>16a</b>–<b>c</b> exhibited antiproliferative activities against the multidrug resistant cell lines (SW620/AD300 and NCI-H460/MX20). It was shown that the most effective compound <b>16b</b> possesses a strong inhibitory activity with an IC₅₀ value 21-fold lower than that of oridonin in MCF-7 cells and also exhibits selective cytotoxicity toward the cancer cells. Intriguingly, compound <b>16b</b> has been demonstrated to significantly induce apoptosis and affect cell cycle progression in human hepatoma Bel-7402 cells

Antioxidant Properties of Novel Dimers Derived from Natural β‑Elemene through Inhibiting H₂O₂‑Induced Apoptosis

A series of novel β-elemene dimer derivatives were synthesized and evaluated for their antioxidant activities. The results indicated that most of the target compounds showed more potent cytoprotective effects than positive control vitamin E. In particular, dimer <b>D5</b> exhibited the strongest antioxidant activity, which was significantly superior to the active compound <b>D1</b> obtained in our previous study. Besides, <b>D5</b> did not produce obvious cytotoxicity in normal human umbilical vein endothelial cells (HUVECs) and increased the viability of HUVECs injured by H₂O₂ in a concentration-dependent manner. Further studies suggested that the cytoprotective action of <b>D5</b> might be mediated, at least in part, by increasing the intracellular superoxide dismutase activity and nitric oxide secretion as well as decreasing the intracellular malonyldialdehyde content and lactate dehydrogenase release. Furthermore, <b>D5</b> observably inhibited ROS generation and prevented H₂O₂-induced apoptosis in HUVECs possibly via inhibiting the activation of the MAPK signaling pathway