Homo-Mannich Reaction of Cyclopropanols: A Versatile Tool for Natural Product Synthesis.

ConspectusThe Mannich reaction, involving the nucleophilic addition of an enol(ate) intermediate to an imine or iminium ion, is one of the most widely used synthetic methods for the synthesis of β-amino carbonyl compounds. Nevertheless, the homo-Mannich reaction, which utilizes a homoenolate intermediate as the nucleophilic partner and provides straightforward access to the valuable γ-amino carbonyl compounds, remains underexplored. This can be largely attributed to the difficulties in generation and manipulation of the homoenolate species, despite various homoenolate equivalents that have been developed.

DNA-compatible one-pot synthesis of multi-substituted dihydrofuran pyridinium ylide-mediated cyclization.

Synthesis of chemically diverse heterocyclic scaffolds in DNA-encoded libraries is highly demanded. We herein reported a convenient one-pot multi-component on-DNA synthetic strategy to afford multi-substituted 2,3-dihydrofuran scaffolds pyridinium ylide-mediated cyclization. This reaction exhibited modest to excellent conversions for a broad range of DNA-conjugated aldehydes, β-ketonitriles and pyridinium salts under mild reaction conditions.

Injectable supramolecular hydrogel co-loading abemaciclib/NLG919 for neoadjuvant immunotherapy of triple-negative breast cancer.

The efficacy of cancer immunotherapy relies on a sufficient amount of functional immune cells. Triple-negative breast cancer lacks enough immune cell infiltration, and adjuvant therapy is necessary to prime anti-tumor immunity. However, the improvement in efficacy is unsatisfactory with concern about inducing systemic immunotoxicity.

The Evolution of Nucleic Acid Nanotechnology: From DNA Assembly to DNA-Encoded Library.

Deoxyribonucleic acid (DNA), a fundamental biomacromolecule in living organisms, serves as the carrier of genetic information. Beyond its role in encoding biological functions, DNA's inherent ability to hybridize through base pairing has opened new avenues for its application in biological sciences. This review introduces DNA nanotechnology and DNA-encoded library (DEL), and highlights their shared design principles related to DNA assembly.

A Review on Branched-Chain Amino Acid Aminotransferase (BCAT) Inhibitors: Current Status, Challenges and Perspectives.

Branched-chain amino acids (BCAAs) are essential amino acids for humans and play an indispensable role in many physiological and pathological processes. Branched-chain amino acid aminotransferase (BCAT) is a key enzyme that catalyzes the metabolism of BCAAs. BCAT is upregulated in many cancers and implicated in the development and progress of some other diseases, such as metabolic and neurological diseases; and therefore, targeting BCAT might be a potential therapeutic approach for these diseases.

Design, synthesis, and structure-activity relationships of five-membered heterocyclic incorporated aryl(alkyl)azoles: From antiproliferative thiazoles to safer anticonvulsant oxadiazoles.

In the current study, a novel series of 1,2,4-oxadiazoles were designed, synthesized, and evaluated for their biological activities. A cell-based antiproliferative screening was accomplished on the newly synthesized 1,2,4-oxadiazoles along with our previously reported aryl(alkyl)azoles (AAAs) containing middle heterocyclic cores thiazole and oxazole. Among the tested compounds, naphthyl- thiazoles demonstrated higher antiproliferative activity and B3 was identified as the most potent compound with IC values in the range of 2.

Anti-inflammatory Withanolides from Physalis angulate. var. villosa Bonati.

Two new withanolide derivatives (1 and 2) and 12 known withanolide analogues (3-14) were identified from the aerial part of Physalis angulata var. villosa Bonati. Their structures were determined by various spectral data, quantum chemical calculations, and sugar derivatization methods.

BrCFCN for photocatalytic cyanodifluoromethylation.

Considering the unique electronic properties of the CF and the CN groups, the CFCN group has significant potential in drug and agrochemical development, as well as material sciences. However, incorporating a CFCN group remains a considerable challenge. In this work, we disclose a use of bromodifluoroacetonitrile (BrCFCN), a cost-effective and readily available reagent, as a radical source for cyanodifluoromethylation of alkyl alkenes, aryl alkenes, alkynes, and (hetero)arenes under photocatalytic conditions.

(Curtis) P. Karst. Immunomodulatory Protein Has the Potential to Improve the Prognosis of Breast Cancer Through the Regulation of Key Prognosis-Related Genes.

: Breast cancer in women is the most commonly diagnosed and most malignant tumor. Although luminal A breast cancer (LumA) has a relatively better prognosis, it still has a persistent pattern of recurrence. (Curtis) P.

Identification of a Potential PGK1 Inhibitor with the Suppression of Breast Cancer Cells Using Virtual Screening and Molecular Docking.

Background/objectives: Breast cancer is the second most common malignancy worldwide and poses a significant threat to women's health. However, the prognostic biomarkers and therapeutic targets of breast cancer are unclear. A prognostic model can help in identifying biomarkers and targets for breast cancer.

Targeting cryptic allosteric sites of G protein-coupled receptors as a novel strategy for biased drug discovery.

G protein-coupled receptors (GPCRs) represent the largest family of membrane receptors and are highly effective targets for therapeutic drugs. GPCRs couple different downstream effectors, including G proteins (such as Gi/o, Gs, G12, and Gq) and β-arrestins (such as β-arrestin 1 and β-arrestin 2) to mediate diverse cellular and physiological responses. Biased signaling allows for the specific activation of certain pathways from the full range of receptors' signaling capabilities.

Serum levels of oxidative stress, IL-8, and pepsinogen I/II ratio in Helicobacter pylori and gastric cancer patients: potential diagnostic biomarkers.

Background And Aim: Helicobacter pylori (H.pylori), a gram-negative bacterial pathogen associated with an increased risk of gastric cancer. This study investigates potential factors in the incidence of gastric cancer in patients with H.

Glycan Sequencing Based on Glycosidase-Assisted Nanopore Sensing.

Nanopores are promising sensors for glycan analysis with the accurate identification of complex glycans laying the foundation for nanopore-based sequencing. However, their applicability toward continuous glycan sequencing has not yet been demonstrated. Here, we present a proof-of-concept of glycan sequencing by combining nanopore technology with glycosidase-hydrolyzing reactions.

Advances in structure-based allosteric drug design.

The identification of allosteric binding sites forms a critical connection between structural and computational biology, substantially advancing the discovery of allosteric drugs. However, the prevailing strategies for allosteric drug development predominantly rely on high-throughput screening, which suffers from high failure rates due to a limited understanding of allosteric mechanisms. This review collects insights from case studies on allosteric mechanisms, protein structure databases and computation algorithm developments, aiming to enhance our comprehension of allostery and guide more effective allosteric drug development.

Incorporation of a rigid 1,3-diketone-containing fragment led to significantly improved AXL inhibitory activity: design, synthesis, and SAR of the anilinopyrimidine AXL inhibitors.

Overexpressed AXL kinase is involved in various human malignancies, which incurs tumor progression, poor prognosis, and drug resistance. Suppression of the aberrant AXL axis with genetic tools or small-molecule inhibitors has achieved valid antitumor efficacies in both preclinical studies and clinical antitumor campaigns. Herein we will report the design, synthesis, and structure-activity relationship (SAR) exploration of a series of anilinopyrimidine type II AXL inhibitors.

A prodrug nanodevice co-delivering docetaxel and ROR1 siRNA for enhanced triple negative breast cancer therapy.

Triple-negative breast cancer (TNBC) has been a clinical challenge due to its high recurrence and metastasis rates. Chemotherapy remains the primary treatment for TNBC after surgery ablation, but it lacks targeted specificity and causes side effects in normal tissues. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is significantly expressed in TNBC cells, and small interference RNA (siRNA) targeting ROR1 can effectively suppress ROR1 gene expression, thereby inhibiting proliferation and metastasis.

Targeting IL-20 alleviates inflammatory mechanical allodynia and reduces epidural fibrosis in post-laminectomy syndrome rat model.

Background: Post-laminectomy syndrome (PLS) manifests as recurrent chronic back pain, with or without radiating leg pain, affecting 10-40% of patients following laminectomy. While surgical interventions can alleviate recurrent disc herniation or joint instability, medical management of PLS remains challenging due to unsatisfactory outcomes. Epidural fibrosis is a frequent cause of PLS, leading to nerve root tethering and dural sac compression.

Advances in the selective c-MET kinase inhibitors: Application of fused [5,6]-Bicyclic nitrogen-containing cores for anticancer drug design.

Over the past two decades, small molecules bearing [5,6]-bicyclic nitrogen-containing cores have emerged as one of the most extensively studied structures for the development of selective c-MET kinase inhibitors. Structure-activity relationship (SAR) studies have demonstrated that modifying these cores can significantly impact the biological properties of c-MET inhibitors, including safety/toxicity, potency, and metabolic stability. For example, although c-MET kinase inhibitors containing the [1,2,4]triazolo[4,3-b][1,2,4]triazine scaffold (core P) exhibit high inhibitory potency, they often face challenges due to metabolic stability defects.

The Furan-Thiol-Amine Reaction Facilitates DNA-Compatible Thiopyrrole-Grafted Macrocyclization and Late-Stage Amine Transformation.

We here report an efficient DNA-compatible furan-thiol-amine reaction for macrocyclization and late-stage amine transformation. This reaction, conducted under mild conditions, enables the facile cyclization of DNA-conjugated linear peptides into thiopyrrole-grafted macrocycles regardless of ring size or side-chain modification with good to excellent conversion yields. Additionally, this strategy was employed for the late-stage transformation of terminal amines, serving as critical intermediates in the construction of DNA-encoded peptide libraries.

Discovery of a non-nucleotide stimulator of interferon genes (STING) agonist with systemic antitumor effect.

Agonists of the stimulator of interferon genes (STING) pathway are increasingly being recognized as a promising new approach in the treatment of cancer. Although progress in clinical trials for STING agonists in antitumor applications has been slow, there is still an urgent need for developing new potent STING agonists with versatile potential applications. Herein, we developed and identified a non-nucleotide STING agonist called DW18343.

Personalized Multi-Epitope Nanovaccine Unlocks B Cell-Mediated Multiple Pathways of Antitumor Immunity.

B lymphocytes have emerged as an important immune-regulating target. Inoculation with tumor cell membrane-derived vaccines is a promising strategy to activate B cells, yet their efficiency is limited due to lack of costimulatory molecules. To amplify B cell responses against tumor, herein, a spatiotemporally-synchronized antigen-adjuvant integrated nanovaccine, termed as CM-CpG-aCD40, is constructed by conjugating the immune stimulative CpG oligonucleotide and the anti-CD40 antibody (aCD40) onto the membrane vesicles derived from triple negative breast cancer cells.

A saccharides regulated fluorescence ratio sensing array for bacterial recognition based on lectin response.

Array sensing employs cross-identification among analytes and various sensing units to identify substances or complex systems. This manuscript presents a fluorescence ratio sensing array based on lectin responses for the accurate identification of different bacteria. This strategy uses a saccharide-sensitive polymer as the sensing unit within the sensor.

Denatonium inhibits RANKL-induced osteoclast differentiation and rescues the osteoporotic phenotype by blocking p65 signaling pathway.

Background: Bone remodeling is a critical process that maintains skeletal integrity, orchestrated by the balanced activities of osteoclasts, which resorb bone, and osteoblasts, which form bone. Osteoclastogenesis, the formation of osteoclasts, is primarily driven by NFATc1, a process activated through c-Fos and NF-κB signaling pathways in response to receptor activator of nuclear factor κB ligand (RANKL). Dysregulation of RANKL signaling is a key contributor to pathological bone loss, as seen in conditions such as osteoporosis.

Gastroprotective Effects of Betahistine Against an Indomethacin-Induced Gastric Mucosal Ulcer in Rats: The Role of CINC-2α Gene.

Background: The role of histamine H3 receptors (H3Rs) in gastric protection and anti-inflammatory function is controversial. In this study, we investigated the gastroprotective effect of a histamine H3 receptor antagonist drug, betahistine, on cytokine-induced neutrophil chemoattractant (CINC) gene expression in a rat model of indomethacin-induced gastric mucosal injury.

Methods: In this experiment, rats were divided into four groups; the control group received no treatment, group 2 was treated with indomethacin at a dose of 25 mg/kg, group 3 pre-treated with famotidine at a dose of 50 mg/kg, and group 4 pre-treated with betahistine (as a reference drug) at a dose of 50 mg/kg.