In Vivo Self-Assembly of PROTACs by Bioorthogonal Chemistry for Precision Cancer Therapy.

Proteolysis targeting chimeras (PROTACs) hold immense promise for targeted protein degradation; however, challenges such as off-target effects, poor drug-likeness properties, and the "hook effect" remain. This study introduces Nano-Click-formed PROTACs (Nano-CLIPTACs) for precise tumor protein degradation in vivo. Traditional PROTACs with high molecular weight were first divided into two smaller druglike precursors capable of self-assembling to form functional PROTACs through a bioorthogonal reaction.

Employing genome-wide association studies to investigate acid adaptation mechanisms in Listeria monocytogenes.

Listeria monocytogenes is a critical foodborne pathogen known to develop adaptation traits in mildly acidic food processing environments. This study analyzed the genomic data of 49 strains derived from clinical and food sources, utilizing genome-wide association studies (GWAS) to explore the correlation between the genotypic and phenotypic traits of L. monocytogenes, thereby identifying the genetic determinants of its acid adaptation capability.

Synthesis of 4-Hydroxy-5-phenylaminoimidazoles through a Three-Component Reaction of Sulfur Ylides, Nitrosobenzenes, and Amidines.

A novel annulation reaction of amidines with sulfur ylides and nitrobenzenes has been developed, affording various novel 4-hydroxy-5-phenylaminoimidazoles in moderate to excellent yields. The 4-hydroxy-5-phenylaminoimidazoles have been further converted into α-ketoamide and imidazol-4-imine derivatives. Moreover, a plausible mechanism for this multicomponent reaction is proposed.

The Synthesis of Benzazepines via Sequential [3 + 2]-Annulation and [3,3]-Sigmatropic Rearrangement.

A novel annulation reaction of prop-2-ynylsulfonium salts with sulfur ylides and nitrosobenzenes has been developed, affording various benzazepines in moderate to good yields. Prop-2-ynylsulfonium salts act as C synthons in the reactions, providing a promising benzazepine skeleton in a one-pot operation with readily accessible starting materials.

Exploration of novel 20S proteasome activators featuring anthraquinone structures and their application in hypoxic cardiomyocyte protection.

Under hypoxic conditions, the accumulation of misfolded proteins primarily relies on the autonomous activity of 20S proteasome for degradation. The buildup of toxic proteins in cardiomyocyte contribute to various cardiovascular diseases. Therefore, enhancing the 20S proteasome degradation capacity and restoring protein homeostasis in myocardial cells with small molecule activators represent a promising therapeutic strategy for the treatment of ischemic cardiomyopathy.

Synthesis of 1,1,3-Polyfunctionalized Cyclobutane Derivatives from the Reaction of Sulfur Ylides with Bicyclo[1.1.0]butanes.

1,1,3-Polyfunctionalized cyclobutane derivatives have been synthesized from sulfur ylides and bicyclo[1.1.0]butanes (BCBs).

Formation and recovery of Listeria monocytogenes in viable but nonculturable state under different temperatures combined with low nutrition and high NaCl concentration.

The viable but nonculturable (VBNC) state occurs when bacteria lose their ability to grow and multiply on conventional media when stressed by adverse environmental factors, but they remain active and can revive under certain conditions, posing a food safety risk. In this study, the VBNC state of Listeria monocytogenes was induced with different temperatures combined with low nutrient conditions; the VBNC state of L. monocytogenes was confirmed in conjunction with the housekeeping gene abcZ using a molecular biology assay (PMA-qPCR) to calculate the viable bacterial count; The resuscitation conditions for the VBNC state of L.

An Obstacle Detection Method Based on Longitudinal Active Vision.

The types of obstacles encountered in the road environment are complex and diverse, and accurate and reliable detection of obstacles is the key to improving traffic safety. Traditional obstacle detection methods are limited by the type of samples and therefore cannot detect others comprehensively. Therefore, this paper proposes an obstacle detection method based on longitudinal active vision.

Discovery of MT-1207: A Novel, Potent Multitarget Inhibitor as a Promising Clinical Candidate for the Treatment of Hypertension.

Herein, a series of novel arylpiperazine (piperidine) derivatives were designed, synthesized, and evaluated for mechanisms of action through and studies. The most promising compound, (later named as ), is a potent α and 5-HT receptor antagonist with remarkable IC in the picomolar level. Importantly, in the assay, achieved an effective blood pressure (BP) reduction in the 2K2C rat model without damaging renal function.

Direct Synthesis of α-Ketothioamide Derivatives through a One-Pot Reaction of Sulfur Ylides, Nitrosobenzenes, and Thioacetic Acid.

A one-pot approach has been developed for the synthesis of α-ketothioamide derivatives from sulfur ylides, nitrosobenzenes, and thioacetic acid. This protocol is carried out under mild reaction conditions in generally moderate to excellent yields without any precious catalysts, affording the derivatives with structural diversity. Additionally, a possible mechanism for this chemical transformation is proposed.

Proteasome activation: A novel strategy for targeting undruggable intrinsically disordered proteins.

Intrinsically disordered proteins (IDPs) are characterized by their inability to adopt well-defined tertiary structures under physiological conditions. Nonetheless, they often play pivotal roles in the progression of various diseases, including cancer, neurodegenerative disorders, and cardiovascular ailments. Owing to their inherent dynamism, conventional drug design approaches based on structural considerations encounter substantial challenges when applied to IDPs.

Discovery of novel β-elemene hybrids with hydrogen sulfide-releasing moiety possessing cardiovascular protective activity for the treatment of atherosclerosis.

Herein, a series of novel β-elemene hybrids with different types of hydrogen sulfide (HS) donors was designed and synthesized for the first time. In addition, all compounds were tested for HS release in phosphate buffer solution assay, among which the derivatives with 5--hydroxyphenyl-3-1,2-dithiole-3-thione (ADT-OH) as the HS donor released the best level. The results of the isolated vasodilation assay revealed that all the compounds exhibited a degree of vasodilatory effect, and the representative compound "β-elemene-HS gas donor" hybrid L13-2h produced more than 50% vasodilatory activity at a concentration of 20 μM.

Direct Access to 3-Thioether-Substituted Dihydrofuro[2,3-]benzofurans via Tandem Reactions of Sulfur Ylides and 2-Nitrobenzofurans.

The synthesis of 3-thioether-substituted dihydrofuro[2,3-]benzofurans involving the [3 + 2] coupling of sulfur ylides with 2-nitrobenzofurans has been realized in moderate to good yields under mild conditions without any precious catalysts or additives. It is worth mentioning that the reutilization of the departed nitro-anion in the reaction process facilitates this new chemical transformation and presents a manner of high atom economy to provide products with a complex structure.

Discovery of novel hypoxia-activated, nitroimidazole constructed multi-target kinase inhibitors on the basis of AZD9291 for the treatment of human lung cancer.

A group of 4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine derivatives containing a hypoxia-activated nitroimidazole group were designed as EGFR inhibitors. Among this series, A14 was identified as the optimal compound, exhibiting potent anti-proliferative activities against H1975 and HCC827 cells. Under hypoxic condition, the anti-proliferative activities of A14 improved by 4-6-fold (IC < 10 nM), indicating its hypoxia-selectivity.

Exploration of novel four-membered-heterocycle constructed peptidyl proteasome inhibitors with improved metabolic stability for cancer treatment.

Peptides have limitations as active pharmaceutical agents due to rapid hydrolysis by proteases and poor cell permeability. To overcome these limitations, a series of peptidyl proteasome inhibitors embedded with four-membered heterocycles were designed to enhance their metabolic stabilities. All synthesized compounds were screened for their inhibitory activities against human 20S proteasome, and 12 target compounds displayed potent efficacy with IC values lower than 20 nM.

Exploration of novel dihydroquinoxalinone derivatives as EGFR tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer.

To overcome or delay the drug-resistance of first-generation epidermal growth factor receptor (EGFR) kinase inhibitors and non-selectivity toxicity mediated by second-generation inhibitors, splicing principle was employed to design and synthesize a series of Osimertinib derivatives containing dihydroquinoxalinone (8-30) as the novel third-generation inhibitors against double mutant L858R/T790M in EGFR. Among them, compound 29 showed excellent kinase inhibitory activity against EGFR with an IC value of 0.55 ± 0.

Pd(II) Complexes of Chiral Proline-Derived Ligands: Application for Dynamic Thermodynamic Resolution of α-Amino Acids and Their Antibacterial Activities.

Novel type of Pd(II) complexes have been synthesized under operationally simple and convenient conditions and applied in the dynamic thermodynamic resolution of racemic ,-unprotected α-amino acids. After rapid hydrolysis, these Pd(II) complexes produced the corresponding α-amino acids in satisfactory yields and enantioselectivities, accompanied by the recyclable proline-derived ligand. In addition, the method can be readily applied for / interconversion to obtain unnatural ()-α-amino acids from readily available ()-α-amino acids.

An update on the recent advances and discovery of novel tubulin colchicine binding inhibitors.

Microtubules, formed by α- and β-tubulin heterodimer, are considered as a major target to prevent the proliferation of tumor cells. Microtubule-targeted agents have become increasingly effective anticancer drugs. However, due to the relatively sophisticated chemical structure of taxane and vinblastine, their application has faced numerous obstacles.

Discovery of Norbornene as a Novel Hydrophobic Tag Applied in Protein Degradation.

Hydrophobic tagging (HyT) is a potential therapeutic strategy for targeted protein degradation (TPD). Norbornene was discovered as an unprecedented hydrophobic tag in this study and was used to degrade the anaplastic lymphoma kinase (ALK) fusion protein by linking it to ALK inhibitors. The most promising degrader, Hyt-9, potently reduced ALK levels through Hsp70 and the ubiquitin-proteasome system (UPS) in vitro without compensatory upregulation of ALK.