Design, synthesis, and evaluation of novel stilbene derivatives that degrade acidic nucleoplasmic DNA-binding protein 1 (And1) and synergize with PARP1 inhibitor in NSCLC cells.

Specifically inducing the degradation of acidic nucleoplasmic DNA-binding protein 1 (And1) is a promising antitumor strategy. Our previous study identified Bazedoxifene (BZA) and CH3 as specific And1 degraders and validated their activity in reversing radiotherapy resistance in vitro and in vivo. However, unelucidated structure-activity relationships and moderate activity have limited their application. In this study, 27 novel CH3 derivatives were designed and synthesised based on the cavity topology of the WD40 domain of And1. Among them, A15 with a "V" conformation significantly induced And1 degradation in NSCLC cells. In addition, this study demonstrated a potential synthetic lethal effect of And1 degraders and PARP1 inhibitors. 1 µM of Olaparib in combination with 5 µM of A15 significantly inhibited the proliferation of A549 and H460 cells. Overall, these compounds are valuable tools for elucidating And1 biology, and their special spatial conformation make them promising candidates for future optimisation studies.

Bazedoxifene analogs as potential WDHD1 degraders and antitumor agents: Synthesis, evaluation and molecular dynamics simulation studies.

DNA repair is strongly associated with tumor resistance to radiotherapy and chemotherapy. WD repeat and HMG-box DNA binding protein 1 (WDHD1) is a key adaptor for homologous recombination repair of DNA, and its overexpression is relevant to the poor prognosis of many tumor patients. We previously have identified and validated bazedoxifene (BZA), which had 60% inhibitory rate on WDHD1 in MCF7 cells at 10 µM, from the Food and Drug Administration-approved compound library. Here, we initially established the binding model of BZA, synthesized and evaluated eight BZA analogs. Further, we detailed the use of molecular dynamics simulations to provide insights into the basis for activity against WDHD1. This binding mode will be instructive for the development of new WDHD1 degraders.

Optimization of extraction and bioactivity detection of celery leaf flavonoids using BP neural network combined with genetic algorithm and response.

In the present study, ultrasound-assisted extraction was employed to extract the general flavone from celery leaves using response surface methodology and BP neural network model with a genetic algorithm (GA). The effects of temperature, time, solid-liquid ratio, and ethanol concentration on the extraction results were assessed by Box-Behnken design. Further optimization of the process was performed by GA-BP. Our results showed that the optimal conditions were an ethanol concentration of 70.31%, a temperature of 67.2 °C and an extraction time of 26.6 min. In addition, significant antioxidant activity and in vitro bacteriostasis were observed. We found that the total flavonoids of the celery leaves exerted a strong inhibitory effect on Escherichia coli, Staphylococcus aureus, and Bacillus subtilis. Additionally, considerable DPPH· and ·OH scavenging effects were exerted by flavonoids. Therefore, flavonoids from celery leaves can be considered natural antioxidants and bacterial inhibitors.

Discovery of novel triazole compounds as selective IL-1ß releasement inhibitors.

Inflammation and immunity are closely related to the occurrence and development of a variety of immune diseases. Although IL-1ß has been identified as a key cytokine in many immune diseases, safe and specific small molecular IL-1ß releasement inhibitors are still scarce and urgently required in clinic. The investigation prospect of triazoleis limited by its complicated pharmacological effect which exhibited inferior effects on IL-1ß and TNF-α. Herein, 36 novel derivatives were designed and synthesized, and nearly half of the derivatives exhibited much better selectivity on IL-1ß releasement inhibition as well as keep similar inhibitory activities to lead compound. In 20 µM, compound 19 exhibited IL-1ß releasement inhibitory activity (IC50 = 5.489 µM) which closed to the original compound, and 4.5-fold superior selectivity (SI = 4.71) to the lead compound (SI = 0.82). A probable SAR model of triazole derivatives for IL-1ß releasement inhibition and selectivity was also proposed, which might promote the discovery of more effective and specific IL-1ß releasement inhibitors in the future.

Role of the ubiquitin-proteasome system and autophagy in regulation of insulin sensitivity in serum-starved 3T3-L1 adipocytes.

The ubiquitin-proteasome system (UPS) and autophagy are two conserved intracellular proteolytic pathways, responsible for degradation of most cellular proteins in living cells. Currently, both the UPS and autophagy have been suggested to be associated with pathogenesis of insulin resistance and diabetes. However, underlying mechanism remains largely unknown. The purpose of the present study is to investigate the impact of the UPS and autophagy on insulin sensitivity in serum-starved 3T3-L1 adipocytes. Our results show that serum depletion resulted in activation of the UPS and autophagy, accompanied with increased insulin sensitivity. Inhibition of the UPS with bortezomib (BZM), a highly selective, reversible 26S proteasome inhibitor induced compensatory activation of autophagy but did not affect significantly insulin action. Genetic and pharmacological inhibition of autophagy dramatically mitigated serum starvation-elevated insulin sensitivity. In addition, autophagy inhibition compromised UPS function and led to endoplasmic reticulum (ER) stress and unfolded protein response (UPR). Inability of the UPS by BMZ exacerbated autophagy inhibition-induced ER stress and UPR. These results suggest that protein quality control maintained by the UPS and autophagy is required for preserving insulin sensitivity. Importantly, adaptive activation of autophagy plays a critical role in serum starvation-induced insulin sensitization in 3T3-L1 adipocytes.

Analysis of guide wire displacement in robot-assisted spinal pedicle screw implantation.

Robot-assisted pedicle screw placement is prone to guide wire migration, and the related influencing factors have not yet been discussed. Therefore, this study aimed to investigate and analyze the causes of robot-assisted spinal pedicle guide wire displacement and summarize the relevant treatment strategies. The surgical outcomes of 82 patients who underwent robotic-assisted pedicle screw spinal placement at our hospital between July 2022 and June 2023 were retrospectively analyzed. A total of 342 screws were placed in 82 patients; 47 guide wires were offset, 47 guide wires were replaced, and 295 guide wires were not significantly offset, with a first guide wire offset rate of 13.7% and a total guide wire offset rate of 12.1%. Univariate analysis showed that Screw placement level, whether respiration was controlled during guide wire placement, Hu value of CT, the position of needle insertion point, and operation time had a significant effect on guide wire deviation (P < 0.05). Multivariate logistic regression analysis showed that the inclusion of screw placement segments, whether breathing was controlled during guide wire placement, and Hu value of CT had a significant effect on guide wire offset (P < 0.05). Whether the guide wire was offset had no significant effect on the accuracy of subsequent pedicle screw implantation (P > 0.05). The level of screw placement, whether breathing was controlled during guide wire placement, and Hu value of CT were independent risk factors for guide wire deviation. When causing an excursion, screw orientation can be adjusted during intraoperative screw placement, and guide wire excursion has no significant impact on the accuracy of subsequent pedicle screw placement.

SREBP inhibitors: an updated patent review for 2008-present.

INTRODUCTION: Sterol regulatory element-binding proteins (SREBPs) are a family of membrane-binding transcription factors that activate genes encoding enzymes required for cholesterol and unsaturated fatty acid synthesis. Overactivation of SREBP is related to the occurrence and development of diabetes, nonalcoholic fatty liver, tumor, and other diseases. In the past period, many SREBP inhibitors have been found. AREAS COVERED: This manuscript is a patent review of SREBP inhibitors. We searched 2008 to date for all data from the US patent database (https://www.uspto.gov/) and the European patent database (https://www.epo.org/) with 'SREBP' and 'inhibitor' as keywords and analyzed the search results. EXPERT OPINION: Both synthetic and natural SREBP inhibitors have been reported. Despite the lack of cocrystal structure of SREBP inhibitor, the mechanisms of several compounds have been clarified. Importantly, some SREBP inhibitors have been proved to have good activity in preclinical studies. As the characteristics of lipid metabolism reprogramming in cardio-cerebrovascular diseases and tumors are gradually revealed, more and more attention will be focused on SREBP.

Development of a Highly Specific 18F-Labeled Radioligand for Imaging of the Sigma-2 Receptor in Brain Tumors.

Novel ligands with the 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline or 5,6-dimethoxyisoindoline pharmacophore were designed and synthesized for evaluation of their structure-activity relationship to the sigma-2 (σ2) receptor and developed as suitable PET radioligands. Compound 1 was found to possess nanomolar affinity (Ki(σ1) = 2.57 nM) for the σ2 receptor, high subtype selectivity (>2000-fold), and high selectivity over 40 other receptors and transporters. Radioligand [18F]1 was prepared with radiochemical yield of 37-54%, > 99% radiochemical purity, and molar activity of 107-189 GBq/µmol. Biodistribution and blocking studies in mice and micro-PET/CT imaging of [18F]1 in rats indicated excellent binding specificity to the σ2 receptors in vivo. Micro-PET/CT imaging of [18F]1 in the U87MG glioma xenograft model demonstrated clear tumor visualization with high tumor uptake and tumor-to-background ratio. Co-injection with CM398 (5 µmol/kg) led to a remarkable reduction of tumor uptake (80%, 60-70 min), indicating high specific binding of [18F]1 in U87MG glioma xenografts.

SUMO-specific protease 1 inhibitors-A literature and patent overview.

INTRODUCTION: Cancer is currently one of the biggest killers threatening human health. More and more studies have confirmed that SUMO-specific protease 1 (SENP1) is over-expressed in various cancer tissues. Therefore, targeting SENP1 expression may become a new strategy for tumor therapy. AREAS COVERED: This review reports the latest advances in literature and patents on SENP1 inhibitor development over the past 10 years. With SENP1 as the keyword, articles and patents from PubMed, Google scholar and ScienceDirect databases were covered. EXPERT OPINION: The available complex crystal structures of SENP1-SUMO1, afforded structure-based drug design opportunities, which led to the development of various isoform-selective small molecule inhibitors belonging to diverse classes (derivatives of benzamides, naphthalenesulfonic acids, pyridones, and the like). Preclinical studies have initially shown the potential advantages of these compounds, which have certain significance for the development of anticancer drugs.

Targeted inhibition of acidic nucleoplasmic DNA-binding protein 1 enhances radiosensitivity of non-small cell lung cancer.

Acidic nucleoplasmic DNA binding protein 1 (AND-1, also known as WD repeat and HMG-box DNA-binding protein 1, WDHD1) plays an important role in DNA replication and repair, but the relationship between AND-1 and radiosensitivity is not well understood. This research explored the impact of AND-1 on the radiosensitivity of non-small cell lung cancer (NSCLC) for the first time. NSCLC cells were treated with AND-1 siRNA or a new AND-1 inhibitor, CH-3, and clonogenic survival assay was used to characterize cell radiosensitivity. Cell cycle and apoptosis were examined by flow cytometry. DNA damage was detected by comet assay, immunofluorescence, and homologous recombination (HR) repair assay. Finally, the radiosensitization effect of CH-3 was investigated in vivo in a xenograft tumor model. The results showed that AND-1 inhibition significantly increased the radiosensitivity of NSCLC cells. Mechanistically, AND-1 inhibitor (CH-3) induced G2/M phase arrest by regulating the ATM signaling pathway and enhanced irradiation-induced DNA damage by inhibiting the DNA HR repair pathway. CH-3 enhanced the radiosensitivity of NSCLC cells in vivo. The development of radiosensitizers that target AND-1 may provide an alternative strategy to inhibit NSCLC.

Recent progress in small-molecule inhibitors for critical therapeutic targets of necroptosis.

Nonapoptotic types of regulated cell death have attracted widespread interest since the discovery that certain forms of cell necrosis can be regulated. In particular, research into cell necroptosis has made significant progress in connection with kidney, inflammatory, degenerative and neoplastic diseases. Inhibitors targeting the critical necroptosis-associated proteins RIPK1/3 and MLKL have been in development for more than a decade. Herein the authors compile a list of the known small-molecule inhibitors of these enzymes and representative structures of compounds co-crystallized with these proteins and put forward some thoughts regarding their future development.

Discovery and characterization of potent And-1 inhibitors for cancer treatment.

Acidic nucleoplasmic DNA-binding protein 1 (And-1), an important factor for deoxyribonucleic acid (DNA) replication and repair, is overexpressed in many types of cancer but not in normal tissues. Although multiple independent studies have elucidated And-1 as a promising target gene for cancer therapy, an And-1 inhibitor has yet to be identified. Using an And-1 luciferase reporter assay to screen the Library of Pharmacologically Active Compounds (LOPAC) in a high throughput screening (HTS) platform, and then further screen the compound analog collection, we identified two potent And-1 inhibitors, bazedoxifene acetate (BZA) and an uncharacterized compound [(E)-5-(3,4-dichlorostyryl)benzo[c][1,2]oxaborol-1(3H)-ol] (CH3), which specifically inhibit And-1 by promoting its degradation. Specifically, through direct interaction with And-1 WD40 domain, CH3 interrupts the polymerization of And-1. Depolymerization of And-1 promotes its interaction with E3 ligase Cullin 4B (CUL4B), resulting in its ubiquitination and subsequent degradation. Furthermore, CH3 suppresses the growth of a broad range of cancers. Moreover, And-1 inhibitors re-sensitize platinum-resistant ovarian cancer cells to platinum drugs in vitro and in vivo. Since BZA is an FDA approved drug, we expect a clinical trial of BZA-mediated cancer therapy in the near future. Taken together, our findings suggest that targeting And-1 by its inhibitors is a potential broad-spectrum anti-cancer chemotherapy regimen.

DBU coupled ionic liquid-catalyzed efficient synthesis of quinazolinones from CO2 and 2-aminobenzonitriles under mild conditions.

Efficient and green strategy for the chemical conversion and fixation of CO2 is an attractive topic. In this work, we reported an efficient catalytic system of organic base coupled ionic liquids that could catalyse the synthesis of quinazolinones via cyclization of 2-aminobenzonitriles with CO2 under mild conditions (e.g., 60 °C, 0.1 MPa). It was found that 1,8-diazabicyclo[5.4.0]undec-7-ene coupled 1-butyl-3-methylimidazole acetate ionic liquids (DBU/[Bmim][OAc]) displayed excellent performance in catalysing the reactions of CO2 with 2-aminobenzonitriles, and a series of quinazolinones were obtained in high yields at atmospheric pressure. Moreover, the ILs had high stability and reusability, and can be reused at least five times without considerable decrease in catalytic activity. This protocol could also be conducted on a gram scale, and may have promising and practical applications in the production of quinazolinones.

Interaction between multi-walled carbon nanotubes and propranolol.

Carbon nanotubes could accumulate in organism and have a negative impact on the structure and function of the ecosystem when they were discharged into environment. Furthermore, it will affect the migration and fate of pollutants in the water body. The study is mainly to explore the adsorption behavior and mechanism of beta-blocker on multi-walled carbon nanotubes (MWCNTs). Propranolol (PRO) was selected as the representative of beta-blocker. The effects of different environmental factors such as pH, ionic strength and humic acid (HA) on the adsorption process were investigated. The adsorption results were characterized by Zeta potential. At the same time, the effects of different types of drugs on the adsorption process were explored and the possible adsorption mechanisms were analyzed. The experimental results showed that the adsorption behavior was significantly different under different pH conditions. π-π EDA interaction, hydrophobic interaction and hydrogen bonding were speculated to be the main adsorption mechanisms for PRO adsorption on MWCNTs.

Acetyl-CoA carboxylase (ACC) as a therapeutic target for metabolic syndrome and recent developments in ACC1/2 inhibitors.

Introduction: Acetyl-CoA Carboxylase (ACC) is an essential rate-limiting enzyme in fatty acid metabolism. For many years, ACC inhibitors have gained great attention for developing therapeutics for various human diseases including microbial infections, metabolic syndrome, obesity, diabetes, and cancer. Areas covered: We present a comprehensive review and update of ACC inhibitors. We look at the current advance of ACC inhibitors in clinical studies and the implications in drug discovery. We searched ScienceDirect ( https://www.sciencedirect.com/ ), ACS ( https://pubs.acs.org/ ), Wiley ( https://onlinelibrary.wiley.com/ ), NCBI ( https://www.ncbi.nlm.nih.gov/ ) and World Health Organization ( https://www.who.int/ ). The keywords used were Acetyl-CoA Carboxylase, lipid, inhibitors and metabolic syndrome. All documents were published before June 2019. Expert opinion: The key regulatory role of ACC in fatty acid synthesis and oxidation pathways makes it an attractive target for various metabolic diseases. In particular, the combination of ACC inhibitors with other drugs is a new strategy for the treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Expanding the clinical indications for ACC inhibitors will be one of the hot directions in the future. It is also worth looking forward to exploring safe and efficient inhibitors that act on the BC domain of ACC.

Synthesis of Novel Phenyl Porous Organic Polymers and Their Excellent Visible Light Photocatalytic Performance on Antibiotics.

The efficient and green removal of residual antibiotics in the environment is an attractive topic. In this work, four different phenyl porous organic polymers (P-POPs) photocatalysts were successfully synthesized, and a series of techniques, such as Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), nitrogen adsorption and desorption experimentation, and solid ultraviolet visible spectroscopy (UV-vis) were conducted to characterize the obtained P-POPs. Moreover, the photocatalytic property of P-POPs in the removal of tetracycline was studied, and the reaction conditions were optimized. Further study indicated that the P-POPs were also efficient for removing other antibiotics, such as chloramphenicol, in a high removal rate of 77%. Furthermore, the separation of the photocatalysts from the solution was easy, and the photocatalysts could be reused at least four times without a considerable loss in catalytic activity.