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A series of versatile 4-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)pyridine intermediates have been developed to efficiently produce biaryls, amines, ethers, and thioethers. These hydrolysis-stable ether intermediates exhibit reactivity toward electron-donating groups and nucleophiles in cross-coupling and nucleophilic substitution reactions while surpassing the stability of corresponding aryl halides. In comparison to conventional coupling methods, this protocol offers an alternative pathway for accessing natural product and drug-like compounds without the need for metal catalysts. With assistance of this approach, we successfully obtained a potent P-glycoprotein inhibitor 4k (YS-370), a potent epidermal growth factor receptor inhibitor 4l (YS-363), and a promising lysine-specific demethylase 1 inhibitor 5g .

Peripheral nerve injury (PNI) involving the loss of sensory and movement functions is challenging to repair. Although the gold standard of PNI repair is still the use of autologous nerve grafts, the destruction of the donor side is inevitable. In the present study, peripheral nerve tissueoids (PNTs) composed of a Schwann cell (SC)-based neurotrophin-3 (NT-3) delivery system and a decellularized optic nerve (DON) with naturally oriented channels were engineered to investigate the mechanism of PNTs in nerve regeneration. Proteomic analysis and mRNA sequencing revealed that PNTs have the advantage of promoting nerve regeneration by the three mechanisms of chemotaxis, adhesion and intrinsic mobilisation. The results demonstrated that a local NT-3-enriched pool was constructed by laminin γ3 (LAMC3) in PNTs, creating a niche for the colonization of TrkC-positive SCs, attraction of axons to the defect/graft area, and remyelination. In addition, LAMC3 in PNTs can rapidly promote axon adhesion through integrin aVβ6 and can precisely guide long projecting axons to target tissues. Furthermore, the interactions among the NT-3/TrkC, LAMC3/integrin aVβ6 and the scaffold synergistically activate the PI3K-AKT signalling pathway in damaged neurons, further stimulating the intrinsic regenerative drive within the neurons to ultimately achieve the rapid reinnervation and the improvement of sensory and movement functions in the hindlimb., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

In 2022, the U.S. Food and Drug Administration approved a total of 16 marketing applications for small molecule drugs, which not only provided dominant scaffolds but also introduced novel mechanisms of action and clinical indications. The successful cases provide valuable information for optimizing efficacy and enhancing pharmacokinetic properties through strategies like macrocyclization, bioequivalent group utilization, prodrug synthesis, and conformation restriction. Therefore, gaining an in-depth understanding of the design principles and strategies underlying these drugs will greatly facilitate the development of new therapeutic agents. This review focuses on the research and development process of these newly approved small molecule drugs including drug design, structural modification, and improvement of pharmacokinetic properties to inspire future research in this field., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

In 2023, the U.S. Food and Drug Administration has approved 55 novel medications, consisting of 17 biologics license applications and 38 new molecular entities. Although the biologics license applications including antibody and enzyme replacement therapy set a historical record, the new molecular entities comprising small molecule drugs, diagnostic agent, RNA interference therapy and biomacromolecular peptide still account for over 50 % of the newly approved medications. The novel and privileged scaffolds derived from drugs, active molecules and natural products are consistently associated with the discovery of new mechanisms, the expansion of clinical indications and the reduction of side effects. Moreover, the structural modifications based on the promising scaffolds can provide the clinical candidates with the improved biological activities, bypass the patent protection and greatly shorten the period of new drug discovery. Therefore, conducting an appraisal of drug approval experience and related information will expedite the identification of more potent drug molecules. In this review, we comprehensively summarized the pertinent information encompassing the clinical application, mechanism, elegant design and development processes of 28 small molecule drugs, and expected to provide the promising structural basis and design inspiration for pharmaceutical chemists., Competing Interests: Declaration of competing interest All authors have approved the final submission to the journal. The authors declare no conflict of interest., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

In 2023, the U.S. Food and Drug Administration has approved 29 small molecule drugs. These newly approved small molecule drugs possess the distinct scaffolds, thereby exhibiting diverse mechanisms of action and binding modalities. Moreover, the marketed drugs have always been an important source of new drug development and creative inspiration, thereby fostering analogous endeavors in drug discovery that potentially extend to the diverse clinical indications. Therefore, conducting a comprehensive evaluation of drug approval experience and associated information will facilitate the expedited identification of highly potent drug molecules. In this review, we comprehensively summarized the relevant information regarding the clinical applications, mechanisms of action and chemical synthesis of 29 small molecule drugs, with the aim of providing a promising structural basis and design inspiration for pharmaceutical chemists., (© 2024 Wiley Periodicals LLC.)

Chemotherapies are commonly used in cancer therapy, their applications are limited to low specificity, severe adverse reactions, and long-term medication-induced drug resistance. Poly(ADP-ribose) polymerase (PARP) inhibitors are a novel class of antitumor drugs developed to solve these intractable problems based on the mechanism of DNA damage repair, which have been widely applied in the treatment of ovarian cancer, breast cancer, and other cancers through inducing synthetic lethal effect and trapping PARP-DNA complex in BRCA gene mutated cancer cells. In recent years, PARP inhibitors have been widely used in combination with various first-line chemotherapy drugs, targeted drugs and immune checkpoint inhibitors to expand the scope of clinical application. However, the intricate mechanisms underlying the drug resistance to PARP inhibitors, including the restoration of homologous recombination, stabilization of DNA replication forks, overexpression of drug efflux protein, and epigenetic modifications pose great challenges and desirability in the development of novel PARP inhibitors. In this review, we will focus on the mechanism, structure-activity relationship, and multidrug resistance associated with the representative PARP inhibitors. Furthermore, we aim to provide insights into the development prospects and emerging trends to offer guidance for the clinical application and inspiration for the development of novel PARP inhibitors and degraders., (© 2024 Wiley Periodicals LLC.)

The objective of this study was to explore the effects of different amounts of biochar on the migration process and characteristics of NO 3 - -N in loessial soil. In this study, six groups of mixed soil samples with biochar and loessial soil mass ratios of 0% (T0), 1% (T1), 2% (T2), 3% (T3), 4% (T4), and 5% (T5) were used as research objects. NO 3 - -N was used as the tracer. Through the indoor soil column solute transport simulation tests, the effects of different biochar application amounts on the NO 3 - -N transport process in loessial soil were simulated and studied. The results showed that the breakthrough curve of NO 3 - -N in loessial soil shifted to the right with the increasing of biochar application, and the peak value gradually decreased. The initial penetration time, complete penetration time, and total penetration time increased with the increasing of biochar application amount. The total penetration time of NO 3 - in the T1, T2, T3, T4, and T5 treatments was 1.26, 2.31, 2.72, 3.22, and 3.57 times that of T0, respectively. The R 2 was > 0.997 and RMSE was < 2.083 of the two-zone model (TRM). Compared with the convection-dispersion equation (CDE), the TRM model had higher fitting accuracy and could better simulate the NO 3 - -N migration process in loessial soil after the application of different contents of biochar. The analysis of the fitting parameters of the TRM model showed that the average pore velocity, hydrodynamic dispersion coefficient, and water content ratio in the movable zone gradually decreased with the increasing of biochar application, whereas the dispersion and mass exchange coefficient showed an increasing trend. The results showed that biochar application could effectively enhance the ability of loessial soil to fix NO 3 - -N, reduce the leakage of NO 3 - -N to groundwater, and play an important role in maintaining soil fertility and preventing groundwater pollution.

Background: Programmed death 1 (PD-1) inhibitor demonstrated durable antitumor activity in advanced esophageal squamous cell carcinoma (ESCC), but the clinical benefit of perioperative immunotherapy in ESCC remains unclear. This study evaluated the efficacy and safety of neoadjuvant chemoradiotherapy (nCRT) combined with the PD-1 inhibitor toripalimab in patients with resectable ESCC., Methods: From July 2020 to July 2022, 21 patients with histopathologically confirmed thoracic ESCC and clinical staged as cT1-4aN1-2M0/cT3-4aN0M0 were enrolled. Eligible patients received radiotherapy (23 fractions of 1.8 Gy, 5 fractions a week) with concurrent chemotherapy of paclitaxel/cisplatin (paclitaxel 45 mg/m 2 and cisplatin 25 mg/m 2 ) on days 1, 8, 15, 22, 29 and two cycles of toripalimab 240 mg every 3 weeks after nCRT for neoadjuvant therapy before surgery, four cycles of toripalimab 240 mg every 3 weeks for adjuvant therapy after surgery. The primary endpoint was the major pathological response (MPR) rate. The secondary endpoints were safety and survival outcomes., Results: A total of 21 patients were included, of whom 20 patients underwent surgery, 1 patient refused surgery and another patient was confirmed adenocarcinoma after surgery. The MPR and pathological complete response (pCR) rates were 78.9% (15/19) and 47.4% (9/19) for surgery ESCC patients. 21 patients (100.0%) had any-grade treatment-related adverse events, with the most common being lymphopenia (100.0%), leukopenia (85.7%), neutropenia (52.4%). 14 patients (66.7%) had adverse events of grade 3 with the most common being lymphopenia (66.7%). The maximum standardized uptake value and total lesion glycolysis of positron emission tomography/CT after neoadjuvant therapy well predicted the pathological response. The peripheral CD4+%, CD3+HLA-DR+/CD3+%, CD8+HLA-DR+/CD8+%, and IL-6 were significant differences between pCR and non-pCR groups at different times during neoadjuvant therapy. Three patients had tumor relapse and patients with MPR have longer disease-free survival than non-MPR patients., Conclusions: nCRT combined with perioperative toripalimab is effective and safe for locally advanced resectable ESCC. Long-term survival outcomes remain to be determined., Trial Registration Number: NCT04437212., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Following nearly two decades of development, significant advancements have been achieved in PROTAC technology. As of the end of 2022, more than 20 drugs have entered clinical trials, with ARV-471 targeting estrogen receptor (ER) showing remarkable progress by entering phase III clinical studies. In 2022, significant progress has been made on multiple targets. The first reversible covalent degrader designed to target the KRAS G12C mutant protein, based on cyclopropionamide, has been reported. Additionally, the activity HDCA1 degrader surpassed submicromolar levels during the same year. A novel FEM1B covalent ligand called EN106 was also discovered, expanding the range of available ligands. Furthermore, the first PROTAC drug targeting SOS1 was reported. Additionally, the first-in-class degraders that specifically target BRD4 isoforms (BRD4 L and BRD4 S) have recently been reported, providing a valuable tool for further investigating the biological functions of these isoforms. Lastly, a breakthrough was also achieved with the first degrader targeting both CDK9 and Cyclin T1. In this review, we aimed to update the PROTAC degraders as potential anticancer agents covering articles published in 2022. The design strategies, degradation effects, and anticancer activities were highlighted, which might provide an updated sight to develop novel PROTAC degraders with great potential as anticancer agents as well as favorable drug-like properties., Competing Interests: Declaration of competing interest There is no conflict of interest about this article to declare., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)