Design, Synthesis, and Structure-Activity Relationship of Novel Pyridazinone-Based PARP7/HDACs Dual Inhibitors for Elucidating the Relationship between Antitumor Immunity and HDACs Inhibition.

Histone deacetylases (HDACs) inhibitors such as vorinostat (SAHA) has been used to treat hematologic malignancies (rather than solid tumors) and have been found to suppress the JAK/STAT, a critical signal pathway for antitumor immunity, while PARP7 inhibitor RBN-2397 could activate the type I interferons (IFN-I) pathway, facilitating downstream effects such as STAT1 phosphorylation and immune activation. To elucidate whether simultaneous inhibition of these two targets could interfere with these two signal pathways, a series of pyridazinone-based PARP7/HDACs dual inhibitors have been designed, synthesized, and evaluated in vitro and in vivo experiments. Compound 9l was identified as a potent and balanced dual inhibitor for the first time, exhibiting excellent antitumor capabilities both in vitro and in vivo. This suggests that 9l can be used as a valuable tool molecule for investigating the relationship between anticancer immunity and HDAC inhibition.

Design, synthesis and biological evaluation of novel 1,2,4a,5-tetrahydro-4H-benzo[b][1,4]oxazino[4,3-d][1,4]oxazine-based AAK1 inhibitors with anti-viral property against SARS-CoV-2.

Coronavirus entry into host cells hinges on the interaction between the spike glycoprotein of the virus and the cell-surface receptor angiotensin-converting enzyme 2 (ACE2), initiating the subsequent clathrin-mediated endocytosis (CME) pathway. AP-2-associated protein kinase 1 (AAK1) holds a pivotal role in this pathway, regulating CME by modulating the phosphorylation of the µ subunit of adaptor protein 2 (AP2M1). Herein, we report a series of novel AAK1 inhibitors based on previously reported 1,2,4a,5-tetrahydro-4H-benzo[b] [1,4]oxazino[4,3-d] [1,4]oxazine scaffold. Among 23 synthesized compounds, compound 12e is the most potent one with an IC50 value of 9.38 ± 0.34 nM against AAK1. The in vitro antiviral activity of 12e against SARS-CoV-2 was evaluated using a model involving SARS-CoV-2 pseudovirus infecting hACE2-HEK293 host cells. The results revealed that 12e was superior in vitro antiviral activity against SARS-CoV-2 entry into host cells when compared to SGC-AAK1-1 and LX9211, and its activity was comparable to that of a related and reference compound 8. Mechanistically, all AAK1 inhibitors attenuated AAK1-induced phosphorylation of AP2M1 threonine 156 and disrupted the direct interaction between AP2M1 and ACE2, ultimately inhibiting SARS-CoV-2 infection. Notably, compounds 8 and 12e exhibited a more potent effect in suppressing the phosphorylation of AP2M1 T156 and the interaction between AP2M1 and ACE2. In conclusion, novel AAK1 inhibitor 12e demonstrates significant efficacy in suppressing SARS-CoV-2 infection, and holds promise as a potential candidate for developing novel antiviral drugs against SARS-CoV-2 and other coronavirus infections.

Prevention and Potential Treatment Strategies for Respiratory Syncytial Virus.

Respiratory syncytial virus (RSV) is a significant viral pathogen that causes respiratory infections in infants, the elderly, and immunocompromised individuals. RSV-related illnesses impose a substantial economic burden worldwide annually. The molecular structure, function, and in vivo interaction mechanisms of RSV have received more comprehensive attention in recent times, and significant progress has been made in developing inhibitors targeting various stages of the RSV replication cycle. These include fusion inhibitors, RSV polymerase inhibitors, and nucleoprotein inhibitors, as well as FDA-approved RSV prophylactic drugs palivizumab and nirsevimab. The research community is hopeful that these developments might provide easier access to knowledge and might spark new ideas for research programs.

Determining optimal ALT cut-off values for predicting significant hepatic histological changes in patients with normal ALT in the grey zone of chronic hepatitis B virus infection.

BACKGROUND AND AIMS: We aimed to define gender-specific, optimal alanine aminotransferase (ALT) cut-off values for the prediction of significant liver histological changes (SLHC) in Chinese patients with grey zone (GZ) chronic hepatitis B (CHB) and normal ALT. METHODS: In a retrospective study, we included 1101 consecutive patients with GZ CHB and normal ALT assigned to training or internal validation cohorts. We included an independent cohort of 842 patients for external validation. We performed receiver operating characteristic (ROC) curve, smoothed curve fitting, and threshold effect analyses to determine optimal ALT cut-off values. Area under the curve (AUC) values were calculated to assess their predictive performance. RESULTS: A proportion of 79.3% of patients with GZ CHB and normal ALT (≤40 U/L) had SLHC. ROC curve analysis initially identified optimal ALT cut-off values of 29 U/L (male) and 22 U/L (female). After smoothed curve fitting and threshold effect analyses, new optimal cut-off values were 27 U/L for males and 24 U/L for females. AUCs for these values were 0.836 (male) and 0.833 (female) in the internal validation cohort, and 0.849 (male) and 0.844 (female) in the external validation cohort. The accuracy and discriminative ability of the newly defined ALT cut-off values were greater than those of the current recommendations. CONCLUSION: This study established novel optimal ALT cut-off values for more precise prediction of SLHC among Chinese patients with GZ CHB and normal ALT levels. This may help identify individuals who will benefit from timely antiviral therapy.

Discovery of plant-derived anti-tumor natural products: Potential leads for anti-tumor drug discovery.

Natural products represent a paramount source of novel drugs. Numerous plant-derived natural products have demonstrated potent anti-tumor properties, thereby garnering considerable interest in their potential as anti-tumor drugs. This review compiles an overview of 242 recently discovered natural products, spanning the period from 2018 to the present. These natural products, which include 69 terpenoids, 42 alkaloids, 39 flavonoids, 21 steroids, 14 phenylpropanoids, 5 quinolines and 52 other compounds, are characterized by their respective chemical structures, anti-tumor activities, and mechanisms of action. By providing an essential reference and fresh insights, this review aims to support and inspire researchers engaged in the fields of natural products and anti-tumor drug discovery.

Recent progress in discovery of novel AAK1 inhibitors: from pain therapy to potential anti-viral agents.

Adaptor associated kinase 1 (AAK1), a member of the Ark1/Prk1 family of Ser/Thr kinases, is a specific key kinase regulating Thr156 phosphorylation at the µ2 subunit of the adapter complex-2 (AP-2) protein. Due to their important biological functions, AAK1 systems have been validated in clinics for neuropathic pain therapy, and are being explored as potential therapeutic targets for diseases caused by various viruses such as Hepatitis C (HCV), Dengue, Ebola, and COVID-19 viruses and for amyotrophic lateral sclerosis (ALS). Centreing on the advances of drug discovery programs in this field up to 2023, AAK1 inhibitors are discussed from the aspects of the structure-based rational molecular design, pharmacology, toxicology and synthetic routes for the compounds of interest in this review. The aim is to provide the medicinal chemistry community with up-to-date information and to accelerate the drug discovery programs in the field of AAK1 small molecule inhibitors.

Discovery of 12 (BMS-986172) as a Highly Potent MGAT2 Inhibitor that Achieved Targeted Efficacious Exposures at a Low Human Dose for the Treatment of Metabolic Disorders.

A series of dihydropyridinone (DHP) compounds was prepared and evaluated for MGAT2 activity. The efforts led to the identification of novel tetrazolones with potent MGAT2 inhibitory activity and favorable in vitro profiles. Further tests of select analogues in mouse models revealed significant reduction in food intake and body weight. Subsequent studies in MGAT2 knockout mice with the lead candidate 12 (BMS-986172) showed on-target- and mechanism-based pharmacology. Moreover, its favorable pharmacokinetic (PK) profile and the lack of species variability in the glucuronidation potential resulted in a greater confidence level in the projection of a low dose for achieving targeted efficacious exposures in humans. Consistent with these projections, PK data from a phase 1 trial confirmed that targeted efficacious exposures could be achieved at a low dose in humans, which supported compound 12 as our second and potentially superior development candidate for the treatment of various metabolic disorders.

Design, synthesis and anti-tumor efficacy evaluation of novel 1,3-diaryl propane-based polyphenols obtained from Claisen rearrangement reaction.

Polyphenols such as resveratrol, honokiol and nordihydroguaiaretic acid are widely existing in nature products or synthetic compounds with interesting biological activities. Inspired by their structural feature, a total of 49 1,3-diaryl propane-based polyphenols were designed and synthesized through Claisen rearrangement reaction. New compounds were initially assessed for their anti-proliferative activities against various cancer cell lines (PC-3, U87MG, U251, HCT116) at a concentration of 50 µM, and the results guided the SAR of this series of compounds. Further screening of selected compounds against seven cancer cell lines (three additional colon cancer cell lines namely COLO205, HT29 and SW480 were chosen) led to the identification of two advanced leads 2t and 3t with IC50 values ranging from 8.2 ± 0.1 to 19.3 ± 1.9 µM. Both compounds also showed promising anti-proliferative activities against COLO205 in dose- and time-dependent manners. Furthermore, 2t and 3t exhibited good anti-tumor efficacy in COLO205 xenografted mice model with TGI values ranging from 38% to 58%. These results warrant the further investigation of this series of compounds.

Recent Progress in Asymmetric Domino Intramolecular Cyclization/Cascade Reactions of Substituted Olefins.

The domino cyclization/coupling strategy is one of the most effective methods to produce cyclized and multi-functionalized compounds from olefins, which has attracted huge attention from chemists and biochemists especially for its considerable potential of enantiocontrol. Nowadays, more and more studies are developed to achieve difunctionalization of substituted olefins through an asymmetric domino intramolecular cyclization/cascade reaction, which is still an elegant choice to accomplish several synthetic ideas such as complex natural products and drugs. This review surveys the recent advances in this field through reaction type classification. It might serve as useful knowledge desktop for the community and accelerate their research.

Development a novel nomogram model for predicting significant hepatic histological changes in chronic hepatitis B virus carriers.

A proportion of chronic hepatitis B virus (HBV) carriers with normal alanine transaminase (ALT) present with significant liver histological changes (SLHC). To construct a noninvasive nomogram model to identify SLHC in chronic HBV carriers with different upper limits of normal (ULNs) for ALT. The training cohort consisted of 732 chronic HBV carriers who were stratified into four sets according to different ULNs for ALT: chronic HBV carriers I, II, III, and IV. The external validation cohort comprised 277 chronic HBV carriers. Logistic regression and least absolute shrinkage and selection operator analyses were applied to develop a nomogram model to predict SLHC. A nomogram model-HBGP (based on hepatitis B surface antigen, gamma-glutamyl transpeptidase, and platelet count) demonstrated good performance in diagnosing SLHC with area under the curve (AUCs) of 0.866 (95% confidence interval [CI]: 0.839-0.892) and 0.885 (95% CI: 0.845-0.925) in the training and validation cohorts, respectively. Furthermore, HBGP displayed high diagnostic values for SLHC with AUCs of 0.866 (95% CI: 0.839-0.892), 0.868 (95% CI: 0.838-0.898), 0.865 (95% CI: 0.828-0.901), and 0.853 (95% CI: 0.798-0.908) in chronic HBV carriers I, II, III, and IV, respectively. Additionally, HBGP showed greater ability in predicting SLHC compared with the existing predictors. HBGP has shown high predictive performance for SLHC, and thus may lead to an informed decision on the initiation of antiviral treatment.

Design, Synthesis and Biological Evaluation of Histone Deacetylase Inhibitors Based on Pyrrolo[2,3-d]pyrimidine and Pyrrolo[2,3-b]pyridine Scaffolds.

Histone deacetylases (HDACs) are validated targets for the development of anticancer drugs in epigenetics. We have designed and synthesized a series of novel HDAC inhibitors based on pyrrolo[2,3-d]pyrimidine and pyrrolo[2,3-b]pyridine scaffolds. Compound B3 {(E)-3-(4-(((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide} exhibits potent inhibitory activity against HDACs 1, 2, 3, 6, and 8 with IC50 values of 5.2, 6.0, 8.8, 4.4, and 173.0 nM, respectively. It exhibited potent antiproliferative effects against three tumour cell lines (IC50 values of 0.13, 0.37, and 1.11 µM, against MV-4-11, K562, and WSU-DLCL-2 cells, respectively) with two- to sixfold improvement relative to suberoylanilide hydroxamic acid (SAHA). Mechanistic studies on WSU-DLCL-2 cells revealed that B3 exhibits anticancer effects through the induction of G0 /G1 -phase arrest and promotion of apoptosis. The results of this study warrant further investigation of this compound series for the treatment of hematological malignancy.

Design, synthesis and biological evaluation of novel histone deacetylase (HDAC) inhibitors derived from ß-elemene scaffold.

ß-Elemene is the major active ingredient of TCM anticancer drug elemene extracts. To further improve its antitumor activity and poor solubility, a polar HDACi pharmacophore was incorporated its scaffold. Systematic SAR studies led to the discovery of compounds 27f and 39f, which exhibited potent inhibitory activity against HDACs (HDAC1: IC50 = 22 and 9 nM; HDAC6: 8 and 14 nM, respectively). In cellular levels, 27f and 39f significantly inhibited cell proliferation of five tumour cell lines (IC50: 0.79 - 4.42 µM). Preliminary mechanistic studies indicated that 27f and 39f efficiently induced cell apoptosis. Unexpectedly, compound 39f could also stimulate cell cycle arrest in G1 phase. Further in vivo study in WSU-DLCL-2 xenografted mouse model validated the antitumor activities of 27f, without significant toxicity. The results suggest the therapeutic potential of these HDACs inhibitors in lymphoma and provide valuable insight and understanding for further structural optimisation around ß-elemene scaffold.

Combination of chemotherapy and gaseous signaling molecular therapy: Novel ß-elemene nitric oxide donor derivatives against leukemia.

This study aimed to design and synthesize active hybrids of ß-elemene and nitric oxide (NO) donor pharmacophore as potential agents for treating leukemia. Derivatives reported herein exerted better inhibitory effects against human chronic myeloid leukemia K562 cells compared to ß-elemene (IC50 > 100 µM). The most potent compound 18f showed an IC50 value of 0.53 µM against K562 cells, as well as a high NO release level in vitro. In the K562 xenograft tumor mice model, compound 18f effectively inhibited the growth of the tumor, with a significant inhibition rate of 73.18%. After treatment with compound 18f, the body weight of mice did not decrease, indicating that it possessed good safety profile. All these proved that compound 18f was an excellent potential agent against leukemia.

Alkenyl Thioetherification Enabled by Nickel Catalysis.

This paper describes an efficient strategy to promote alkenyl thioetherifications via the Ni-catalyzed cross-coupling of inactivated or ß-aryl-substituted (E)-alkenyl halides with thio-alcohols/phenols. The present strategy with easy-to-operate reaction conditions represents one of the most effective alkenyl C(sp2)-S bond-forming methods via readily accessible nickel catalysis. Notably, the mildly basic conditions employed facilitate access to a broad scope including protected amino acids, saccharides, and heterocycles. Moreover, this work presents its attractive usefulness by the application in late-stage modifications of several structurally complex natural products and pharmaceuticals.

Novel druggable mechanism of Parkinson's disease: Potential therapeutics and underlying pathogenesis based on ferroptosis.

Genetics, age, environmental factors, and oxidative stress have all been implicated in the development of Parkinson's disease (PD); however, a complete understanding of its pathology remains elusive. At present, there is no cure for PD, and currently available therapeutics are insufficient to meet patient needs. Ferroptosis, a distinctive iron-dependent cell death mode characterized by lipid peroxidation and oxidative stress, has pathophysiological features similar to those of PD, including iron accumulation, reactive oxygen species-induced oxidative damage, and mitochondrial dysfunction. Ferroptosis has been identified as a specific pathway of neuronal death and is closely related to the pathogenesis of PD. Despite the similarities in the biological targets involved in PD pathogenesis and ferroptosis, the relationship between novel targets in PD and ferroptosis has been neglected in the literature. In this review, the mechanism of ferroptosis is discussed, and the potential therapeutic targets implicated in both PD and ferroptosis are compared. Furthermore, the anti-PD effects of several ferroptosis inhibitors, as well as clinical studies thereof, and the identification of novel lead compounds for the treatment of PD and the inhibition of ferroptosis are reviewed. It is hoped that this review can promote research to further elucidate the relationship between ferroptosis and PD and provide new strategies for the development of novel ferroptosis-targeting PD therapy.

Microwave-assisted rapid synthesis of chiral oxazolines.

Chiral oxazoline compounds play an extremely important role in asymmetric synthesis and drug discovery. Herein a simpler, greener and more efficient microwave-assisted protocol to rapidly access chiral oxazolines is developed using aryl nitriles or cyano-containing compounds and chiral ß-amino alcohols as starting materials. The reaction proceeds smoothly in the presence of a recoverable heterogeneous catalyst in either concentrated solution or under solvent-free conditions. The advantages of this method include rapidness, convenience, environmental protection, high atom economy, and excellent yields. The protocol should find wider application in the community in the future.

Recent advances of novel fourth generation EGFR inhibitors in overcoming C797S mutation of lung cancer therapy.

Lung cancer is the second place among the global cancer population in term of the morbidity and mortality, while non-small cell lung cancer (NSCLC) accounts for the largest proportion of all lung cancer patient. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are commonly used in the treatment of NSCLC. Despite of the success in coping with EGFR kinase resistance lung cancer using the first three generations of EGFR-TK inhibitors (EGFR-TKIs), the new problem of resistance to Osimertinib occurred due to the newly developed EGFRC797S mutation. In recent years, scientists have proposed several pharmacochemical strategies for the treatment of Osimertinib-resistant NSCLC patients. This paper intends to collect the references in this field since 2021 and to summarize the pharmacochemical processes and strategies in discovery of novel EGFR-TKIs for overcoming C797S mutation in lung cancer patients. It could serve as quick information provider for further structural modifications and drug discovery.

Recent progress in nickel-catalyzed carboboration of alkenes.

Alkenes represent one of the most useful building blocks for organic synthesis, owing to their abundance and versatile reactivity. Transition metal (Pd, Cu, Co, Ni, Fe, etc.) catalyzed difunctionalization of alkenes provides efficient access to substituted molecules from readily available alkenes by installing functional groups across their carbon-carbon double bonds. Particularly, Nickel-based catalytic complexes have attracted a great deal of attention. This is because they are prone to undergoing oxidative addition and slow ß-hydride elimination, and can access both two-electron and radical pathways. Numerous elegant Ni-catalyzed cross-coupling methods, e.g., (hetero)arylboration, alkenylboration, alkylboration and alkynylboration of alkenes, have been developed with broad scopes and a high tolerance to a variety of functional groups. Therefore, the Ni-catalyzed carboboration of alkenes has become an efficient synthetic protocol to deliver substituted compounds by the cross-coupling of alkenes, electrophiles, and B2Pin2. Despite this progress, a number of challenging issues remaining in the field include broadening the types of carboboration reactions, especially the asymmetric ones, diversifying electrophile types (which is limited to halogens for now) and gaining profound insight into the reaction mechanisms. This review summarizes the recent progress in this emerging field from the literature published since 2018. It will provide the scientific community with convenience to access collective information and to accelerate their further research in order to broaden the scope of methodology and application in drug discovery programs.

Design, synthesis and antitumor efficacy evaluation of a series of novel ß-elemene-based macrocycles.

ß-Elemene is the major constituent of the antitumor drugs elemene extract approved in China. By incorporating macrocyclization strategy into the ß-elemene skeleton, we designed a series of novel macrocycles retaining three key carbon-carbon double bonds. Four different methods have been successfully developed for these challenging ring systems. A total of twenty-eight 14- to 24-membered macrocycles were synthesized. Most of these macrocycles exhibited good antitumor activity against several cancer cell lines (PC-3, A549, U87MG, U251 and HCT116), with up to 40 folds improvement of activity comparing to ß-elemene. Additionally, X-ray single crystal structures of compounds Ic, Ip, and IIh were successfully solved as the proof of macrocycle formation. The results warrant the further investigation of this novel class macrocycles in pharmacokinetic and pharmacodynamics studies, which will be reported in due course.

Novel hydroxyl carboximates derived from ß-elemene: design, synthesis and anti-tumour activities evaluation.

A series of novel N-alkyl-N-hydroxyl carboximates derived from ß-elemene were fortuitously discovered. Most of them showed more potent anti-proliferative activities than their lead compound ß-elemene (1). Notably, compound 11i exhibited significant inhibitory effects on the proliferation of three lung cell lines (H1975, A549 and H460) and several other tumour cell lines (H1299, U87MG, MV4-11, and SU-DHL-2). Preliminary mechanistic studies revealed that compound 11i could significantly induce cell apoptosis. Further in vivo study in the H460 xenograft mouse model validated the anti-tumour activities of 11i with a greater tumour growth inhibition (TGI, 68.3%) than ß-elemene and SAHA (50.1% and 55.9% respectively) at 60 mg/kg ip dosing, without obvious body weight loss and toxicity. Thus, such N-alkyl-N-hydroxyl carboximate class of compounds exemplified as 11i demonstrated potent anticancer activities both in vitro and in vivo, and should warrant further investigation for potential anticancer therapy.