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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Natural terpenoids with anti-inflammatory activities: Potential leads for anti-inflammatory drug discovery.

Natural products are mainly secondary metabolites produced by plants, microorganisms, and animals, which are still abundant in modern drug discovery. Terpenoids are the most diverse group of natural products, attracting extensive attention owing to their various biological activities. This manuscript reviewed the chemical structures, anti-inflammatory activities, and mechanisms of action of 281 terpenoid natural products reported from 2010 to the present. Their biological targets and both in vitro and in vivo screening models were also surveyed and statistically summarized. This review will provide potential anti-inflammatory lead compounds and helpful information to researchers engaged in natural products and anti-inflammatory drug discovery.

HDAC1/MAO-B dual inhibitors against Alzheimer's disease: Design, synthesis and biological evaluation of N-propargylamine-hydroxamic acid/o-aminobenzamide hybrids.

A series of N-propargylamine-hydroxamic acid/o-aminobenzamide hybrids inhibitors combining the typical pharmacophores of hydroxamic acid/o-aminobenzamide and propargylamine were designed and synthesized as HDAC1/MAO-B dual inhibitors for the treatment of Alzheimer's disease. Most of the hybrids displayed moderate to good MAO-B inhibitory activities. Among them, Hybrid If exhibited the most potent activity against MAO-B and HDAC1 (MAO-B, IC50 = 99.0 nM; HDAC1, IC50 = 21.4 nM) and excellent MAO selectively (MAO-A, IC50 = 9923.0 nM; SI = 100.2). Moreover, compound If significantly reversed Aß1-42-induced PC12 cell damage and decreased the production of intracellular ROS, exhibiting favorable antioxidant activity. More importantly, hybrid If instantly penetrated the BBB and accumulated in brain tissue as well as markedly ameliorated cognitive dysfunction in a Morris water maze ICR mice model. In summary, HDAC1/MAO-B dual inhibitor If is a promising potential agent for the therapy of Alzheimer's disease.

Second generation ß-elemene nitric oxide derivatives with reasonable linkers: potential hybrids against malignant brain glioma.

Elemene is a second-line broad-spectrum anti-tumour drug that has been used in China for more than two decades. However, its main anti-tumour ingredient, ß-elemene, has disadvantages, including excessive lipophilicity and relatively weak anti-tumour efficacy. To improve the anti-tumour activity of ß-elemene, based on its minor molecular weight character, we introduced furoxan nitric oxide (NO) donors into the ß-elemene structure and designed six series of new generation ß-elemene NO donor hybrids. The synthesised compounds could effectively release NO in vitro, displayed significant anti-proliferative effects on U87MG, NCI-H520, and SW620 cell lines. In the orthotopic glioma model, compound Id significantly and continuously suppressed the growth of gliomas in nude mice, and the brain glioma of the treatment group was markedly inhibited (>90%). In short, the structural fusion design of NO donor and ß-elemene is a feasible strategy to improve the in vivo anti-tumour activity of ß-elemene.

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.

Races of small molecule clinical trials for the treatment of COVID-19: An up-to-date comprehensive review.

The coronavirus disease-19 (COVID-19) pandemic has become a global threat since its first outbreak at the end of 2019. Several review articles have been published recently, focusing on the aspects of target biology, drug repurposing, and mechanisms of action (MOAs) for potential treatment. This review gathers all small molecules currently in active clinical trials, categorizes them into six sub-classes, and summarizes their clinical progress. The aim is to provide the researchers from both pharmaceutical industries and academic institutes with the handful information and dataset to accelerate their research programs in searching effective small molecule therapy for treatment of COVID-19.

Recent Advances in Synergistic Antitumor Effects Exploited from the Inhibition of Ataxia Telangiectasia and RAD3-Related Protein Kinase (ATR).

As one of the key phosphatidylinositol 3-kinase-related kinases (PIKKs) family members, ataxia telangiectasia and RAD3-related protein kinase (ATR) is crucial in maintaining mammalian cell genomic integrity in DNA damage response (DDR) and repair pathways. Dysregulation of ATR has been found across different cancer types. In recent years, the inhibition of ATR has been proven to be effective in cancer therapy in preclinical and clinical studies. Importantly, tumor-specific alterations such as ATM loss and Cyclin E1 (CCNE1) amplification are more sensitive to ATR inhibition and are being exploited in synthetic lethality (SL) strategy. Besides SL, synergistic anticancer effects involving ATRi have been reported in an increasing number in recent years. This review focuses on the recent advances in different forms of synergistic antitumor effects, summarizes the pharmacological benefits and ongoing clinical trials behind the biological mechanism, and provides perspectives for future challenges and opportunities. The hope is to draw awareness to the community that targeting ATR should have great potential in developing effective anticancer medicines.

Anti-Tumor Drug Discovery Based on Natural Product ß-Elemene: Anti-Tumor Mechanisms and Structural Modification.

Natural products are important sources for drug discovery, especially anti-tumor drugs. ß-Elemene, the prominent active ingredient extract from the rhizome of Curcuma wenyujin, is a representative natural product with broad anti-tumor activities. The main molecular mechanism of ß-elemene is to inhibit tumor growth and proliferation, induce apoptosis, inhibit tumor cell invasion and metastasis, enhance the sensitivity of chemoradiotherapy, regulate the immune system, and reverse multidrug resistance (MDR). Elemene oral emulsion and elemene injection were approved by the China Food and Drug Administration (CFDA) for the treatment of various cancers and bone metastasis in 1994. However, the lipophilicity and low bioavailability limit its application. To discover better ß-elemene-derived anti-tumor drugs with satisfying drug-like properties, researchers have modified its structure under the premise of not damaging the basic scaffold structure. In this review, we comprehensively discuss and summarize the potential anti-tumor mechanisms and the progress of structural modifications of ß-elemene.

4-Hydroxy-3-methylbenzofuran-2-carbohydrazones as novel LSD1 inhibitors.

Histone lysine specific demethylase 1 (LSD1 or KDM1A) is a potential therapeutic target in oncology due to its overexpression in various human tumors. We report herein a new class of benzofuran acylhydrazones as potent LSD1 inhibitors. Among the 31 compounds prepared, 14 compounds exhibited excellent LSD1 inhibitory activity with IC50 values ranging from 7.2 to 68.8 nM. In cellular assays, several compounds inhibited the proliferations of various cancer cell lines, including PC-3, MCG-803, U87 MG, PANC-1, HT-29 and MCF-7. This opens up the opportunity for further optimization and investigation of this class compounds for potential cancer treatment.