Visible light-induced chemoselective 1,2-diheteroarylation of alkenes.

Visible-light photocatalysis has evolved as a powerful technique to enable controllable radical reactions. Exploring unique photocatalytic mode for obtaining new chemoselectivity and product diversity is of great significance. Herein, we present a photo-induced chemoselective 1,2-diheteroarylation of unactivated alkenes utilizing halopyridines and quinolines. The ring-fused azaarenes serve as not only substrate, but also potential precursors for halogen-atom abstraction for pyridyl radical generation in this photocatalysis. As a complement to metal catalysis, this photo-induced radical process with mild and redox neutral conditions assembles two different heteroaryl groups into alkenes regioselectively and contribute to broad substrates scope. The obtained products containing aza-arene units permit various further diversifications, demonstrating the synthetic utility of this protocol. We anticipate that this protocol will trigger the further advancement of photo-induced alkyl/aryl halides activation.

Expanding the horizons of targeted protein degradation: A non-small molecule perspective.

Targeted protein degradation (TPD) represented by proteolysis targeting chimeras (PROTACs) marks a significant stride in drug discovery. A plethora of innovative technologies inspired by PROTAC have not only revolutionized the landscape of TPD but have the potential to unlock functionalities beyond degradation. Non-small-molecule-based approaches play an irreplaceable role in this field. A wide variety of agents spanning a broad chemical spectrum, including peptides, nucleic acids, antibodies, and even vaccines, which not only prove instrumental in overcoming the constraints of conventional small molecule entities but also provided rapidly renewing paradigms. Herein we summarize the burgeoning non-small molecule technological platforms inspired by PROTACs, including three major trajectories, to provide insights for the design strategies based on novel paradigms.

A promising future of metal-N-heterocyclic carbene complexes in medicinal chemistry: The emerging bioorganometallic antitumor agents.

Metal complexes based on N-heterocyclic carbene (NHC) ligands have emerged as promising broad-spectrum antitumor agents in bioorganometallic medicinal chemistry. In recent decades, studies on cytotoxic metal-NHC complexes have yielded numerous compounds exhibiting superior cytotoxicity compared to cisplatin. Although the molecular mechanisms of these anticancer complexes are not fully understood, some potential targets and modes of action have been identified. However, a comprehensive review of their biological mechanisms is currently absent. In general, apoptosis caused by metal-NHCs is common in tumor cells. They can cause a series of changes after entering cells, such as mitochondrial membrane potential (MMP) variation, reactive oxygen species (ROS) generation, cytochrome c (cyt c) release, endoplasmic reticulum (ER) stress, lysosome damage, and caspase activation, ultimately leading to apoptosis. Therefore, a detailed understanding of the influence of metal-NHCs on cancer cell apoptosis is crucial. In this review, we provide a comprehensive summary of recent advances in metal-NHC complexes that trigger apoptotic cell death via different apoptosis-related targets or signaling pathways, including B-cell lymphoma 2 (Bcl-2 family), p53, cyt c, ER stress, lysosome damage, thioredoxin reductase (TrxR) inhibition, and so forth. We also discuss the challenges, limitations, and future directions of metal-NHC complexes to elucidate their emerging application in medicinal chemistry.

Recent Advances on Small-Molecule Inhibitors of Lipocalin-like Proteins.

Lipid transfer proteins (LTPs) are crucial players in nonvesicular lipid trafficking. LTPs sharing a lipocalin lipid transfer domain (lipocalin-like proteins) have a wide range of biological functions, such as regulating immune responses and cell proliferation, differentiation, and death as well as participating in the pathogenesis of inflammatory, metabolic, and neurological disorders and cancer. Therefore, the development of small-molecule inhibitors targeting these LTPs is important and has potential clinical applications. Herein, we summarize the structure and function of lipocalin-like proteins, mainly including retinol-binding proteins, lipocalins, and fatty acid-binding proteins and discuss the recent advances on small-molecule inhibitors for these protein families and their applications in disease treatment. The findings of our Perspective can provide guidance for the development of inhibitors of these LTPs and highlight the challenges that might be faced during the procedures.

Research advances of Zanthoxylum bungeanum Maxim. polyphenols in inflammatory diseases.

Zanthoxylum bungeanum Maxim., commonly known as Chinese prickly ash, is a well-known spice and traditional Chinese medicine ingredient with a rich history of use in treating inflammatory conditions. This review provides a comprehensive overview of the botanical classification, traditional applications, and anti-inflammatory effects of Z. bungeanum, with a specific focus on its polyphenolic components. These polyphenols have exhibited considerable promise, as evidenced by preclinical studies in animal models, suggesting their therapeutic potential in human inflammatory diseases such as ulcerative colitis, arthritis, asthma, chronic obstructive pulmonary disease, cardiovascular disease, and neurodegenerative conditions. This positions them as a promising class of natural compounds with the potential to enhance human well-being. However, further research is necessary to fully elucidate their mechanisms of action and develop safe and effective therapeutic applications.

Design, synthesis, and biological evaluation of novel discoidin domain receptor inhibitors for the treatment of lung adenocarcinoma and pulmonary fibrosis.

Discoidin domain receptors (DDR) play crucial roles in cell proliferation and differentiation. When DDRs are overexpressed, it has been associated with various diseases such as cancers, fibrotic disorders, and inflammation. This study aimed to expand on previous research by using a structure-based drug design approach to develop a series of new indole-urea derivatives as potent inhibitors of DDR1. Through biochemical analyses, it was found that these compounds effectively inhibited DDR1/2, with compound 7s demonstrating the highest activity against A549 cells (IC50 value of 1.84 µM) while maintaining selectivity for other kinases. In vivo studies showed that compound 7s exhibited stronger antitumor activity compared to dasatinib, without causing significant weight loss at a dose of 30 mg/kg. Further investigation revealed that compound 7s hindered the migration of A549 cells by targeting the ERK, Akt1, and EMT pathways. Additionally, cellular experiments demonstrated that compound 7s suppressed the activation of fibroblasts induced by TGF-ß1. In vivo experiments confirmed that compound 7s, at a dose of 30 mg/kg, effectively inhibited DDR1 activation, resulting in a reduction of lung injury and fibrosis induced by bleomycin. Overall, these findings highlight the potential of these novel DDR1 inhibitors as promising therapeutic candidates for the treatment of DDR-related diseases.

[Retracted] MicroRNA­138 suppresses proliferation, invasion and glycolysis in malignant melanoma cells by targeting HIF­1α.

[This retracts the article DOI: 10.3892/etm.2016.3220.].

Targeting autophagy and beyond: Deconvoluting the complexity of Beclin-1 from biological function to cancer therapy.

Beclin-1 is the firstly-identified mammalian protein of the autophagy machinery, which functions as a molecular scaffold for the assembly of PI3KC3 (class III phosphatidylinositol 3 kinase) complex, thus controlling autophagy induction and other cellular trafficking events. Notably, there is mounting evidence establishing the implications of Beclin-1 in diverse tumorigenesis processes, including tumor suppression and progression as well as resistance to cancer therapeutics and CSC (cancer stem-like cell) maintenance. More importantly, Beclin-1 has been confirmed as a potential target for the treatment of multiple cancers. In this review, we provide a comprehensive survey of the structure, functions, and regulations of Beclin-1, and we discuss recent advances in understanding the controversial roles of Beclin-1 in oncology. Moreover, we focus on summarizing the targeted Beclin-1-regulating strategies in cancer therapy, providing novel insights into a promising strategy for regulating Beclin-1 to improve cancer therapeutics in the future.

Mechanisms of PANoptosis and relevant small-molecule compounds for fighting diseases.

Pyroptosis, apoptosis, and necroptosis are mainly programmed cell death (PCD) pathways for host defense and homeostasis. PANoptosis is a newly distinct inflammatory PCD pathway that is uniquely regulated by multifaceted PANoptosome complexes and highlights significant crosstalk and coordination among pyroptosis (P), apoptosis (A), and/or necroptosis(N). Although some studies have focused on the possible role of PANpoptosis in diseases, the pathogenesis of PANoptosis is complex and underestimated. Furthermore, the progress of PANoptosis and related agonists or inhibitors in disorders has not yet been thoroughly discussed. In this perspective, we provide perspectives on PANoptosome and PANoptosis in the context of diverse pathological conditions and human diseases. The treatment targeting on PANoptosis is also summarized. In conclusion, PANoptosis is involved in plenty of disorders including but not limited to microbial infections, cancers, acute lung injury/acute respiratory distress syndrome (ALI/ARDS), ischemia-reperfusion, and organic failure. PANoptosis seems to be a double-edged sword in diverse conditions, as PANoptosis induces a negative impact on treatment and prognosis in disorders like COVID-19 and ALI/ARDS, while PANoptosis provides host protection from HSV1 or Francisella novicida infection, and kills cancer cells and suppresses tumor growth in colorectal cancer, adrenocortical carcinoma, and other cancers. Compounds and endogenous molecules focused on PANoptosis are promising therapeutic strategies, which can act on PANoptosomes-associated members to regulate PANoptosis. More researches on PANoptosis are needed to better understand the pathology of human conditions and develop better treatment.

Polyphenolic natural products as photosensitizers for antimicrobial photodynamic therapy: recent advances and future prospects.

Antimicrobial photodynamic therapy (aPDT) has become a potent contender in the fight against microbial infections, especially in the context of the rising antibiotic resistance crisis. Recently, there has been significant interest in polyphenolic natural products as potential photosensitizers (PSs) in aPDT, given their unique chemical structures and inherent antimicrobial properties. Polyphenolic natural products, abundant and readily obtainable from natural sources, are generally regarded as safe and highly compatible with the human body. This comprehensive review focuses on the latest developments and future implications of using natural polyphenols as PSs in aPDT. Paramount polyphenolic compounds, including curcumin, hypericin, quercetin, hypocrellin, celastrol, riboflavin, resveratrol, gallic acid, and aloe emodin, are elaborated upon with respect to their structural characteristics, absorption properties, and antimicrobial effects. Furthermore, the aPDT mechanism, specifically its targeted action on microbial cells and biofilms, is also discussed. Polyphenolic natural products demonstrate immense potential as PSs in aPDT, representing a promising alternate approach to counteract antibiotic-resistant bacteria and biofilm-related infections.

Recent advances in targeting the "undruggable" proteins: from drug discovery to clinical trials.

Undruggable proteins are a class of proteins that are often characterized by large, complex structures or functions that are difficult to interfere with using conventional drug design strategies. Targeting such undruggable targets has been considered also a great opportunity for treatment of human diseases and has attracted substantial efforts in the field of medicine. Therefore, in this review, we focus on the recent development of drug discovery targeting "undruggable" proteins and their application in clinic. To make this review well organized, we discuss the design strategies targeting the undruggable proteins, including covalent regulation, allosteric inhibition, protein-protein/DNA interaction inhibition, targeted proteins regulation, nucleic acid-based approach, immunotherapy and others.

Corrigendum: Discovery of spirooxindole-derived small-molecule compounds as novel HDAC/MDM2 dual inhibitors and investigation of their anticancer activity.

[This corrects the article DOI: 10.3389/fonc.2022.972372.].

Small-molecule dual inhibitors targeting heat shock protein 90 for cancer targeted therapy.

Heat shock protein 90, also known as Hsp90, is an extensively preserved molecular chaperone that performs a critical function in organizing various biological pathways and cellular operations. As a potential drug target, Hsp90 is closely linked to cancer. Hsp90 inhibitors are a class of drugs that have been extensively studied in preclinical models and have shown promise in a variety of diseases, especially cancer. However, Hsp90 inhibitors have encountered several challenges in clinical development, such as low efficacy, toxicity, or drug resistance, few Hsp90 small molecule inhibitors have been approved worldwide. Nonetheless, combining Hsp90 inhibitors with other tumor inhibitors, such as HDAC inhibitors, tubulin inhibitors, and Topo II inhibitors, has been shown to have synergistic antitumor effects. Consequently, the development of Hsp90 dual-target inhibitors is an effective strategy in cancer treatment, as it enhances potency while reducing drug resistance. This article provides an overview of Hsp90's domain structure and biological functions, as well as a discussion of the design, discovery, and structure-activity relationships of Hsp90 dual inhibitors, aiming to provide insights into clinical drug research from a medicinal chemistry perspective and discover novel Hsp90 dual inhibitors.

Silver/chiral pyrrolidinopyridine relay catalytic cycloisomerization/(2 + 3) cycloadditions of enynamides to asymmetrically synthesize bispirocyclopentenes as PDE1B inhibitors.

Significant progress has been made in asymmetric synthesis through the use of transition metal catalysts combined with Lewis bases. However, the use of a dual catalytic system involving 4-aminopyridine and transition metal has received little attention. Here we show a metal/Lewis base relay catalytic system featuring silver acetate and a modified chiral pyrrolidinopyridine (PPY). It was successfully applied in the cycloisomerization/(2 + 3) cycloaddition reaction of enynamides. Bispirocyclopentene pyrazolone products could be efficiently synthesized in a stereoselective and economical manner (up to >19:1 dr, 99.5:0.5 er). Transformations of the product could access stereodivergent diastereoisomers and densely functionalized polycyclic derivatives. Mechanistic studies illustrated the relay catalytic model and the origin of the uncommon chemoselectivity. In subsequent bioassays, the products containing a privileged drug-like scaffold exhibited isoform-selective phosphodiesterase 1 (PDE1) inhibitory activity in vitro. The optimal lead compound displayed a good therapeutic effect for ameliorating pulmonary fibrosis via inhibiting PDE1 in vivo.

Targeting bromodomain-containing proteins: research advances of drug discovery.

Bromodomain (BD) is an evolutionarily conserved protein module found in 46 different BD-containing proteins (BCPs). BD acts as a specific reader for acetylated lysine residues (KAc) and serves an essential role in transcriptional regulation, chromatin remodeling, DNA damage repair, and cell proliferation. On the other hand, BCPs have been shown to be involved in the pathogenesis of a variety of diseases, including cancers, inflammation, cardiovascular diseases, and viral infections. Over the past decade, researchers have brought new therapeutic strategies to relevant diseases by inhibiting the activity or downregulating the expression of BCPs to interfere with the transcription of pathogenic genes. An increasing number of potent inhibitors and degraders of BCPs have been developed, some of which are already in clinical trials. In this paper, we provide a comprehensive review of recent advances in the study of drugs that inhibit or down-regulate BCPs, focusing on the development history, molecular structure, biological activity, interaction with BCPs and therapeutic potentials of these drugs. In addition, we discuss current challenges, issues to be addressed and future research directions for the development of BCPs inhibitors. Lessons learned from the successful or unsuccessful development experiences of these inhibitors or degraders will facilitate the further development of efficient, selective and less toxic inhibitors of BCPs and eventually achieve drug application in the clinic.

Interleukin-18 and IL-18BP in inflammatory dermatological diseases.

Interleukin (IL)-18, an interferon-γ inducer, belongs to the IL-1 family of pleiotropic pro-inflammatory factors, and IL-18 binding protein (IL-18BP) is a native antagonist of IL-18 in vivo, regulating its activity. Moreover, IL-18 exerts an influential function in host innate and adaptive immunity, and IL-18BP has elevated levels of interferon-γ in diverse cells, suggesting that IL-18BP is a negative feedback inhibitor of IL-18-mediated immunity. Similar to IL-1ß, the IL-18 cytokine is produced as an indolent precursor that requires further processing into an active cytokine by caspase-1 and mediating downstream signaling pathways through MyD88. IL-18 has been implicated to play a role in psoriasis, atopic dermatitis, rosacea, and bullous pemphigoid in human inflammatory skin diseases. Currently, IL-18BP is less explored in treating inflammatory skin diseases, while IL-18BP is being tested in clinical trials for other diseases. Thereby, IL-18BP is a prospective therapeutic target.

The biological role and immunotherapy of gangliosides and GD3 synthase in cancers.

Gangliosides are a large subfamily of glycosphingolipids that broadly exist in the nervous system and interact with signaling molecules in the lipid rafts. GD3 and GD2 are two types of disialogangliosides (GDs) that include two sialic acid residues. The expression of GD3 and GD2 in various cancers is mostly upregulated and is involved in tumor proliferation, invasion, metastasis, and immune responses. GD3 synthase (GD3S, ST8SiaI), a subclass of sialyltransferases, regulates the biosynthesis of GD3 and GD2. GD3S is also upregulated in most tumors and plays an important role in the development and progression of tumors. Many clinical trials targeting GD2 are ongoing and various immunotherapy studies targeting gangliosides and GD3S are gradually attracting much interest and attention. This review summarizes the function, molecular mechanisms, and ongoing clinical applications of GD3, GD2, and GD3S in abundant types of tumors, which aims to provide novel targets for future cancer therapy.

Recent Advances on Small-Molecule Bromodomain-Containing Histone Acetyltransferase Inhibitors.

In recent years, substantial research has been conducted on molecular mechanisms and inhibitors targeting bromodomains (BRDs) and extra-terminal (BET) family proteins. On this basis, non-BET BRD is gradually becoming a research hot spot. BRDs are abundant in histone acetyltransferase (HAT)-associated activating transcription factors, and BRD-containing HATs have been linked to cancer, inflammation, and viral replication. Therefore, the development of BRD-containing HATs as chemical probes is useful for understanding the specific biological roles of BRDs in diseases and drug discovery. Several types of BRD-containing HATs, including CBP/P300, PCAF/GCN5, and TAF1, are discussed in this context in terms of their structures, functions, and small-molecule inhibitors. Additionally, progress in BRD inhibitors/chemical probes and proteolysis targeting chimeras in terms of drug design, biological activity, and disease application are summarized. These findings provide insights into the development of BRD inhibitors as potential drug candidates for various diseases.

Design, synthesis and anti-ovarian cancer activities of thieno[2,3-d]pyrimidine based chimeric BRD4 inhibitor/nitric oxide-donator.

Bromodomain protein 4 (BRD4) is an attractive epigenetic target that regulating diverse cellular processes, and the discovery of dual-target inhibitors including BRD4 is an effective approach in cancer treatment to increase potency and reduce drug resistance. Based on the multifunctional drug development strategy, a series of new derivatives of nitrooxy (ONO2) or furoxan (1,2,5-oxadiazole 2-oxide) with BRD4 inhibitor capable of inhibiting BRD4 and simultaneously releasing NO were designed and synthesized. When NO concentrations were measured with Griess reagent under physiological conditions, all compounds released NO at micromolar levels, reaching effective antitumor concentrations. Biological studies showed that the most potent BRD4/NO hybrid 11a exhibited good BRD4 inhibitory activity and selectivity. Further mechanistic studies revealed that 11a significantly decreased the expression of BRD4 and c-Myc, as well as induced cellular apoptosis and autophagic cell death both in vitro and in vivo. In summary, we optimized the chimeric BRD4-inhibitor/NO-donor based on our previous studies, and it should be a lead compound for targeted therapy of OC (ovarian cancer) in the future. This interesting strategy could expand the usage of BRDi in human malignancies and endogenous gastro-transmitters.

Discovery of tetrahydrofuranyl spirooxindole-based SMYD3 inhibitors against gastric cancer via inducing lethal autophagy.

SMYD3 is a histone methyltransferase involved in transcriptional regulation, and its overexpression in various forms of cancer justifies that blocking SMYD3 functions can serve as a novel therapeutic strategy in cancer treatment. Herein, a series of novel tetrahydrofuranyl spirooxindoles were designed and synthesized based on a structure-based drug design strategy. Subsequent biochemical analysis suggested that these novel SMYD3 inhibitors showed good anticancer activity against stomach adenocarcinoma both in vitro and in vivo. Among them, compound 7r exhibited potent inhibitory capacities against SMYD3 and BGC823 cells with IC50 values of 0.81 and 0.75 µM, respectively. Mechanistic investigations showed that 7r could suppress Akt methylation and activation by SMYD3 and trigger lethal autophagic flux inhibition via the Akt-mTOR pathway. Collectively, our results may bridge the rational discovery of privileged structures, epigenetic targeting of SMYD3, and regulation of autophagic cell death.